21.1 Diagnosis of polyneuropathy [link]
21.2 Nerve biopsy [link]
21.3 Treatment of polyneuropathy [link]
21.4 Charcot–Marie-Tooth disease [link]
21.5 Hereditary neuropathy with liability to pressure palsies [link]
21.6 Hereditary sensory and autonomic neuropathies [link]
21.7 Other inherited polyneuropathies [link]
21.8 Inherited metabolic disorders causing polyneuropathy [link]
21.8.1 Refsum disease [link]
21.8.2 Metachromatic leucodystrophy [link]
21.8.3 Krabbe disease [link]
21.8.4 Adrenoleucodystrophy [link]
21.8.5 Fabry’s disease [link]
21.8.6 Porphyric neuropathy [link]
21.8.7 Tangier disease [link]
21.8.8 Abetalipoproteinaemia [link]
21.8.9 Cerebrotendinous xanthomatosis [link]
21.9 Amyloid neuropathy [link]
21.10 Acute idiopathic polyneuropathies and the Guillain–Barré syndrome [link]
21.11 Chronic idiopathic polyneuropathies [link]
21.11.1 The spectrum of disorders [link]
21.11.2 Chronic inflammatory demyelinating polyneuropathy [link]
21.11.3 Multifocal motor neuropathy with conduction block [link]
21.11.4 Pure motor demyelinating neuropathy [link]
21.11.5 Chronic ataxic polyneuropathy [link]
21.11.6 Multifocal motor and sensory neuropathy [link]
21.11.7 Chronic autonomic neuropathy [link]
21.11.8 Chronic idiopathic axonal polyneuropathy [link]
21.12 Neuropathies associated with lymphoproliferative disorders [link]
21.13 Carcinomatous neuropathy [link]
21.14 Neuropathy due to infections [link]
21.15 Vasculopathic neuropathy [link]
21.16 Sensory perineuritis and migrant sensory neuritis [link]
21.17 Diabetic neuropathy [link]
21.17.1 Range of disorders [link]
21.17.2 Diabetic polyneuropathy [link]
21.17.3 Diabetic proximal neuropathy [link]
21.17.4 Diabetic truncal neuropathy [link]
21.17.5 Diabetic autonomic neuropathy [link]
21.17.6 Diabetic mononeuropathy [link]
21.17.7 Chronic inflammatory demyelinating polyneuropathy in diabetics [link]
21.18 Neuropathy due to systemic medical disorders [link]
21.18.1 Chronic renal failure [link]
21.18.2 Hypothyroidism [link]
21.18.3 Acromegaly [link]
21.18.4 Primary biliary cirrhosis [link]
21.18.5 Systemic lupus erythematosus [link]
21.18.6 Sarcoidosis [link]
21.18.7 Eosinophilia–myalgia syndrome [link]
21.18.8 Hypereosinophilic syndrome [link]
21.18.9 Critical illness polyneuropathy [link]
21.18.10 Sjogren’s syndrome [link]
21.18.11 Gastrointestinal disease [link]
21.19 Drug-induced polyneuropathy [link]
21.19.1 Alcohol [link]
21.19.2 Amiodarone [link]
21.19.3 Chloroquine [link]
21.19.4 Cisplatin [link]
21.19.5 Colchicine [link]
21.19.6 Dapsone [link]
21.19.7 Didanosine and antiretroviral drugs [link]
21.19.8 Disulfiram [link]
21.19.9 Ethambutol [link]
21.19.10 Gold [link]
21.19.11 Isoniazid [link]
21.19.12 Leflunomide [link]
21.19.13 Lithium [link]
21.19.14 Metronidazole [link]
21.19.15 Nitrofurantoin [link]
21.19.16 Phenytoin [link]
21.19.17 Pyridoxine [link]
21.19.18 Statins [link]
21.19.19 Suramin [link]
21.19.20 Tacrolimus [link]
21.19.21 Taxol [link]
21.19.22 Thalidomide [link]
21.19.23 Tumour necrosis factor inhibitors [link]
21.19.24 Vinca alkaloids [link]
21.20 Metal-poisoning polyneuropathy [link]
21.21 Polyneuropathy due to industrial and agricultural chemicals [link]
21.21.1 Acrylamide [link]
21.21.2 Carbon disulphide [link]
21.21.3 Dimethylaminopropionitrile [link]
21.21.4 Diethylene glycol [link]
21.21.5 Ethylene oxide [link]
21.21.6 Herbicides [link]
21.21.7 Hexacarbons [link]
21.21.8 Methylbromide [link]
21.21.9 Pesticides [link]
21.21.10 Trichloroethylene [link]
21.21.11 Vacor [link]
21.22 Vitamin deficiency polyneuropathy [link]
21.1 Diagnosis of polyneuropathy
Peripheral neuropathy has a multitude of causes, many of which can be diagnosed by careful clinical and electrophysiological evaluation. A fundamental distinction should be made between:
♦ Polyneuropathy, a generalized neuropathy affecting all peripheral nerve fibres.
♦ Focal neuropathy, which affects individual peripheral nerves either singly or multiply. Recognized causes of (multi-)focal peripheral neuropathy are listed in Table 22.1. In focal neuropathy the muscle wasting and weakness, reflex loss, and sensory disturbance are restricted to the territories of the affected peripheral nerve(s) or root(s). Occasionally widespread vasculitic involvement of the peripheral nervous system may produce the clinical picture of symmetrical polyneuropathy, rather than the multiple mononeuropathies more usually associated with vasculitis.
Clinical features. Typically polyneuropathy will cause the combination of distal limb muscle weakness, loss of tendon reflexes, and reduced distal limb sensation. There is variable involvement of the autonomic innervation, damage to which causes a dry, vasodilated foot or hand. Loss of tendon reflexes is a cardinal sign of polyneuropathy, often restricted to the ankle jerks in axonal degeneration, but involving more proximal reflexes in acquired demyelinating neuropathies which may involve more proximal segments or the nerve roots. Clinical features suggestive of demyelinating or conduction block polyneuropathy include:
♦ a relative lack of muscle wasting in relation to the degree of weakness because no denervation has occurred;
♦ weakness of proximal muscles as well as distal, because of nerve root involvement; and
Nerve conduction velocity measurements and electromyography (Section 3.5) should be used to distinguish between primarily demyelinating, axonal degeneration, or conduction block polyneuropathies (Fig. 21.1). Nerve conduction studies in demyelinating polyneuropathy show prolonged distal motor latencies, slowed motor conduction velocities, and prolonged F-wave latencies. Evidence of conduction block is particularly likely in acquired forms of demyelinating polyneuropathy. Demyelinating polyneuropathies generally hold a better prospect for recovery than axonal degeneration polyneuropathies although they tend to produce more severe clinical syndromes. Causes of demyelinating polyneuropathy are shown in Table 21.1.
Table 21.1 Causes of demyelinating polyneuropathy
Hereditary motor and sensory neuropathy Type 1 (Section 21.4.4)
Hereditary motor and sensory neuropathy Type 3 (Dejerine–Sottas Disease) (Section 21.4.6)
Hereditary neuropathy with liability to pressure palsies (Section 21.5)
Adrenoleucodystrophy (Section 21.8.4)
Krabbe’s disease (Section 21.8.3)
MNGIE (Section 21.7.6)
Metachromatic leucodystrophy Section (21.8.2)
Refsum disease (phytanic acid accumulation) (Section 21.8.1)
Guillain–Barré syndrome (Section 21.10.1)
Chronic inflammatory demyelinating neuropathy (Section 21.11.2)
Multifocal motor neuropathy with conduction block (Section 21.11.3)
Pure motor demyelinating neuropathy (Section 21.11.4)
Diphtheria (Section 21.14.4.)
Amiodarone neuropathy (Section 21.19.2)
Hexacarbon neuropathy (Section 21.21.7)
Inherited polyneuropathy usually holds a poor prospect for recovery and other family members may require genetic counselling. Inherited polyneuropathy must be considered if there is a family history of neuropathy or foot deformity or parental consanguinity. Compared to acquired polyneuropathy, it tends to evolve slowly, and even marked degrees of weakness may not excite complaint by the patient. Positive sensory symptoms, such as paraesthesiae, spontaneous pains, or thermal sensations, suggest an acquired neuropathy, although they do occur in the polyneuropathy of the inherited metabolic disorders metachromatic leucodystrophy and Fabry disease. Often the suspicion of an inherited basis for a patient’s polyneuropathy can only be confirmed by clinical or electrophysiological examination of relatives or molecular genetic studies.
Sensory neuropathies. Neuropathies purely or predominantly involving sensory fibres are shown in Table 21.2. Some purely sensory neuropathies spare large myelinated fibres, only affecting unmyelinated and small myelinated fibres. In such cases tendon reflexes are preserved and sensory nerve conduction is normal. However, there is usually associated dysfunction of unmyelinated autonomic fibres with postural hypotension and dry, red feet.
Table 21.2 Causes of sensory peripheral neuropathy
Hereditary sensory and autonomic neuropathies (Section 21.6)
Fabry disease (Section 21.8.5)
Tangier disease (Section 21.8.7)
Familial amyloid (Section 21.9.1)
Acute sensory polyneuritis (Section 21.18.10)
Chronic idiopathic ataxic (sensory) neuropathy (Section 21.11.5)
Sjögren’s syndrome (Section 21.18.10)
Primary amyloidosis (Section 21.9.2)
Paraneoplastic sensory neuropathy (Section 21.13.1)
Acquired immune deficiency syndrome (late) (Section 21.14.2)
Leprosy (Section 21.14.1)
Lyme disease (Borrelia infection) (Section 21.14.3)
Sensory perineuritis (Section 21.16.1)
Migrant sensory neuritis of Wartenberg (Section 21.16.2)
Diabetes mellitus (Section 21.17.2)
Vitamin B12 deficiency (Section 21.22.4)
Vitamin E deficiency (Section 21.22.5)
Cisplatin (Section 21.19.4)
Didanosine (Section 21.19.7)
Metronidazole (Section 21.19.14)
Motor neuropathies. Purely or predominantly motor neuropathies are listed in Table 21.3.
Table 21.3 Causes of motor peripheral neuropathy
Charcot-Marie-Tooth disease (some patients) (Section 21.4)
Porphyric neuropathy (Section 21.8.6)
Guillain–Barré syndrome (Section 21.10.1)
Acute motor axonal neuropathy (Section 21.10.2)
Multifocal motor neuropathy with conduction block (Section 21.11.3)
Pure motor demyelinating neuropathy (Section 21.11.4)
Diphtheria (Section 21.14.4)
Dapsone (Section 21.19.6)
Lead poisoning (Section 21.20.2)
Organophosphate poisoning (Section 21.21.9)
Autonomic neuropathies. Some disorders produce a purely or predominantly autonomic neuropathy (Table 21.4). In many the small unmyelinated sensory fibres are also affected, causing impaired pinprick and temperature sensations. Patients present with varying combinations of vasodilation and impaired sweating, sometimes with cardiovascular, gastrointestinal, micturition, or pupillomotor involvement (Freeman 2005).
Table 21.4 Clinically important autonomic involvement in peripheral neuropathy
Primary amyloidosis (Section 21.9.2)
Familial amyloidosis (Section 21.9.1)
Hereditary sensory and autonomic neuropathy
Autosomal dominant sensory neuropathy (Section 21.6.1)
Autosomal recessive sensory neuropathy (Section 21.6.2)
Fabry disease (Section 21.8.5)
Multiple symmetric lipomatosis (Section 21.7.4)
Porphyria (Section 21.8.6)
Familial dysautonomia (Riley-Day syndrome) (Section 21.6.3)
Anhidrotic sensory neuropathy (Section 21.6.4)
Small myelinated fibre deficiency (Section 21.6.5)
Guillain–Barré syndrome (Section 21.10.1)
Idiopathic autonomic neuropathy
Acute sensory neuropathy (Section 21.10.3)
Adies pupil and the Ross syndrome (Section 13.3.4)
Lambert–Eaton myasthenic syndrome (Section 24.10.2)
Alcohol (Section 21.19.1)
Amiodarone (Section 21.19.2)
Cisplatin (Section 21.19.4)
Heavy metals (Section 21.20)
Seafood toxicity (Ciguatoxin) (Section 5.12.1)
Taxol (Section 21.19.21)
Vacor (Section 21.21.11)
Vinca alkaloids (Section 21.19.24)
Trypanosoma cruzi (Chagas’ disease)
Leprosy (Section 21.14.1)
HIV (Section 21.14.2)
Diphtheria (Section 21.14.4)
(from Donaghy M (2007). Autonomic dysfunction in peripheral nerve disease. Mathias C and Bannister R (eds). Autonomic Failure 5th Edition, OUP)
Ageing. After the age of 65, an increasing proportion of asymptomatic people without neuropathic risk factors have unobtainable ankle jerks or loss of vibration sense from the feet, and a few have more extensive abnormalities, such as mild distal muscle weakness (Vrancken et al. 2006). Such features cannot be taken as sole evidence for peripheral nerve disease in the elderly and merely reflect the natural age-related loss of peripheral nerve axons (Jacobs and Love 1985).
21.2 Nerve biopsy
Biopsy of peripheral nerves makes a major diagnostic impact only in a small selected group of patients with peripheral neuropathy. It is of particular use in those patients suspected of suffering from the treatable conditions of vasculitic, sarcoid, or leprous neuropathy, or sensory perineuritis. It may establish the diagnosis in rare conditions such as giant axonal neuropathy or neuroaxonal dystrophy. Traditionally nerve biopsy has demonstrated amyloidosis, but rectal biopsy is similarly sensitive and less invasive. Hereditary neuropathy with liability to pressure palsies is diagnosable by nerve biopsy but this is being replaced by molecular genetic tests. Nerve biopsy usually has little role in establishing a diagnosis of acute or chronic inflammatory demyelinating polyneuropathy. Occasionally in these conditions, examination of teased nerve fibres may show segmental demyelination in suspected cases where motor nerve conduction velocities have been insufficiently slow to be diagnostic.
The nerve most commonly chosen for biopsy is the sural nerve at the ankle, less commonly the radial nerve at the wrist or the superficial peroneal nerve in the calf. The biopsy is carried out under local anaesthesia. Some favour fascicular, rather than full-thickness nerve biopsy, on the grounds that it leaves less residual sensory deficit. There is no difference in the degree of subsequent sensory loss or dysaesthetic pain comparing fascicular and full-thickness nerve biopsies. Full-thickness biopsy is advisable if vasculitis is suspected so as to permit inspection of the maximum number of epineurial blood vessels. The most common complications of nerve biopsy are failure of wound healing, or infection, particularly in patients receiving steroid therapy. Significant pain or paraesthesiae attributable to the biopsy occur in less than 10 per cent of patients after 1 year.
The specimen should be processed immediately by a laboratory experienced in peripheral nerve pathology. It should be divided to provide material for paraffin embedding, and for glutaraldehyde and osmium tetroxide fixation for single nerve fibre teasing, and for electron and light microscopy on 1-mm plastic-embedded sections; additional material may be frozen for immunofluorescent studies (Fig. 21.2). Morphometric analysis may be required to reveal subtle differences in the density of myelinated or unmyelinated fibres, or alterations in the fibre-size distribution; this process is time-consuming and technically demanding. Control morphometric values have been established for a wide age range (Jacobs and Love 1985) and the characteristic pathological changes in a wide variety of diseases (Richardson and De Girolami 1995) will be referred to in the following sections.
Quantitative assessment of immunohistochemically stained epidermal nerve fibres in small punch biopsies of skin is a valuable development in assessing small unmyelinated fibre involvement in neuropathies. This technique seems more sensitive than morphometry of sural nerve biopsies, is less technically complex, and detects unmyelinated fibre involvement in a wide range of polyneuropathies involving sensory fibres (Herrmann et al. 1999). Skin biopsy provides a repeatable tool for assessing progression of neuropathy or the effects of treatments. It can demonstrate loss of nerve fibres in those oft encountered patients with painful burning feet, in whom conventional clinical examination, nerve conduction studies, and sural nerve biopsy fail to reveal abnormalities (Periquet et al. 1999).
21.3 Treatment of polyneuropathy
21.3.1 General principles
Accurate diagnosis of the cause is essential to ensure that correct therapy is provided for certain conditions, for instance immunosuppression for vasculitic neuropathy and chronic inflammatory demyelinating neuropathy; intravenous immunoglobulin for multifocal motor neuropathy with conduction block; plasma exchange or intravenous immunoglobulin for the Guillain–Barré syndrome; cessation of toxic exposure to chemicals, drugs, or alcohol; vitamin replacement; or diet modification in Refsum disease. Hence, the same principles underlying treatment will be considered before detailed description of the different varieties of peripheral nerve disease.
Physiotherapy is important to prevent muscle contractures and keep joints mobile, so that when regeneration of nerve fibres occurs, the limb may be in the best possible condition to profit by the return of nervous function. In the past, firm splinting was commonly employed in order to keep a paralysed muscle in a relaxed position and to preclude movement which was thought to promote contracture of antagonists. However splinting generally has little to commend it, as immobilized muscles tend to atrophy and become fibrotic more quickly.
21.3.2 Assessing recovery
The advent of effective therapies for disabling neuropathies brings the need for reliable assessment of recovery. This is useful both for formal clinical trials of treatment and for assessing effectiveness of a trial of treatment in an individual patient. Estimates of functional ability, such as walking, are more reliable and relevant than quantification of physical signs, such as strength of individual muscles. When assessing an individual’s response to treatment, a set of measurements relevant to that patient’s disability should be drawn up and measured preand post-treatment, paying particular attention to those which signify improvement of use in everyday life.
Various quantitative measures of the neurological examination can be undertaken. Muscle strength can be graded using the MRC scale:
Grade 0 = no contraction
Grade 1 = flicker of contraction
Grade 2 = active movement with gravity eliminated
Grade 3 = active movement against gravity
Grade 4 = active movement against gravity and resistance, and
Grade 5 = normal power.
However this MRC grading is relatively unreliable and unreproducible for the majority of neuropathies encountered in a civilian and non-surgical practice in which most weakness is either Grade 3 or 4. Nerve conduction studies can be quantified, particularly the velocity of motor conduction, the degree of block of motor conduction, or the amplitude of sensory nerve action potentials. However, such neurophysiological measures often show surprisingly little improvement even with clear-cut clinical improvement in conditions such as demyelinating neuropathy. Quantitative sensory testing devices have been developed, particularly for vibration and thermal sensation. Various clinical and electrophysiological parameters are integrated in the Total Neuropathy Score, shown in Table 21.5 (Cornblath et al. 1999).
To see Table 21.5, see Cornblath DR, Chaudhry V, Carter K, et al (1999) Neurology 53: 1660-4.
Symptoms limited to fingers or toes
Symptoms extend to ankle or wrist
Symptoms extend to knee or elbow
Symptoms above knees or elbows, or functionally disabling
Autonomic symptoms, n
4 or 5
Reduced in fingers/toes
Reduced up to wrist/ankle
Reduced up to elbow/knee
Reduced to above elbow/knee
Reduced in fingers/toes
Reduced up to wrist/ankle
Reduced up to elbow/knee
Reduced to above elbove/knee
Ankle reflex reduced
Ankle reflex absent
Ankle reflex absent, others reduced
All reflexes absent
Vibration sensation (QST vibration)
Normal to 125% ULN
Normal/reduced to <5% LLN
76–95% of LLN
51–75% of LLN
26–50% of LLN
0–25% of LLN
Normal/reduced to <5% LLN
76–95% of LLN
51–75% of LLN
26–50% of LLN
0–25% of LLN
QST = quantitative sensory test; ULN = limit of normal; LLN = lower limit of normal. Amplitudes refer to nerve conduction measurements.
In many circumstances a restricted set of measures can provide reliable evidence of improvement. For instance regaining the ability to heel-toe walk, stand on tiptoe, or perform Romberg’s test provide clear-cut and reproducible evidence. Measurement of outstretched arm times, peg-sorting tasks, stair-climbing speed, or walking speed is also reliable unless you suspect that psychological factors may influence the patient’s performance. It is useful for patients to monitor treatment against a variety of everyday tasks (Fig. 21.3).
Overall limb function can be quantified rapidly and reliably in neuropathies such as Guillain–Barré syndrome using a simple overall disability sum score, assessable by telephone if need be (Table 21.6) (Merkies et al. 2002). This is particularly valuable in monitoring recovery, response to treatment, or worsening in severity.
Table 21.6 The overall disability sum score (ODSS) (from Merkies et al. 2002)
Arm disability scale — function checklist
Affected but not prevented
Dressing upper part of body (excluding buttons/zips)
Washing and brushing hair
Turning a key in a lock
Using knife and fork (/spoon—applicable if the patient never uses knife and fork)
Doing/undoing buttons and zips
0 = Normal
1 = Minor symptoms or signs in one or both arms but not affecting any of the functions listed
2 = Moderate symptoms or signs in one or both arms affecting not preventing any of the functions listed
3 = Severe symptoms or signs in one or both arms preventing at least one but not all functions listed
4 =Severe symptoms or signs in both arms preventing all functions listed but some purposeful movements still possible
5 = Severe symptoms and signs in both arms preventing all purposeful movements
Leg disability scale—function checklist
Do you have any problem with your walking?
Do you use a walking aid?
How do you usually get around for about 10 metres?
With one stick or crutch or holding to someone’s arm
With two sticks or crutches or one stick or crutch and holding to someone’s arm
With a wheelchair
If you use a wheelchair, can you stand and walk a few steps with helps?
If you are restricted to bed most of the time, are you able to make some purposeful movements?
0 = Walking is not affected
1 = Walking is affected but does not look abnormal
2 = Walks independently but gait looks abnormal
3 = Usually uses unilateral support to walk 10 metres (25 feet) (stick, single crutch, one arm)
4 = Usually uses bilateral support to walk 10 metres (25 feet) (sticks, crutches, two arms)
5 = Usually uses wheelchair to travel 10 metres (25 feet)
6 = Restricted to wheelchair, unable to stand and walk few steps with help but able to make some purposeful leg movements
7 = Restricted to wheelchair or bed most of the day, preventing all purposeful movements of the legs (e.g. unable to reposition legs in bed)
Overall disability sum score = arm disability scale (range 0–5) + leg disability scale (range 0–7); overall range: 0 (no signs of disability) to 12 (maximum disability).
For the arm disability scale: allocate one arm grade only by completing the function checklist. Indicate whether each function is ‘affected’, ‘affected but not prevented’, or ‘prevented’.
For the leg disability scale: allocate one leg grade only by completing the functional questions.
Immunomodulatory treatments are used successfully in a range of acquired neurological diseases including: acute idiopathic polyneuritis, chronic idiopathic polyneuropathies, neuropathies associated with lymphoproliferative disorders, vasculitic neuropathy, central nervous system vasculitic and collagen vascular disorders, multiple sclerosis, inflammatory myopathy, myasthenias, and cranial arteritis. Whilst detailed discussion of these immunomodulatory treatments and their side effects lies outside the scope of this book, knowledge of important general principles is necessary for managing these diseases.
Steroids are given as oral prednisolone for chronic maintenance treatment, intravenous methylprednisolone for acute disorders, or dexamethasone for raised intracranial pressure. Consideration should be given to alternate day administration of prednisolone in neuromuscular disorders requiring long-term treatment. Increased susceptibility to infections, including opportunistic organisms, is a significant risk, particularly with long-term therapy. Steroid-induced diabetes mellitus, or exacerbation of previously controlled diabetes, may occur. Steroid myopathy may occur with long-term therapy, especially with fluorinated steroids such as dexamethasone. Cataract can be caused or worsened. Steroids can produce, or exacerbate, psychiatric conditions such as paranoia or depression. To offset the osteoporosis induced by chronic steroid therapy, prophylactic therapy with a biphosphorate or a calcitriol should be given from the outset, and hormone replacement therapy considered in post-menopausal women.
Azathioprine is often used as a steroid-sparing treatment when long-term immunosuppression is required. It too increases susceptibility to infection, mediated at least in part by leucopoenia related to dose-related bone marrow suppression. Hypersensitivity reactions, often involving abdominal pain and abnormal liver function tests, are not uncommon and necessitate permanent withdrawal. Regular full blood count and liver function testing are required; weekly for the first 4–8 weeks of therapy, and 3-monthly thereafter. Although the question of azathioprine causing lymphoproliferative disorders has been raised, especially in the setting of renal transplantation, there is no evidence of this complication when it is used in neurological disorders (Amato et al. 1993). Some female patients may wish to continue azathioprine during pregnancy so as to avoid deterioration in their neurological disorder. If so they should be advised that whilst there are occasional reports of chromosomal abnormalities and neonatal haematological disorders, the teratogenic risk is generally considered small to minimal and that the vast majority of such pregnancies end happily.
Cyclophosphamide is used in vasculitis and may be given either orally or pulsed intravenously. Susceptibility to infection is the chief early side effect and the full blood count should be monitored closely for dose-related bone marrow suppression. Simultaneous administration of Mesna helps avoid haemorrhagic cystitis, and it should be noted that cyclophosphamide greatly increases the risk of future bladder cancer.
Plasma exchange is generally carried out by centrifugal or filtration methods, generally for 5 days exchanging 50 ml plasma per kg body weight at each exchange. The rationale is removal of pathogenic antibodies in the plasma fraction, and replacement is usually with human albumin or gelatin solutions. In experienced hands, the technique is largely free of complications. Low-dose heparinization is used to prevent thrombosis and embolization from the indwelling venous catheter.
Intravenous immunoglobulin, IvIg, therapy is generally given in total doses of 2 g/kg body weight over between 2 and 5 days. Repeated administration every 6–10 weeks is required in the treatment of chronic neuropathies. Domiciliary administration may use different régimens, provides effective maintenance administration without hospitalization, and avoids loss of time from work or fluctuations in disease severity (Sewell et al. 1997). The precise mechanisms of IvIg’s action in neurological disease remain unknown; immunomodulatory effects, anti-idiotypic antibodies, cytokine alterations, and direct effects on conduction block or remyelination are all possibilities (Stangel et al. 1999). Significant side effects are unusual, although up to 30 per cent may experience mild, self-limited reactions of headache, myalgia, fever, rash, or vasomotor reactions, which are generally controllable by varying the infusion rate, or by using antihistamines (Stangel et al. 2003). Such side effects seem commoner in IvIg-naïve patients. IgA-deficient patients may develop anaphylactic reactions. Rarely self-limited aseptic meningitis similar to that with OKT3 monoclonal antibodies, viscosity induced thromboembolic events, acute oliguric renal failure, or haemolytic anaemia have occurred. Naturally patients will be concerned about possible transmission of infections by IvIg. The solvent detergent step currently employed in purification inactivates HIV and hepatitis viruses. There is a theoretical risk of transmitting prion disease.
21.4 Charcot–Marie–Tooth disease
21.4.1 Range of disorders
Charcot–Marie–Tooth disease is the commonest cause of the peroneal muscular atrophy syndrome of distal leg muscle wasting and weakness, usually accompanied by pes cavus foot deformity (Figs 21.4 and 21.5). It is also known as peroneal muscular atrophy; hereditary motor and sensory neuropathy; hereditary hypertrophic neuropathy; Roussy–Lévy syndrome; Dejerine–Sottas disease. Charcot–Marie–Tooth death comprises a range of demyelinating and axonal loss neuropathies with various patterns of inheritance associated with numerous gene mutations.
Patients generally present in childhood or adolescence, but symptoms may become evident at any age from birth to senescence. Asymptomatic, yet affected, elderly relatives may be identified. The presenting symptoms are usually difficulty in walking or foot deformity. Positive sensory symptoms such as paraesthesiae make the diagnosis of Charcot–Marie–Tooth disease unlikely and should suggest an acquired neuropathy. Subacute deterioration in Charcot–Marie–Tooth disease, resembling superimposed chronic inflammatory demyelinating neuropathy, has occurred occasionally in association with MPZ and Cx32 mutations (Donaghy et al. 2000; Watanabe et al. 2002). Such patients may be steroid responsive and probably explain earlier reports of steroidresponsive inherited neuropathy. Occasionally Charcot–Marie–Tooth disease is associated with other neurological features such as spastic paraparesis, optic atrophy, pigmentary retinal degeneration, deafness, the dysmorphic Noonan syndrome, or the mental retardation associated with agenesis of the corpus callosum, also known as Andermann syndrome (Dupre et al. 2003).
Charcot–Marie–Tooth disease can be classified into Types 1–4 on clinical, electrophysiological, and genetic grounds. Many of the underlying molecular genetic abnormalities have been identified. The current classification consists of the autosomal dominant or X-linked Type 1 demyelinating and Type 2 axonal, with further subclassification based on inheritance pattern and gene identification. Currently, this classification mainly finds clinical utility in the electrophysiological differentiation of Types 1, demyelinating and 2, axonal forms of the disorder using a cut-off motor conduction velocity in the median nerve ≤ 38 m/s. However there are increasingly extensive subclassifications and overlap of these two types, often correlating with newly described mutations or linkage loci. Type 3 refers to congenital hypomyelination neuropathy. Autosomal recessive forms are extremely rare with demyelinating forms being classified as Charcot–Marie–Tooth disease Type 4, and axonal forms simply described as autosomal recessive. Dominant intermediate forms of Charcot–Marie–Tooth disease are unusual and defined by a range of motor nerve conduction velocities within the family that overlap those of Types 1 and 2.
Four gene abnormalities account for about two-thirds of all patients with Charcot–Marie–Tooth disease (Boerkoel et al. 2002). Over half of them have a reduplication of the gene for peripheral myelin protein 22, PMP22, the CMT1A duplication which produces the Type 1 demyelinating form. Five to ten per cent carry X-linked Connexin-32, Cx32 mutations which variably produce Type 2 axonal or milder degrees of Type 1 demyelinating neuropathy (Hattori et al. 2003). Another 5 per cent are due to various mutations of the myelin protein P0 gene, MPZ, or the PMP22 gene producing a mixture of Type 1 demyelinating and Type 2 axonal phenotypes.
Charcot–Marie–Tooth disease should be distinguished from the other common cause of the peroneal muscular atrophy syndrome: spinal muscular atrophy (Section 23.33). Such patients are less likely to have upper limb weakness, their tendon reflexes are relatively preserved, the sensory examination is normal, and the sensory nerve action potentials are normal (Harding and Thomas 1980a). Symptoms of distal spinal muscular atrophy usually start in childhood, although onset as late as 60 years has been recorded. Both autosomal dominant and recessive forms occur, the former tending to present earlier in life. The condition rarely produces severe disability.
There is no drug therapy to stabilize or improve Charcot–Marie–Tooth disease, save in those occasional patients with superimposed chronic inflammatory demyelinating neuropathy who respond to immunomodulatory therapy. Footdrop may be overcome by ankle orthoses and physiotherapy may reduce tendon contractures, foot deformity, or scoliosis. There is a limited role for orthopaedic surgical correction of severe foot and ankle deformity. Genetic counselling should be undertaken. Prenatal diagnosis is possible in principle, and may have a role in offering prenatal diagnosis in potentially lethal or severely disabling infantile or childhood forms. However, in the vast majority of Charcot–Marie–Tooth disease patients, the disorder is only slowly progressive or stable, without ever causing overwhelming disability, and generally without significantly affecting life expectancy. Maternal Charcot–Marie–Tooth disease merits special obstetric attention since it carried increased risks of foetal presentation abnormalities, postpartum bleeding, and emergency caesarean section (Hoff et al. 2005).
21.4.3 Molecular genetic abnormalities
In total 37 identified genes or loci have been identified so far as responsible for the different forms of Charcot–Marie–Tooth disease (Table 21.7). Of these, 22 reflect demyelinating forms, 13 axonal, and 2 intermediate, with a range of autosomal dominant and recessive and sex-linked recessive transmission. The genetic causes of the severe childhood and congenital hypomyelinating forms are emerging. Confusingly, different mutations affecting the same gene can produce demyelinating, intermediate, or axonal forms of Charcot–Marie–Tooth disease—examples being Type 1B due to myelin protein P0 mutations, and GDAP1 mutations (Kuhlenbaumer et al. 2002; Reilly and Hanna 2002; Berciano and Combarros 2003). Some genetic abnormalities are used routinely for diagnostic testing: the 17p11.2 duplication, and mutations of the MPZ and Cx32 genes. Distinctive clinical and electrophysiological syndromes generally characterize the commoner mutations of these particular genes.
Table 21.7 Classification of Charcot–Marie–Tooth disease
1. DEMYELINATING (MCV <38 m/s) Autosomal dominant (CMT1 or HMSN1)
Duplication PMP22 (rarely point mutation)
Childhoodtypically in 2nd decade
Point mutation Po
Often more severe than CMT1A
Congenital to 2nd decade
Childhood to 2nd decade
Point mutation EGR2
Often more severe than CMT1A
Congenital or 1st decade
Point mutation Cx32
Severe dominant or recessive phenotypes: Dejerine-Sottas disease
(DSD or HMSN-III)
DSD-A (AD or AR)
Point mutation PMP22
DSD-B (AD or AR)
Point mutation Po
DSD-C (AD or AR)
Point mutation EGR2
Congenital hypomyelinating neuropathy (CHN)
Point mutation PMP22
Point mutation Po
CHN-C (AD or AR)
Point mutation EGR2
Severe neuropathy, hypomyelination
Hereditary neuropathy with liability to pressure palsies (HNPP)
Autosomal recessive (CMT4)
Severe neuropathy. Vocal cord and diaphragm paralysis (some).
Focally folded myelin. Severe. Facial and bulbar involvement.
Early childhood (~34 months)
Focally folded myelin, Tunisian families. Glaucoma.
1st or 2nd decade
Resembles CMT1-, +scoliosis
1st or 2nd decade
Progressive deafness, Bulgarian Gypsies (type Lom). Tongue atrophy.
Congenital cataracts, facial dysmorphism and neuropathy. Gypsies
1st or 2nd decade (neuropathy)
Severe neuropathy. More sensory. Folded myelin.
Early childhood (12–24 months)
Severe form, Bulgarian Gypsies (type Russe)
1st or 2nd decade
2. AXONAL (MCV ≥38 m/s) Autosomal dominant (CMT2 or HMSN-II)
Adult (mean ~20 years)
Classical CMT2. More progressive. Optic atrophy.
2nd decade; some asymptomatic
Mainly sensory neuropathy, acral ulcerations (like HSAN)
2nd or 3rd decade
Vocal cord and respiratory involvement
Predominant upper limbs and motor
2nd or 3rd decade
Typical CMT (can resemble DI-CMT)
Childhood to 3rd decade
Classical CMT + trophic changes
2nd or 3rd decade
Point mutation Po
Hearing loss, pupillary dysfunction
4th or 5th decade
CMT2. Proximal involvement.
Autosomal recessive (AR-CMT2)
Proximal. Rapid progression. Muscular dystrophy. Lipodystrophy. Cardiomyopathy.
Early onset. Vocal cord, diaphragm paralysis.
Deafness. Mental retardation.
3. DOMINANT-INTERMEDIATE (DI-CMT)
Typical CMT, axonal and myelin pathology
Typical CMT, axonal and myelin pathology
AD – autosomal dominant; AR – autosomal recessive; CCFDN – congenital cataracts, facial dysmorphism and neuropathy; CHN – congenital hypomyelinating neuropathy; CMT – Charcot-Marie-Tooth disease; Cx32 – connexion 32; CTDP1 – CTD phosphatase 1; DNM21 – dynamin 2; DSD – Dejerine-Sottas disease; EGR – early growth response 2; GARS – glycyl-tRNA synthetase; GDAP1 – ganglioside-induced differentiation associated protein 1; HNPP – hereditary neuropathy with liability to pressure palsy; HMSN – hereditary motor and sensory neuropathy; HSAN – Hereditary Sensory and Autonomic Neuropathy; HSP – small heat shock protein 22 or 27; KIF 1Bβ microtubule motor KIF 1Bβ; LITAF/SIMPLE – lipopolysaccaride-induced tumour necrosis factor-α factor/for small integral membrane protein of the lysosome/late endosome; LMNA – lamin A/C; MCV – median nerve motor conduction velocity; MTMR – myotubularin-related protein; NF-L – neurofilament light gene; NDRG1 – N-myc downstream regulated gene 1; PMP22 – peripheral myelin protein 22; Po – myelin protein zero; RAB7 – GTP-ase late endosomal protein gene; SBF2 – SET binding factor 2; YARS – tyrosyl-tRNA synthetase.
PMP-22. Seventy per cent of Charcot–Marie–Tooth disease Type 1, known as Type 1A, is associated with a duplication of the gene for peripheral myelin protein 22, PMP22, on chromosome 17. This occurs due to unequal crossover during meiosis, particularly on the father’s side. This same myelin protein gene is affected by a mutation in the hypomyelinating Trembler mouse mutant (Timmerman et al. 1992) and is deleted in hereditary liability to pressure palsies (Section 21.5), a condition of hypomyelination (Lenssen et al. 1998). Thus increased copies of the PMP22 gene are associated with decreased growth of the myelin spiral. Unsurprisingly the Charcot–Marie–Tooth disease Type 1A phenotype occurs in trisomy 17, Down’s syndrome (Chance et al. 1992).
Myelin protein P0. This gene is an adhesive protein responsible for compaction of the myelin sheath. Abnormally wide spacing of the myelin lamellae results from some of its mutations (Gabreels-Festen et al. 1996). More than 80 point mutations of the MPZ cause a bewildering array of Charcot–Marie–Tooth disease Type 1B, demyelinating, Type 2, axonal, intermediate forms, congenital hypomyelinating and childhood onset forms, and a late onset form of progressive demyelinating neuropathy with features resembling chronic inflammatory demyelinating polyneuropathy (Donaghy et al. 2000; Shy et al. 2004).
Connexin 32. X-linked forms of HMSN I are associated with more than 150 point mutations in the Connexin-32, Cx32, gene, which encodes the gap junctions occurring at the Schmidt–Lanterman incisures and the paranodal regions of the myelin sheath. These Cx32 mutations may interfere with rapid transport of small molecules between different myelin lamellae.
Many of the myriad genetic abnormalities underlying Charcot–Marie–Tooth disease affect functions likely to be fundamental to biology of the cells of many different tissues, rather than those specifically restricted to peripheral neurones or Schwann cells.
The demyelinating Type 1 phenotype of Charcot–Marie–Tooth disease can be associated with abnormalities of the various genes for the growth arrest protein peripheral myelin protein 22, PMP-22; early growth response element 2, EGR-2; ganglioside induced differentiation associated-protein-1, GDAP-1; myotubularin-related-proteins-2 and -13, MTMR-2; N-MYC-downstream-regulated-gene-1, NDRG-1; epithelial-growth-factor-related-protein-2, EGR-2; periaxin, PRX; a putative protein degradation gene LITAF/SIMPLE; with a novel SH-3/TPR domain protein; and the neurofilament light chain, NF-L (Warner et al. 1998; Kalaydjieva et al. 2000; Houlden et al. 2001a; Nelis et al. 2002; Takashima et al. 2002; Jordanova et al. 2003; Senderek et al. 2003; Street et al. 2003).
The inability to develop or maintain an axon in the axonal Type 2 form of Charcot–Marie–Tooth is founded in straightforward neurobiological logic when due to mutations in the genes for kinesin-motor-protein-1-B, K1F1B-beta, mitofusin 2, or neurofilament light chain, NFL (Fabrizi et al. 2007). These affect axonal transport of motor proteins and axonal structural intermediate filament proteins respectively (Zhao et al., 2001; Jordanova et al. 2003). It is less clear why the axonal Type 2 forms occur as a result of mutations in the small heat shock protein 27 gene, in the small GTP-ase late endosomal RAB-7 gene, or the lamin A/C gene, other mutations of which produce the Emery Dreyfuss muscular dystrophies, limb girdle muscular dystrophies, cardiomyopathy, and partial lipodystrophy (Chaouch et al. 2003; Tazir et al. 2004; Tang et al. 2005; Meggouh et al. 2006). It is intriguing to discover that broadly similar Charcot–Marie–Tooth phenotypes result from such an eclectic array of disturbances of cell biology.
Associated clinical findings occur in a small proportion of patients with Charcot–Marie–Tooth disease, and provide a clue as to the underlying genetic cause (Table 21.8).
Table 21.8 Additional clinical abnormalities in Charcot–Marie–Tooth disease
Type of Charcot–Marie–Tooth disease
Prominent sensory loss/ sensory ataxia
Late onset, pupillary anomalies and hearing loss
P0, GJB1, NDRG1
Vocal cord paresis
Upper limb predominance
transient symptoms— ataxia, dysarthria, weakness with white matter MRI lesions
Agenesis of the corpus callosum and developmental delay
PMP22, P0, GJB1
Skeletal deformities—severe scoliosis
For key see Table 21.7 (Kindly provided by Dr. Yesim Parman, Istanbul Faculty of Medicine)
21.4.4 Type 1: Demyelinating
This demyelinating neuropathy is the commonest form of Charcot–Marie–Tooth disease. It is also known as hereditary motor and sensory neuropathy Type 1, HMSN1. Motor nerve conduction in the median nerve is substantially slowed and nerve biopsy shows segmental demyelination, usually accompanied by hypertrophic ‘onion-bulb’ changes (Fig. 21.6). These concentric layers of Schwann-cell proliferation around axons represent previous cycles of recurrent demyelination followed by attempted remyelination. The inheritance is usually autosomal dominant with a high degree of intrafamilial concordance for the velocity of motor slowing in keeping with the underlying genetic heterogeneity. Seventy per cent of patients with the autosomal dominant form have reduplication of the PMP22 gene, Type 1A (Thomas et al. 1997) and many of the remainder have point mutations of myelin protein P0, Type 1B (De Jonghe et al. 1999). Sex-linked recessive forms, sometimes mildly expressed in female carriers, are usually associated with Cx32 mutations, and may progressively deteriorate involving permanent axonal degeneration (Birouk et al. 1998). Autosomal recessive forms, Type 4, occur occasionally and generally produce more severe disability with even lower motor conduction velocities (Harding and Thomas 1980c).
Clinical features. Distal leg muscle atrophy and weakness, or pes cavus foot deformity (Fig. 21.4) are usually evident in the first or second decades of life. Leg weakness can become severe. Distal wasting may be such that the legs resemble inverted champagne bottles (Fig. 21.5). The ankle jerks are usually lost, but generalized areflexia occurs in only half the patients. Some hand weakness eventually occurs in most patients with Charcot–Marie–Tooth disease Type 1. A few develop tremor or ataxia of the limbs, the so-called ‘Roussy–Lévy syndrome’ which is not genetically distinct from Charcot–Marie–Tooth disease Type 1. All modalities of sensation may be impaired distally in the limbs. Occasional patients develop acrodystrophic changes secondary to severe sensory loss. Scoliosis, pupil abnormalities, or extensor plantar responses occasionally occur. Diaphragmatic weakness may cause dyspnoea or respiratory failure. Palpable nerve thickening, best detected at the great auricular nerve (Fig. 21.7) is found in about a quarter of the cases and is specific to the demyelinating forms of Charcot–Marie–Tooth disease (Harding and Thomas 1980b). Neurophysiological examination of the patient and first-degree relatives is crucial for determining the genetic basis if screening for the usual molecular genetic mutations is negative.
Nerve conduction. The median nerve motor conduction velocity is 38 m/s or less, which distinguishes the condition from the neuronal form, Charcot–Marie–Tooth disease Type 2. Generalized motor slowing is already evident in infancy and early childhood (Garcia et al. 1998). Sensory nerve action potentials are absent or reduced in all patients, allowing distinction from distal spinal muscular atrophy (Harding and Thomas 1980b). Motor conduction velocities in Charcot–Marie–Tooth disease Type 1 rarely lie below 12 m/s, but if so, the diagnosis of Déjérine–Sottas disease or congenital hypomyelinating neuropathy should be considered (Ouvrier et al. 1987). Sural nerve biopsy shows hypertrophic onion-bulb changes (Fig. 21.6) and reduced myelinated fibre density. The spinalfluid protein is usually normal, but is occasionally elevated to 1 g/l or higher (Ouvrier et al. 1987).
Differential diagnosis. The most important differential diagnosis is from chronic inflammatory demyelinating polyneuropathy (Section 21.11.2) which is treatable. Chronic inflammatory demyelinating polyneuropathy too is associated with reduced motor conduction velocity and with segmental demyelination on nerve biopsy, and occasionally with onion-bulb changes. Pointers in favour of Charcot–Marie–Tooth disease Type 1 are pes cavus, palpable nerve thickening, preserved proximal limb muscle power, a spinal fluid protein of less than 0.8 g/l, a slow rate of progression of symptoms, a lack of positive sensory symptoms such as tingling, and onion-bulb changes on nerve biopsy. The diagnosis of Charcot–Marie–Tooth disease may be positively established by molecular genetic testing or by examining close relatives for signs of neuropathy, even if they are asymptomatic. Cases of Charcot–Marie–Tooth disease with ataxia, the Roussy–Lévy syndrome, should be distinguished from Refsum disease (Section 21.8.1) in which the serum phytanic acid is elevated, and from Friedreich’s ataxia, in which nystagmus and extensor plantars are usual, inheritance is autosomal recessive, GAA trinucleotide expansion is present in intron 1 of the Frataxin gene is present and motor nerve conduction velocity is not markedly slowed.
21.4.5 Type 2: Axonal
Otherwise known as the neuronal form of hereditary motor and sensory neuropathy, Charcot–Marie–Tooth disease Type 2 reflects a reduction in the number of primary motor and sensory neurones. Type 2 is less common than Type 1. Motor nerve conduction velocities are higher than 38 m/s and inheritance is usually autosomal dominant (Harding and Thomas 1980b).
Syndromes. There are four clinical and genetically distinct syndromes of dominantly inherited Charcot–Marie–Tooth Type 2 although other variants are increasingly recognized:
♦ Type 2A, the commonest form, involves distal weakness and wasting with lesser degrees of sensory loss and areflexia starting in the second or third decade. It is a classical form of Charcot–Marie–Tooth disease.
♦ Type 2B shows a younger age of onset, often with foot ulceration and preserved ankle tendon reflexes, and may resemble hereditary sensory and autonomic neuropathy.
♦ Type 2C involves vocal cord or diaphragm paralysis in some members of the kinship.
♦ Type 2D characteristically produces more severe arm than leg muscle involvement.
A German kinship with Charcot–Marie–Tooth disease Type 2 has been described with sural nerve axonal swellings filled with neurofilaments (Vogel et al. 1985) but the dominant pattern of inheritance and their normal hair distinguish this family from giant axonal neuropathy (Section 21.7.1). Autosomal recessive forms are encountered occasionally, with an earlier onset of symptoms than the dominant form (Harding and Thomas 1980c). Rare X-linked dominant forms with childhood onset occur in which males are severely affected and females may suffer subclinical or mild disease; no male-to-male transmission occurs.
Clinical features. The clinical features of Charcot–Marie–Tooth disease Type 2 resemble those of Charcot–Marie–Tooth disease Type 1, but the onset of symptoms is generally later, usually in the second or third decade of life (Harding and Thomas 1980b). Onset can be delayed until old age. Patients most commonly present with difficulty in walking due to distal leg muscle weakness and wasting. Pes cavus foot deformity is less frequent than in Charcot–Marie–Tooth disease Type 1. The ankle jerks are usually absent. Hand weakness, tremor or ataxia of the arms, marked sensory loss, or generalized loss of tendon reflexes are less frequently encountered in Type 2 than in Type 1 (Harding and Thomas 1980b). Palpable nerve thickening does not occur in Type 2. Many patients with Charcot–Marie–Tooth Type 2 show little or no deterioration even when reassessed at intervals of many years and serious disability is uncommon. The median nerve motor conduction velocity is usually just within the normal range, and should not lie below 38–40 m/s. The median nerve sensory action potential is absent or reduced in amplitude (Harding and Thomas 1980b). The spinal fluid protein level is normal in Type 2. Nerve biopsies show axonal loss with little evidence of demyelination. Hypertrophic ‘onion-bulb’ changes are observed only rarely.
Differential diagnosis. Late onset Charcot–Marie–Tooth disease Type 2 should be distinguished from chronic idiopathic axonal polyneuropathy (Section 21.11.8). Sensory features predominate and progression occurs in this latter condition (Teunissen et al. 1997). The dominant inheritance should distinguish ataxic forms of Charcot–Marie–Tooth disease Type 2 from inherited causes of vitamin E deficiency (Section 21.22.5) and from Friedreich’s ataxia, which has a poorer prognosis. Abnormal sensory nerve conduction distinguishes patients with predominantly motor forms of Charcot–Marie–Tooth disease Type 2 from distal spinal muscular atrophy.
21.4.6 Infantile and childhood onset
These heterogenous and relatively uncommon progressive sensorimotor demyelinating neuropathies start in infancy or early childhood and are inherited either autosomally recessively or dominantly (Lynch et al. 1997). They are also known as Déjérine–Sottas syndrome or congenital hypomyelination neuropathy. They are caused by various point mutations of the PMP22, MPZ, Periaxin, GDAIP, MTMR2, and EGR2 genes (Parman et al. 2004) (Table 21.7). Affected children usually show delayed onset of walking and often develop ataxia and skeletal deformity. Palpable nerve thickening is common. One form of Charcot–Marie–Tooth disease Type 1, congenital hypomyelination neuropathy, presents at birth. It has a particularly poor prognosis; patients are unable to walk by their teens and may die at any age due to respiratory insufficiency. The prognosis is better if the onset is in childhood, but severe motor disability is usually evident by early adult life. Motor nerve conduction is extremely slow, to less than 12 m/s. This is lower than that generally measured in Charcot–Marie–Tooth disease Type 1 (Ouvrier et al. 1987). Spinal fluid protein is usually elevated to between 0.7 and 2.1 g/l. This can pose difficulties in distinction from the steroid-responsive chronic inflammatory demyelinating polyneuropathy of infancy and childhood (Section 21.11.2). In Charcot–Marie–Tooth disease Type 1 nerve biopsies show extensive onion-bulb formation and marked thinning of the myelin sheaths surrounding axons of all diameters (Ouvrier et al. 1987). Many axons are completely devoid of myelin sheaths in congenital hypomyelination neuropathy. The ataxic forms may cause severe disability and can be distinguished from early onset Friedreich’s ataxia by their slow motor conduction velocities, and from Refsum disease by measurement of the serum phytanic acid level.
21.5 Hereditary neuropathy with liability to pressure palsies
Some families exhibit autosomal dominant inheritance of a tendency to develop mononeuropathies due to their nerves being unusually vulnerable to pressure or traction. This condition is known also as hereditary susceptibility, or liability, to pressure palsies, hereditary pressure sensitive neuropathy, or tomaculous neuropathy. Exposed nerves, such as the radial or lateral popliteal, are especially vulnerable. Painless brachial plexus lesions may result from sleeping in awkward postures or from the shoulder straps of heavy backpacks. Patients present with the motor and sensory features typical of the mononeuropathy in question and recovery occurs over days or weeks. Typically patients experience deadness or tingling of the fingertips after using scissors. Permanent disability may develop after recurrent episodes of paralysis affecting the same nerve. In many, nerve conduction studies show slight but generalized slowing of distal motor latencies or sensory nerve action potentials and minor slowing of motor conduction velocities (Andersson et al. 2000). This can be useful in detecting asymptomatic affected family members, or in raising suspicion of this hereditary neuropathy when investigating a seemingly uncomplicated peripheral nerve palsy. Teased fibres from nerve biopsies show characteristic ‘tomaculous’ (Latin: sausage) swellings due to redundant myelin loops as a result of overgrowth of the myelin spiral (Fig. 21.8). In approximately 80 per cent of the patients, there is a deletion of one PMP22 gene at 17p11.2, and more pronounced evidence of background polyneuropathy (Lenssen et al. 1998). New mutations account for up to 5 per cent of all patients encountered with hereditary liability to pressure palsies.
21.6 Hereditary sensory and autonomic neuropathies
These inherited neuropathies reflect failure of development, or degeneration, of subpopulations of peripheral sensory and autonomic neurones. Prior to recognition that peripheral neuropathy underlay these disorders, they were termed as lumbo-sacral syringomyelia, inherited perforating ulcers or whitlows, acrodystrophic neuropathy, and congenital insensitivity to pain. Also some such patients were considered to suffer from congenital indifference or asymbolia to pain, a term which should be reserved for the rare situation in which there is lack of concern to a painful stimulus, yet one which is well received and in which the peripheral nerves are normal.
Lack of self-protection due to impaired pain appreciation leads to the development of a mutilating acropathy (Fig. 21.9), with ulceration and fissuring of the skin, long-bone fractures, Charcot joints, and digit amputation. The precise symptoms and signs of each neuropathy, and whether there are accompanying nerve conduction abnormalities, is determined by which subpopulation of sensory neurones is most affected. Patients with hereditary sensory and autonomic neuropathies should be instructed to avoid situations likely to cause thermal burns and trauma to the limbs, and to be assessed regularly by a chiropodist. They should be advised to ensure that their shoes are well-fitting and do not contain stones or sharp objects. Hereditary sensory and autonomic neuropathies should be distinguished from familial amyloidotic polyneuropathy (Section 21.9.1) which often affects sphincter control and sexual functioning.
There is no consensus for the classification of hereditary sensory and autonomic neuropathies. Here a descriptive classification (Donaghy et al. 1987) will be followed, indicating the corresponding numerical classification (Dyck et al. 1983) into Types I to V. A molecular genetic classification is emerging which subdivides some of the clinically recognized forms (Verpoorten et al. 2006) (Table 21.9).
Table 21.9 Classification of hereditary sensory and autonomic neuropathies
Autosomal dominant sensory neuropathy (Section 21.6.1)
Distal sensory loss with pains
Mild autonomic involvement
Severe sensory loss and amputations
Additional cough and gastro-oesophageal reflux
Severe sensory loss, ulcers
Autosomal recessive sensory neuropathy (Section 21.6.2)
Severe sensory loss legs and arms
Whole body sensory loss
(Riley–Day syndrome) (Section 21.6.3)
Severe autonomic dysfunction
Loss of pain and temperature
Hereditary anhidrotic sensory neuropathy (Section 21.6.4)
Pain and temperature insensitivity
Channelopathy-associated insensitivity to pain
Deficiency of small myelinated sensory firbres (Section 21.6.5)
Loss of temperature and deep pain
Distal loss of pain and temperature
Key: AD – autosomal dominant; AR – autosomal recessive; CMT 2B – Charcot-Marie-Tooth disease Type 2B; HSAN – Hereditary Sensory and Autonomic Neuropathy; HSN2 – Hereditary Sensory Neuropathy Type 2; IKBKAP – Inhibitor of kappa light polypeptide enhancer in B cells, kinase complex associated protein; NGF B – Nerve growth factor beta; NTRK1 – Neurotrophic tyrosine kinase, receptor, type 1; RAB7 – GTP-ase late endosomal protein gene; SCN9A – Sodium channel 9A; SPTLC1 – Serine palmitoyltransferase long chain base subunit 1. (Adapted from Verpoorten et al 2006.)
21.6.1 Autosomal dominant sensory neuropathy
This is also known as hereditary sensory and autonomic neuropathy Type 1. Patients gradually lose all modalities of sensation from the distal part of their limbs, particularly pain and temperature sensations. Spontaneous shooting pains in the legs may occur early in the disease. Foot ulcers, calluses, and foot deformity develop in many patients. Anhidrosis is not always present and may occur in the regions of impaired sensation. The ankle jerks are usually absent. Patients eventually develop mild distal muscle wasting and weakness, raising the question of overlap with more sensory forms of Charcot–Marie–Tooth disease. Sensory nerve action potentials are reduced or absent and motor conduction velocity is just within the normal range. Autopsy studies show loss of dorsal root ganglion neurones, with replacement by nodules of Nageotte indicating that sensory neurones have degenerated, rather than failing to develop. Mutations of the serine palmitoyltransferase long chain base subunit 1, SPTLC1 gene underlie this form, reflecting a defect in sphingolipid biosynthesis. This dominantly inherited form can be associated rarely with deafness (Horoupian 1989).
Other forms of autosomal dominant sensory neuropathy are of early adult onset with severe sensory loss and autoamputations, involve cough and gastrooesophageal reflex, and overlap with Charcot–Marie–Tooth disease Type 2B (Section 21.4.5).
21.6.2 Autosomal recessive sensory neuropathy
Otherwise known as congenital sensory neuropathy, or hereditary sensory and autonomic neuropathy Type 2, this autosomal recessive condition presents in infancy or childhood with impairment of all modalities of sensation in the limbs and on the trunk. Marked distal limb mutilation occurs with whitlows, paronychia, plantar ulcers, painless long-bone fractures, and Charcot joints. Motor function is preserved. Tendon reflexes are usually lost. Anhidrosis of the hands and feet adversely affects skin texture and contributes to ulceration. Sensory nerve action potentials are usually absent. The cutaneous sensory nerves are virtually devoid of myelinated fibres and depleted of unmyelinated fibres. The neuropathy seems to worsen progressively and patients progressively accumulate acrodystrophic changes. The prognosis is uncertain, but since published reports usually relate to patients under the age of 20, a shortened life span is inferred. Some are associated with mutations of hereditary sensory and autonomic neuropathy Type 2, HSN2, a gene of as yet unknown function. A similar form of hereditary sensory and autonomic neuropathy may be inherited as an X-linked recessive trait (Jestico et al. 1985). Another autosomal recessive form may be associated with spastic paraplegia (Cavanagh et al. 1979).
21.6.3 Familial dysautonomia
Otherwise known as the Riley–Day syndrome, or hereditary sensory and autonomic neuropathy Type 3, this rare congenital disorder is autosomally recessively inherited, principally by Ashkenazi Jews. Affected infants vomit, have impaired control of body temperature and blood pressure, sweat excessively, develop patchy skin blotching, have impaired tear formation, and are prone to pulmonary infection. Typically fungiform papillae are absent from the tongue. There is insensitivity to painful stimuli applied to the skin or eyes. The sensory deficit worsens with age, eventually involving kinaesthesia. There is areflexia and postural hypotension. Motor involvement eventually occurs. Nerve biopsy shows reduced numbers of unmyelinated fibres and a lack of large-diameter sensory myelinated fibres. Intradermal histamine injection fails to cause the erythematous flare of the triple response. About half of the patients die by the age of 20 due to renal or pulmonary failure, or sudden death (Axelrod 2004). The mutations affecting the IKBKAP gene lead to tissue specific expression of the mutant IkB kinase-associated protein.
21.6.4 Hereditary anhidrotic sensory neuropathy
Also known as hereditary sensory and autonomic neuropathy Type 4, patients with this autosomal recessive neuropathy suffer from congenital insensitivity to pain. They present in infancy with bouts of pyrexia, failure to thrive, retarded development, failure to respond to painful stimuli, anhidrosis, and mild mental retardation. The peripheral nerves are virtually devoid of unmyelinated axons and small neurones are absent from dorsal root ganglia. The condition is rare and leads to premature death, often associated with a bout of unexplained fever. It is due to mutations of the NTRK1 gene, a tyrosine kinase gene which encodes the high affinity nerve growth factor receptor (Indo 2002).
21.6.5 Deficiency of small myelinated sensory fibres
This is also termed hereditary sensory and autonomic neuropathy Type 5. A large Kashmiri kinship has shown autosomal recessive inheritance of a mutilating acropathy associated with bilateral corneal opacification due to neurotrophic keratitis. Pain and temperature sensation is absent from the limbs and there is patchy anhidrosis. Motor function, the tendon reflexes, and kinaesthetic sensations are normal. Motor and sensory nerve fibre conduction, which reflect the fastest conducting fibres, are normal. Sural nerve biopsy shows selective reduction of the smaller myelinated fibre population. An identical neuropathy has also occurred sporadically, but associated with normal corneas. This syndrome can reflect mutations either of the neurotrophic tyrosine kinase receptor Type 1, N~TRK1 (Houlden et al. 2001b), or nerve growth factor β, NGFB, genes.
21.6.6 Congenital indifference to pain
True indifference to pain is rare. Most patients so described probably had hereditary sensory neuropathies with selective lack of small myelinated or unmyelinated sensory fibres. This was overlooked because there were no neuropathic abnormalities on examination and sensory nerve conduction was normal, given that large myelinated fibres are preserved in such neuropathies. One family has been described with dominantly inherited indifference to painful stimuli over the whole body and with normal morphometric examination of peripheral nerves (Landrieu et al. 1990).
21.7 Other inherited polyneuropathies
21.7.1 Giant axonal neuropathy
This rare progressive disorder of childhood involves both the peripheral and central nervous systems, causing peripheral neuropathy, ataxia, intellectual loss, and pyramidal tract dysfunction (Demir et al. 2005). It is characterized by accumulations of abnormally closely packed neurofilaments within swollen peripheral nerve axons (Fig. 21.10). The disorder is not restricted to neurofilaments and affects intermediate filament organization in all cell types, including glial fibrillary acidic protein in Schwann cells (Donaghy et al. 1988). Most patients have characteristic tightly curled hair, reflecting an abnormality of keratin, another intermediate filament protein. However, such hair is only variably present, even within affected kinships. The inheritance is autosomal recessive. The disorder is caused by mutations of the Gigaxon gene, GAN on chromosome 16q24.1 (Bruno et al. 2004; Demir et al. 2005). Patients present in childhood before dying from progressive disease in their second or third decade. Toxic neuropathy due to hexacarbons causes a similar histological picture, but the hair is normal, there is a history of exposure to glues or other solvents, and the age of onset is generally later (Section 21.21.7).
21.7.2 Neuropathy in cerebellar ataxia
Friedreich’s ataxia (Section 39.4.1) affects the peripheral as well as the central nervous system. A stocking distribution of impaired light touch sensation spreads proximally with age. The Achilles tendon reflexes are lost early, and vibration and joint-position sensations are impaired in the feet. Pes cavus may occur. The amplitude of sensory nerve action potentials is markedly reduced and sural nerve biopsy shows severe loss of the large myelinated fibres (Caruso et al. 1987). Despite the clinical evidence of progression, actively degenerating fibres are only relatively rarely encountered in biopsies, and the marked absence of large myelinated fibres is unlikely to be explicable by degeneration alone.
A large French kinship with dominantly inherited variable combinations of cerebellar ataxia and pure sensory neuropathy has been designated spinocerebellar ataxia Type 25, SCA25 (Stevanin et al. 2004).
21.7.3 Chédiak–Higashi syndrome
This rare autosomal recessive disease usually presents in infancy or childhood with febrile episodes, pyogenic infections, and partial oculocutaneous albinism. Death within the first two decades usually follows an accelerated phase with lymphoma-like proliferation. Peripheral blood granulocytes contain pathognomonic giant peroxidase-positive lysosomal granules. Patients develop features of spinocerebellar degeneration, and peripheral neuropathy is particularly likely to occur during the accelerated phase. Prednisolone and vincristine may have some effect in controlling the neurological manifestations (Pettit and Berdal 1984). Although Chédiak–Higashi syndrome may be cured by allogeneic bone marrow transplantation in childhood, neurological abnormalities still develop in the third decade (Tardieu et al. 2005).
21.7.4 Multiple symmetric lipomatosis
Patients with this condition develop disfiguring multiple subcutaneous lipomata over the upper trunk and proximal arms also known as Madelung’s disease (Fig. 21.11). The buttocks and legs are spared and are often relatively devoid of the usual subcutaneous fat. Up to 80 per cent of patients develop an axonal peripheral neuropathy, usually sensorimotor but occasionally with autonomic features. The neuropathy presents insidiously in middle age, is usually mild, and has a heterogenous basis. Excessive alcohol consumption was observed in many Italian patients, initially suggesting that alcoholism caused the neuropathy (Enzi et al. 1985). However, a large kinship has shown invariant association of peripheral neuropathy with multiple symmetrical lipomatosis, with possible autosomal recessive inheritance. Since no members of this kinship were alcoholic, the neuropathy of multiple symmetrical lipomatosis is likely to be genetically determined (Chalk et al. 1990). Other patients have abnormalities in Complex IV and multiple deletions of mitochondrial DNA (Klopstock et al. 1994).
Muscle wasting and areflexia may occur in patients with limb chorea and orofacial dyskinesias associated with acanthocytes in peripheral blood. Nerve-conduction studies show an axonal degeneration neuropathy. The condition is often familial, either autosomal dominant involving mutations of the CHAC gene, or X-linked associated with the McLeod blood group variant gene XK (Danek et al. 2001; Saiki et al. 2003). It should be differentiated from the peripheral neuropathy and acanthocytosis which occurs in abetalipoproteinaemia, Bassen–Kornzweig disease, which is treatable with vitamin E (Section 21.8.8).
21.7.6 Mitochondrial disorders
Roughly a quarter of all patients with various forms of mitochondrial cytopathy (Section 24.6.3) have clinical features of mild sensorimotor neuropathy. Asymptomatic electrophysiological evidence of peripheral neuropathy is somewhat commoner (Yiannikas et al. 1986). Sural nerve biopsies show loss of large myelinated fibres, evidence of axonal degeneration, and the Schwann-cell cytoplasm may contain abnormal mitochondria with paracrystalline inclusions. There are particular associations with the neuropathy Ataxia retinitis pigmentosa, or NARP syndrome, and with the MERRF and MELAS syndromes as well as point mutations of the mitochondrial genome (Bouillot et al. 2002).
Severe progressive polyneuropathy occurs in the distinctive syndrome of mitochondrial neuroGastrointestinal encephalomyopathy, or MNGIE. Supranuclear ophthalmoparesis and T2-weighted brain MRI changes are usual accompaniments. Various autosomal recessively inherited mutations of the somatic gene encoding the thymidine phosphorylase gene, TP are responsible. The neuropathy may mimic Charcot–Marie–Tooth disease (Section 21.4) or chronic inflammatory demyelinating polyneuropathy (Section 21.11.2) which is unresponsive to immunomodulatory treatment (Bedlack et al. 2004).
21.7.7 Thermosensitive neuropathy
A French family has shown autosomal dominant inheritance of reversible episodes of ascending muscle weakness, paraesthesiae, and areflexia which seemed to be triggered by pyrexia over 38.5°C (Magy et al. 1997).
21.8 Inherited metabolic disorders causing polyneuropathy
This section addresses the peripheral-nerve manifestations of a number of diseases whose central nervous system manifestations are discussed in Chapter 10 and Section 37.7. In addition to those disorders to be discussed in detail, mild polyneuropathy has been described in lysosomal-storage diseases, Niemann–Pick, Gaucher, or GM gangliosidosis; hyperoxaluria; defective DNA repair, xeroderma pigmentosum, ataxia telangiectasia; and Cockayne’s syndrome. Focal entrapment neuropathies may occur in the mucopolysaccharidoses.
21.8.1 Refsum disease
Refsum disease is also known as phytanic acid oxidase deficiency, heredopathia atactica polyneuritiformis, hereditary motor and sensory neuropathy Type IV, or phytanic acid accumulation. Demyelinating polyneuropathy is a central feature of Refsum disease, associated with retinitis pigmentosa, cerebellar ataxia, and a markedly raised spinal fluid protein. Night blindness is a common presenting symptom. Most patients also show hearing loss, anosmia, ichthyosis, skeletal abnormalities, and cardiomyopathy. The disease is rare, generally occurring in people of northern European racial stock (Refsum et al. 1984). A deficiency of phytanic acid α-hydroxylation due to mutations in the phytanoyl-CoA-hydrolase gene, PHYH, on chromosome 10p13, is inherited as an autosomal recessive trait. This results in a failure to oxidize exogenous phytol with resultant conversion to phytanic acid, which accumulates. The disorder is genetically heterogeneous, with a second gene, PEX 7 on 6q22-24 causing a milder form of Refsum disease (van den Brink et al. 2003). The diagnosis is confirmed by demonstrating a high serum phytanic acid level. Phytates are derived chiefly from dietary dairy products and other animal fats; the chlorophyll of green vegetables is a less well-absorbed source.
Neuropathic symptoms first develop at any time from childhood to the third decade, and may be provoked by infections. Recurrent attacks of polyneuropathy have been described. The neuropathy is usually predominantly distal and motor, and generally preceded by night blindness. Severe disability may develop. Peripheral nerves may be palpably hypertrophied. Motor nerve conduction velocities are greatly slowed. Nerve biopsy confirms the demyelinating nature of the neuropathy, and may reveal hypertrophic changes and round paracrystalline inclusions within Schwann cells. The diagnosis of Refsum disease is of importance, since dietary restriction of phytate ingestion improves or stabilizes the neuropathy, with increased motor nerve conduction velocities. Plasma exchange also helps to lower the phytanic acid level, and is particularly valuable soon after diagnosis before dietary restriction becomes effective (Harari et al. 1991).
21.8.2 Metachromatic leucodystrophy
In this rare group of autosomal recessive diseases, also known as sulfatide lipidosis and arylsulfatase deficiency, a severe demyelinating sensorimotor neuropathy accompanies psychomotor retardation and seizures due to disease of the cerebral white matter. Motor nerve conduction velocity is substantially slowed with elevated spinal fluid protein. The different metachromatic leucodystrophies present variously in late infancy, childhood, or adulthood. Presentation with isolated peripheral neuropathy as late as the sixth decade is recorded (Comabella et al. 2001). Sulfatides accumulate in nervous tissue because of a range of mutations in the arylsulfatase A gene, ARSA located at 22q13, accounting for the varying age of onset and diverse clinical picture associated with this lysosomal storage disorder (Bertelli et al. 2006). The activity of the lysosomal enzymes arylsulphatase A and B are reduced in peripheral blood leucocytes. Metachromatic granules may be demonstrated in an early morning urine deposit. Nerve biopsy shows evidence of demyelination and remyelination, and the presence of metachromatic granules in Schwann-cell cytoplasm after staining with aniline dyes. Electron microscopy shows these to be zebra-like bodies, tuffstone, and prismatic inclusions (Martin et al. 1982). Bone marrow transplantation can be successful in ameliorating symptoms and slowing progression, particularly if performed sufficiently early in the disease (Peters and Steward 2003).
21.8.3 Krabbe disease
This rare autosomal recessive disease is also known as globoid cell leucodystrophy or galactosylceramide lipidosis. It is due to mutations of the galactosylceramide-beta-galactosidase gene, GALC on 14q24.3-32.1. It usually presents in infancy with psychomotor retardation (Husain et al. 2004). Demyelinating sensorimotor peripheral neuropathy generally develops later. Protruding ears may be a feature. A later onset form has been described. After an initial phase of hypereflexia, which reflects central nervous system disease, patients become areflexic as the peripheral neuropathy develops. Motor nerve conduction velocity is substantially reduced. The diagnosis is confirmed by demonstrating reduced leucocyte galactosylceramide-beta-galactosidase levels.
X-linked adrenoleucodystrophy (Section 37.6.2) is also known as adrenomyeloneuropathy. It causes adrenal insufficiency and neurological dysfunction associated with raised plasma levels of very-long-chain saturated fatty acids, such as hexacosanoic, pentacosanoic, and tetracosanoic acids. Different phenotypes occur with different ages of onset, within the same kinship, and even between monozygotic twins (Sobue et al. 1994). Over a hundred mutations in the ALD gene are identified, with little genotype– phenotype correlation (Dodd et al. 1997). The peripheral neuropathy is generally mild and causes little disability compared to the associated spastic and ataxic paraparesis. Nerve conduction may be slowed, but a mixed axonal and demyelinating picture is usual; female carriers may show electrophysiological evidence of neuropathy (van Geel et al. 1996).
21.8.5 Fabry’s disease
This X-linked disorder is also known as angiokeratoma corporis diffusum or Anderson–Fabry disease and reflects α-galactosidase deficiency. It is due to mutations in the gene encoding the lysosomal hydrolase α-Gal A, at Xq22.1. This leads to accumulation of ceramide trihexoside in neural, renal, endothelial, and corneal tissues. It usually presents in childhood or early adult life with burning pain and paraesthesiae distally in the limbs or occasionally with a cramp-fasciculation syndrome in adulthood (Nance et al. 2006). Discrete crises of pain may be provoked by exercise or heat. These can be sufficiently severe to prevent or impede walking. Anhidrosis may occur. Most patients have angiokeratoma corporis diffusum, a characteristic crimson maculopapular rash in the ‘bathing-trunks’ area which may be overlooked on cursory examination (Fig. 21.12). Strokes, hypertension, renal failure, and corneal opacification are common (MacDermot et al. 2001). Muscle strength, kinaesthetic sensation, and nerve conduction studies are usually normal; thermal threshold testing is often abnormal (Luciano et al. 2002). Excess lysosomal storage of glycosphingolipids occurs in blood vessel walls, and selected populations of neurones, including ganglia. The diagnosis is confirmed by measuring blood leucocyte lysosomal α-galactosidase.
21.8.6 Porphyric neuropathy
Neurological symptoms occur in all three autosomal dominantly inherited hepatic porphyrias: acute intermittent, hereditary coproporphyria, and variegate porphyria. A fourth form is autosomal recessive, ALA dehydratase deficiency. All exhibit similar neuropsychiatric features during acute porphyric attacks. Only hereditary coproporphyria and variegate porphyria produce photosensitive skin lesions. Acute attacks may be diagnosed by measuring elevated levels of δ-aminolevulinic acid in the plasma, of porphobilinogen in the urine, and of faecal porphyrins. The underlying enzyme defects can be identified in cultured fibroblasts, the genes cloned, and disease-specific mutations mapped (Albers and Fink 2004).
Acute attacks are provoked by a wide variety of drugs, hormones, intercurrent infections, by reduced dietary carbohydrate intake or by lead intoxication (Section 21.20.2). Lead-exposed workers whose blood and urine lead levels lay within accepted safety limits may nonetheless develop wrist drop due to plumboporphyria (Dyer et al. 1993). During an acute attack, the urine characteristically turns red on standing due to oxidation of porphobilinogen. The first manifestation is usually abdominal pain. This is often associated with constipation, tachycardia, sweating, tremor, fever, and hypertension. These features reflect acute sympathetic outflow activity and may be associated with sudden death. They are followed by the neuropsychiatric features of insomnia, confusion, hallucinations, delusion, or depression. Seizures may occur. A dilutional hyponatraemia may contribute to the central nervous system dysfunction. Imaging evidence points to porphyrin precursor toxicity as the cause of acute neurological attacks, rather than the underlying haem deficiency (Solis et al. 2004).
A wide variety of neuromuscular manifestations have been described and occur in up to 40 per cent of porphyric attacks (Albers and Fink 2004). Acute weakness may start symmetrically in proximal muscles, preceded by myalgias and cramps. The onset may be restricted to only one limb for the first few hours or days. Weakness can take weeks to develop fully, and eventually may be most marked distally. The resultant tetraplegia is often maximal in the arms. Dysphagia, facial paralysis, and diplopia may occur in severe cases. Assisted ventilation may be required for diaphragm weakness. Tendon reflexes are absent or diminished in nearly all patients; characteristically the ankle jerks are most likely to be preserved. Paraesthesiae, dysaesthesiae, or numbness of the limbs may be present from the outset. Distal glove and stocking diminution of superficial sensation, and vibration sense abnormalities can be evident. It is unusual for the sensory disturbance to precede motor weakness. Some patients develop truncal sensory deficits, either in band-like distributions or in a bathing-trunks distribution. Postural hypotension and urinary retention can occur, reflecting autonomic neuropathy. Nerve conduction studies in established attacks are consistent with an axonal degeneration neuropathy. However, nerve conduction may be normal early in an attack, although mild myopathic features may be noted on electromyography of affected muscles. We still lack a cogent pathogenic explanation for the early weakness. The early proximal muscle involvement and relatively prompt recovery suggest a reversible myopathic or conduction block element, rather than axonal degeneration.
The treatment should aim to control pain with opiate analgesics. Sedation with phenothiazines is helpful. Epilepsy should be treated with low-dose clonazepam or sodium valproate and by correcting the underlying dilutional hyponatraemia. Other major anticonvulsants such as phenytoin, carbemazepine, or barbiturates are likely to worsen the severity of the underlying porphyric attack. The porphyric attack itself should be terminated by withdrawing precipitating drugs, by treating any underlying infections, by rehydration, and by administration of a high carbohydrate load either parenterally or orally. If the attack is severe or unresponsive to the preceding measures, haematin infusion may be effective. The neurological deficit recovers gradually over months although permanent deficits may result.
Identical neurological crises may occur in children with autosomal recessive hereditary tyrosinaemia (Mitchell et al. 1990) and in patients with lead poisoning. d-Aminolevulinic acid excretion is increased in both these conditions, as in porphyria.
21.8.7 Tangier disease
Plasma high-density lipoproteins are severely reduced in this rare autosomal recessive disorder which is also known as familial high-density lipoprotein deficiency or analphalipoproteinaemia. It is due to mutations in the ATP-binding cassette transporter 1 gene, ABCA1. Diagnostically there is absence or severe reduction in plasma HDL cholesterol and ApO A-1. Cholesterol esters accumulate in body tissues, producing cardiovascular disease, splenomegaly, and visibly swollen, orange-coloured pharyngeal tonsils. Most patients eventually develop peripheral neuropathy which can take either of two forms. Most commonly there is a relapsing and remitting multiple mononeuropathy which can be confused with leprosy (Sinha et al. 2004). Less often there is a slowly progressive symmetrical sensory neuropathy in which the distribution of the sensory disturbance resembles syringomyelia, with dissociated sensory loss affecting the upper limbs and wasting of the arm and facial muscles. These two contrasting peripheral neuropathies reflect severe demyelination and axonal degeneration, respectively (Zuchner et al. 2003). There is no specific treatment.
This rare autosomal recessive disorder is also known as Bassen–Kornzweig disease syndrome or acanthocytosis. Associated with the acanthocytes in peripheral blood, there is fat malabsorption, retinitis pigmentosa, and a spinocerebellar degeneration resembling early onset Friedreich’s ataxia. The associated axonal degeneration peripheral neuropathy produces areflexia and impaired vibration and joint-position sensation (Brin et al. 1986). It is due to deficiency of the microsomal triglyceride transfer protein (Wetterau et al. 1992). High-dose vitamin E therapy may prevent progression of the neurological symptoms and can produce improvement (Muller et al. 1985).
21.8.9 Cerebrotendinous xanthomatosis
Cholestanol accumulates in the tissues in this rare autosomal recessive disorder which is due to a block in hepatic bile acid synthesis resulting from mutations of the sterol 27-hydrolase gene, CYP27. A sensorimotor peripheral neuropathy is associated with juvenile cataracts, chronic diarrhoea, dementia, spastic paraparesis, cerebellar ataxia, and tendon xanthomas (Fig. 21.13) (Moghadasian et al. 2002). A high blood level of cholestanol confirms the diagnosis. Chenodeoxycholic acid therapy may produce some minor neurological improvement, including increased nerve conduction velocities. Presymptomatic detection of the mutation in at-risk family members allows presymptomatic treatment to try and stave off clinical disease.
21.9 Amyloid neuropathy
Amyloidotic polyneuropathy results from deposition within nerves of various non-branching, fibrillar proteins which all possess the crystallographic characteristic of forming a β-pleated sheet. Histologically, amyloid material is recognized by its property of staining with congo-red dye and exhibiting apple-green birefringence when viewed under polarizing light (Fig. 21.14).
Amyloidotic neuropathy occurs in two main groups of patients. The familial amyloidotic neuropathies reflect inherited substitutions of single amino acids in the proteins which are deposited: transthyretin, or pre-albumin, or less frequently apolipoprotein A-1 or gelsolin. Primary amyloidosis is due to tissue deposition of immunoglobulin light chains, usually derived from benign or malignant plasma cell tumours. It is rare for peripheral neuropathy, apart from carpal tunnel syndrome, to complicate the reactive or secondary amyloidoses, which are associated with circulating serum amyloid A protein, and which result from chronic inflammatory conditions.
21.9.1 Familial amyloidosis
Genetics. These neuropathies are inherited as autosomal dominant traits. Penetrance often varies within affected families. Onset of neuropathic symptoms is usually in the third to sixth decades. The original clinical and geographical classification into Types I–IV has been replaced by a molecular genetic classification (Hund et al. 2001). Molecular genetic analysis can now be applied to affected families for diagnostic, presymptomatic, and prenatal testing. Types I, originally Portuguese, and II, Indiana/Swiss, are due to the deposition of abnormal transthyretin within the body tissues, including the peripheral nerves. Well over 30 different point mutations have been identified in the transthyretin gene, TTR, on chromosome 18q11.2-q12.1 (Reilly et al. 1995; Plante-Bordeneuve et al. 1998). Of these the methionine 30, Met30 mutation is by far the commonest. Type III, Iowa, familial amyloidosis is due to deposition of mutant apolipoprotein A-1, resulting from various single base-pair substitutions in the gene on chromosome 11 (Nichols et al. 1988). Type IV, originally Finnish, is due to gelsolin gene mutations (Paunio et al. 1995; Conceicao et al. 2003).
Clinical features. Suspicion of hereditary amyloid neuropathy should always be raised by the combination of a small fibre neuropathy involving autonomic fibres coupled with cardiac disease. The polyneuropathy is similar in all these different types of familial amyloidosis. Numbness is usually associated with impaired pain and temperature sensations in the hands and feet. This may eventually lead to trophic ulceration. Spontaneous pains occur in the limbs. Areflexia develops. Weakness generally follows the sensory disturbance and affects distal muscles, particularly the small hand muscles and ankle dorsiflexors. Autonomic involvement affects the pupillary reactions to light, impairs gastrointestinal motility, and produces impotence and postural hypotension. The spinal fluid protein is often raised. Nerve conduction studies show an axonal degeneration neuropathy. Proteinuria, renal failure, and cardiac involvement contribute to premature death.
There are some noteworthy variations in the presentation of the different clinical forms of familial amyloidosis (Hund et al. 2001). In Type II the earliest symptom is usually a carpal tunnel syndrome, due to deposition of amyloid in the flexor retinaculum at the wrist. Renal and sphincter involvement do not occur in Type II amyloidosis. Type IV presents with lattice dystrophy of the cornea and patients may develop amyloid infiltration of the facial skin and involvement of the facial and auditory nerves.
Pathology. Nerve biopsies show amyloid deposition within nerve fascicles and around endoneurial blood vessels. At autopsy, widespread amyloid deposition is seen in the peripheral nervous system, affecting nerve plexuses, dorsal root and sympathetic ganglia. Leptomeningeal transthyretin amyloid deposits may have been symptomatic or noted in imaging. Multiple mechanisms probably contribute to the peripheral nerve damage. Amyloid deposits in the dorsal root ganglia may cause a sensory neuronopathy. Ischaemic changes may result from amyloid deposition around endoneurial blood vessels. Multifocal interruption of axons by small amyloid deposits along the course of a nerve may summate distally to produce a picture of diffuse fibre loss.
Treatment. Untreated, patients diagnosed with familial amyloid polyneuropathy survived about 10 years, although this varies geographically and in relation to different mutations. Liver transplantation has been introduced to treat transthyretin amyloid polyneuropathy on the grounds that the liver produces more than 90 per cent of this protein. Transplantation reduces mutated transthyretin in the blood and halts the progression of polyneuropathy with additional benefits for general health and gastrointestinal symptoms. There is little objective evidence of significant improvement in the neuropathy but further loss of myelinated axons from peripheral nerves largely ceases (Adams et al. 2000). Transplantation carries a significant mortality in amyloidosis, with only 60 per cent survival at 5 years (Parrilla et al. 1997). Poor prognosis is predicted by an already heavy load of amyloid deposition prior to transplantation, as revealed by symptomatic postural hypotension, urinary incontinence, or cardiac involvement. In principle, liver transplantation should be considered early in the disease so as to forestall amyloid deposition in the nerves and other organs.
21.9.2 Primary amyloidosis
Systemic amyloidosis due to immunoglobulin light-chain deposition is unusual before middle age. The peripheral nervous system is affected in about one-third of all cases (Duston et al. 1989). Various underlying lymphoproliferative disorders may be responsible for the monoclonal immunoglobulin production, ranging from malignant myeloma to benign paraproteinaemia. Serum paraproteinaemia and/or free light chains in the urine, known as Bence–Jones protein, may be detected. This form of amyloidosis is occasionally associated with hypernephroma.
Clinical features. Peripheral neuropathy is the presenting symptom in less than 10 per cent of patients with primary amyloidosis and these patients tend to have the longest survival. The initial symptoms tend to be sensory or, less frequently, autonomic. Impaired pain and temperature sensations and numbness affect the limbs. Spontaneous lancinating or burning dysaesthetic pains occur and may respond to carbamazepine therapy. Sometimes these lancinating pains are focal, for instance picking out a particular finger for a few weeks. Muscle weakness and areflexia occur later in the course of the neuropathy. Autonomic symptoms include postural hypotension, impotence, constipation, anhidrosis, and hypoactive pupils. Sensorimotor symptoms can be distributed asymmetrically, suggesting that individual peripheral nerves or dorsal root ganglia may be infiltrated to differing degrees by amyloid. Involvement of the ocular motor, trigeminal, or facial cranial nerves may be prominent (Traynor et al. 1991). Other features suggesting a diagnosis of primary amyloidosis include macroglossia, hepatosplenomegaly, proteinuria, or nephrotic syndrome, elevated serum alkaline phosphatase and paraproteinaemia (Park et al. 2003). Muscular stiffness, hypertrophy, and weakness occasionally complicate amyloid deposition in muscles. Nerve conduction studies show an axonal degeneration neuropathy. The spinal fluid protein is usually elevated. The diagnosis is confirmed by demonstrating amyloid deposition within biopsied peripheral nerves. However, it is simpler to establish the diagnosis of amyloidosis by rectal biopsy, which can be positive even when a nerve biopsy has not shown amyloid. The neuropathological features at autopsy resemble those of familial amyloidotic polyneuropathy (Section 21.9.1).
Treatment. The neuropathy progresses relentlessly. Eighty per cent of patients die within 3 years, usually due to associated renal or cardiac disease. Attempts at drug therapy have been generally unsuccessful, although there are recent glimmers of hope. Chemotherapy with melphalan and prednisolone does not alter perceptibly the downhill course of the neuropathy. However, trials have shown modestly enhanced survival in amyloidosis patients treated with melphalan and prednisolone compared to colchicine and retrospective analysis has shown that colchicine improves the median survival. Stabilisation or improvement of systemic manifestations of primary amyloidosis has followed autologous stem cell transplantation in selected patients; although the mortality is high in these with cardiovascular involvement (Mollee et al. 2004). However there has been no systematic study of how these more aggressive therapeutic approaches may benefit an existing polyneuropathy, or influence its emergence.
21.10 Acute idiopathic polyneuropathies and the Guillain–Barré syndrome
These conditions produce acute and diffuse demyelination or conduction block, or less frequently axonal degeneration affecting the spinal roots and peripheral nerves, and occasionally the cranial nerves. They are usually post-infective and recover spontaneously. The term Guillain–Barré syndrome includes two main entities now recognized as distinct: acute idiopathic demyelinating polyradiculoneuropathy (Section 21.10.1) and acute motor axonal neuropathy (Section 21.10.2).
21.10.1 Acute idiopathic demyelinating polyneuropathy
The term Guillain–Barré syndrome tends to be used interchangeably with acute idiopathic demyelinating polyneuropathy. Other names used for the condition have included: acute post-infective polyradiculoneuropathy, acute infectious polyneuritis, Landry–Guillain–Barré–Strohl syndrome, and post-infective polyneuritis.
Epidemiology. The Guillain–Barré syndrome is one of the commoner forms of polyneuropathy. Many cases were observed among troops during the 1914–18 war. The condition may occur in either sex, with slight male preponderance, and at any age, occasionally including infancy. The mean age of onset is around 40 but many series have shown a bimodal distribution with peaks in the third and sixth decades of life. There is no obvious seasonal clustering of cases. The crude average annual incidence rate varies in different countries from 0.6 to 1.9 per 100 000 people (Ropper et al. 1991; Chio et al. 2003). Familial occurrences do suggest some as yet unidentified genetic susceptibility factor (Geleijns et al. 2004).
Antecedent infections. Over half of Guillain–Barré syndrome patients experience symptoms of viral respiratory or gastrointestinal infections during the 1–3 weeks prior to the onset of neurological symptoms (Winer et al. 1988b). Serological studies have implicated a wide range of infective agents. Cytomegalovirus and Campylobacter jejuni, in approximately 30 per cent, are the commonest (Hadden et al. 2001). Epstein–Barr virus, Mycoplasma pneumoniae, human immunodeficiency virus, and childhood exanthems are also reported. The Guillain–Barré syndrome may accompany primary infection with HIV at a stage before viral antibodies are detectable in the serum; measurement of the p24 capsid antigen proving the underlying infection.
Cytomegalovirus and Campylobacter infections precipitate differing forms of Guillain–Barré syndrome. That associated with cytomegalovirus tends to occur in younger patients, with a high occurrence of respiratory muscle weakness, cranial nerve involvement, and significant sensory involvement (Visser et al. 1996). By contrast, Campylobacter jejuni infection is associated with preceding diarrhoeal illness in 70 per cent, a pure motor disorder (Section 21.10.2) is common, the electrophysiology often points to axonal dysfunction rather than demyelination, and recovery can be markedly slow. Forms of Guillain–Barré syndrome precipitated by both Campylobacter and cytomegalovirus may show delayed recovery compared to cases unassociated with these two infections (Visser et al. 1996).
When Campylobacter jejuni enteritis has precipitated Guillain–Barré syndrome, stool culture may be positive and serum IgM antibodies detected. Preceding Campylobacter jejuni infections can evoke Guillain–Barré syndrome even if there has been prompt treatment with antibiotics. Unusual forms of acute polyneuritis may occur following Campylobacter infection including variants with ophthalmoplegia. Different Penner serotypes of Campylobacter seem to provoke differing forms of acute polyneuritis, based upon studies in Japanese patients (Koga et al. 2005; Kimoto et al. 2006). Ganglioside epitopes on Campylobacter are thought to probe antibodies that cross-react with peripheral nerve glycolipids. Although some patients with Guillain–Barré syndrome, often the acute motor axonal variant, have anti-GM1 and anti-GD1A antibodies associated with infection by the HS:19 bacterial strain, this is by no means universal, and the association shows overlap with other clinical subtypes.
After immunization in 1976 of more than 40 million adults in the United States with swine influenza virus vaccine A/New Jersey/76 more than 500 cases of Guillain–Barré syndrome were reported in vaccinated individuals. It is estimated that this vaccine resulted in an excess incidence of one case of Guillain–Barré syndrome per 100 000 population, approximately doubling the normal incidence. No other causal relationship linking Guillain–Barré syndrome with vaccination by different strains of influenza virus has been shown. A prospective case-control study in England showed no significant excess of any form of vaccination during the 3 months preceding the Guillain–Barré syndrome (Winer et al. 1988a). The Guillain–Barré syndrome may be occasionally associated with underlying lymphoma, usually Hodgkin’s disease. It can appear in patients already being treated with substantial doses of steroids, and is occasionally seen after renal transplantation from a cytomegalovirus positive donor, and after bone marrow or hepatic engraftment.
Immunopathogenesis. An autoimmune basis for the Guillain–Barré syndrome seems likely but remains unproven. Although antibodies to various gangliosides are described in Guillain–Barré syndrome, particularly following Campylobacter infection, it remains unclear whether these antibodies are pathogenic. Certainly no single antibody is ubiquitous for Guillain–Barré syndrome. Guillain–Barré syndrome bears a strong histological resemblance to experimental allergic neuritis, an acute monophasic disorder induced by immunization of experimental animals with peripheral nerve myelin proteins, particularly P2 and galactocerebroside. It is likely that diverse immunopathogenic mechanisms occur, including both antibody and cell-mediated immune mechanisms. Prominent neural inflammatory infiltrates can occur in both Guillain–Barré syndrome and experimental allergic neuritis.
Circumstantial support for autoantibody mediation of the neuropathy comes from the finding that plasma exchange shortens the duration of the disease. However, unlike most organ-specific autoimmune diseases, the Guillain–Barré syndrome shows no clear association with other autoimmune diseases or with major histocompatibility complex antigens. There is controversy as to whether demyelination or conduction block can be induced by injection of Guillain–Barré sera into animal nerves.
Pathology. The peripheral nerves in acute Guillain–Barré syndrome often show inflammatory cell infiltrate, with associated areas of demyelination, resembling experimental allergic neuritis. This inflammatory infiltrate is mainly perivascular and comprised of lymphocytes and macrophages. Electron microscopy shows that macrophages cause the myelin damage, and penetrate the basement membrane around nerve fibres before stripping myelin sheaths off axons. Spinal nerve roots may be particularly affected, but changes are found at all levels of the peripheral nervous system. Teased peripheral sensory nerve fibre preparations may show marked segmental demyelination (Fig. 21.15). Some Wallerian degeneration may occur. Biopsy of the sural nerve may show surprisingly few abnormalities in comparison to the marked clinical severity of the neuropathy; this may reflect the distal and purely sensory nature of the sural nerve. Sensory nerve biopsy is generally unhelpful in establishing the diagnosis of Guillain–Barré syndrome; more typical demyelinative changes being present in motor nerves, which are not amenable to routine biopsy. Clinical criteria, spinal fluid protein elevation, and nerve conduction abnormalities remain the mainstay of diagnosis.
Occasional patients display motor–sensory axonal, rather than demyelinating, forms of Guillain–Barré syndrome. Opinion has been divided as to whether this represented secondary axonal degeneration induced by severe oedematous swelling of nerve roots, or whether it represented a primary attack on axonal antigens; evidence tends to support the latter (Lu et al. 2000). Characteristically, these patients have electrically inexcitable motor nerves early in their illness, electromyographic evidence of denervation within 2–5 weeks, marked muscle wasting, and protracted weakness with a generally poor recovery.
The neurological illness is preceded by symptoms of respiratory tract infection in approximately 40 per cent and gastrointestinal infection in less than 20 per cent in an English series; 8 per cent had undergone an operation in the preceding 3 months (Winer et al. 1988b). Neurological symptoms first develop 1–4 weeks after this infection. The Guillain–Barré syndrome produces a relatively symmetrical areflexic tetraparesis; the essential diagnostic criteria consist of progressive motor weakness of more than one limb, coupled with areflexia. Although sensory symptoms usually occur first, it is profound muscle weakness which is the main clinical feature in most patients once the disease is established.
Sensory features. In three-quarters of patients, the first neurological symptom is of paraesthesiae in the toes, less often in the fingers. Simultaneously, or soon afterwards, patients develop progressive limb weakness, often first noted as difficulty in walking. Despite the sensory nature of the initial symptoms, it is unusual for the eventual sensory loss to be particularly severe when compared to the profound motor loss. When sensory signs are present, they usually consist of impaired vibration and joint-position sensations. Half the patients experience pain which may be present from the outset and severe. It is generally maximal in the back and buttocks and may require short-term opiate analgesia. It usually resolves as recovery starts.
Motor features. Muscle weakness usually starts in the legs and ascends to the arms. Proximal muscle weakness may be prominent from the outset. The weakness is fairly symmetrical and usually involves the trunk musculature. It is unusual for the arms to be more severely weakened than the legs. Maximal weakness generally develops within 12–14 days of the onset of neurological symptoms. Although cessation of symptom progression within 4 weeks is often regarded as a necessary criterion for the diagnosis of Guillain–Barré syndrome, it is clear that in a small proportion of patients symptoms and signs continue to increase for up to 6 weeks from the onset. At the height of the disease, the majority of the patients are bed-bound and many of these have complete paralysis of all four limbs. Only 12 per cent remain able to walk throughout the illness. Those patients who become bed-bound and ventilator-dependent within 5 days tend to have the most prolonged disability and may develop severe permanent weakness. Significant sphincter dysfunction does not occur in Guillain–Barré syndrome, although urinary retention may result from abdominal wall weakness, particularly in patients with pre-existing urinary outflow tract obstruction.
Reflexes. Tendon reflexes are usually lost early in the disease. Total areflexia occurs in over 80 per cent of patients at some stage of the illness. The remainder usually lose their ankle jerks in isolation. Occasionally the tendon reflexes are preserved throughout the illness.
Cranial nerves. Approximately half the patients develop cranial-nerve palsies, usually in the wake of severe ascending limb weakness. Isolated unilateral or bilateral facial palsy is the commonest cranial-nerve lesion in Guillain–Barré syndrome. If weakness of the face is out of proportion to that of the limbs, Bannwarth’s syndrome or Lyme disease (Section 21.14.3) should be considered, especially if the spinal fluid cell count is raised. Bulbar palsy and weakness of the muscles of mastication are the next commonest cranial-nerve abnormalities. With bulbar weakness there is a considerable risk of aspiration leading to acute respiratory failure or pneumonia, and endotracheal intubation should be performed if this seems likely to occur. Ocular palsy only occurs in about 10 per cent of patients, usually following severe limb and respiratory muscle weakness.
Breathing. Respiratory failure of sufficient severity to require assisted ventilation occurs in one-quarter of patients, although milder degrees of respiratory muscle involvement are much commoner. Patients with imminent respiratory failure may complain of orthopnoea and may be unable to complete more than a brief phrase of speech before pausing for breath. All patients with the evolving Guillain–Barré syndrome need to have their vital capacity and diaphragmatic movements assessed regularly so as to predict their requirement for assisted ventilation before a respiratory crisis occurs. Usually ventilation needs to be considered when the vital capacity falls below 1l in adults with otherwise normal lungs.
Autonomic dysfunction. This is common in the Guillain–Barré syndrome occurring in over 60 per cent (Zochodne et al. 1987). It contributes to the cardiac arrhythmias which are a leading cause of death, particularly in elderly patients. The presence of autonomic neuropathy cannot be predicted from the severity of the motor and sensory nerve abnormalities. Autonomic dysfunction may manifest either as excessive or as inadequate activity of the sympathetic or parasympathetic nervous systems. Wide fluctuations in blood pressure and heart rate, episodes of facial flushing, pupil abnormalities, patchy anhidrosis, paralytic ileus, or urinary retention may occur. Paroxysmal episodes of increased autonomic activity, causing hypertension, tachycardia, or facial flushing, are associated with a poor prognosis. They can be antecedents of sudden cardiac death in the Guillain–Barré syndrome. The pathophysiological basis of these varied autonomic manifestations is not known, but lymphocytic infiltrations of autonomic ganglia have been described.
Other neurological abnormalities. These occur occasionally in Guillain–Barré syndrome. Papilloedema occasionally develops. If so, it is sometimes associated with headache and raised spinal fluid pressure and tends to occur after a delay of some weeks. In some patients, it may reflect altered spinal fluid hydrodynamics resulting from the high protein content. However, other mechanisms must also be considered, since cases of papilloedema have been documented with normal spinal fluid protein levels. Optic neuritis and pyramidal tract signs are other rare manifestations which may point to a mild associated acute disseminated encephalomyelitis.
Relapsing forms. Recurrent Guillain–Barré syndrome occurs in up to 3 per cent, often after an interval of many years. The separate episodes may each be precipitated by new infections, such as recurrent cytomegalovirus exposure or two different infections such as respiratory syncytial virus and C. jejuni, or booster vaccinations with tetanus toxoid. Up to six separate episodes have been recorded, each in itself typical of Guillain–Barré syndrome. Relapsing Guillain–Barré syndrome can be distinguished from relapsing forms of chronic idiopathic demyelinating polyneuropathy by the rapidity of onset, the marked degree of recovery, normal CSF protein at the onset of an attack, the high incidence of preceding infections, and the lack of response to immunosuppressant drugs. The distinction from forms of chronic idiopathic demyelinating neuropathy of acute onset is particularly difficult, with late or multiple deteriorations being the chief distinguishing feature favouring the latter diagnosis (Ruts et al. 2005).
Regional variants. Some patients present without the ascending evolution of areflexic tetraparesis so typical of Guillain–Barré syndrome. However, their time course of deterioration and recovery, acellular spinal fluid with raised protein, and electrophysiological evidence of demyelination, coupled with some otherwise typical clinical features, make these likely to be regional variants of Guillain–Barré syndrome. Those which are recognized include: bifacial paresis, lateral rectus paresis plus paraesthesiae plus hyporeflexia, areflexic paraparesis, pharyngeal–cervical–brachial weakness, and Miller–Fisher syndrome coupled with weakness of bulbar or arm muscles (Ropper 1994). Isolated arm weakness may occur, either as a motor–sensory demyelination or as pure motor axonal involvement with anti-GM1 antibodies. No treatment trials have been undertaken for these rare variants, and it seems wise to treat them according to principles established for Guillain–Barré syndrome.
CSF. In 80 per cent of cases the spinal fluid characteristically shows ‘dissociation albumino-cytologique’ in which the protein content is elevated, often exceeding 2 g/l, with a normal cell count. Normal spinal fluid protein concentration is commonest when the spinal tap is performed during the first few days of neurological symptoms. This limits the diagnostic value of lumbar puncture in early cases. About 10 per cent of patients have a lymphocytic spinal fluid, which should raise consideration of Lyme disease or HIV infection. Some patients develop a reduced serum sodium, possibly due to resetting of osmoreceptor responses.
Nerve conduction studies. These studies can be surprisingly normal early in the Guillain–Barré syndrome, despite severe paralysis. This reflects the purely radicular location of early demyelination or conduction block in many patients; conventional conduction studies merely measure motor conduction over the distal segments of peripheral nerves. Sometimes many peripheral nerves must be studied before diagnostic abnormalities are detected. Within the first 2 weeks, the commonest findings are of mildly prolonged distal motor latencies and of conduction block in which the amplitude of the compound muscle action potential progressively diminishes with more proximal sites of nerve stimulation. ‘F’-waves may be absent or prolonged. As the disease progresses, the sensory nerve action potentials are usually lost, and motor slowing may become more evident distally. Permanent disability is predicted by electrical inexcitability of nerves early on and tends to be associated with electrophysiological evidence of axonal degeneration.
The Guillain–Barré syndrome usually presents a distinctive clinical picture. The potential range of differential diagnosis of acutely evolving paralysis is enormous: spinal cord disease; neuromuscular transmission disorders; myopathy; vasculitic neuropathy; porphyria; malignant meningitis; infective neuropathies such as Diphtheria, Borreliosis, or Poliomyelitis; biological toxins such as tick paralysis or Botulism; drug and chemical toxins; metabolic abnormalities; critical illness polyneuropathy; and psychologically determined weakness (Ropper et al. 1991).
Acute spinal-cord lesions pose the commonest diagnostic difficulty and spinal MRI need to be undertaken in cases of doubt. However, the distinction is usually simple because of the extensor plantar responses, sensory level, prominent sphincter involvement, and the cellular spinal fluid encountered in acute ascending or transverse myelitis. It is rare for acute inflammatory myopathies to be confused with the Guillain–Barré syndrome. Pointers to primary muscle disease include the absence of sensory symptoms, preserved reflexes, normal spinal fluid protein, abnormal electromyogram, and raised serum creatine kinase levels.
Three rare acute neuropathies should be distinguished from the Guillain–Barré syndrome because they require different approaches to therapy. Borrelia infection causing Lyme disease or Bannwarth’s syndrome (Section 21.14.3) is suggested by prominent unilateral or bilateral facial paralysis, radicular pain, and a cellular CSF. Porphyric polyneuropathy (Section 21.8.6) is associated with early neuropsychiatric abnormalities, abdominal pain, a purely motor syndrome, and preservation of the ankle jerks despite loss of the knee jerks. Diphtheritic polyneuropathy (Section 21.14.4) is now rare in Western countries, although resurgent in Eastern Europe, and should be considered in patients with descending demyelinating polyneuritis starting as bulbar palsy.
Survival in the Guillain–Barré syndrome depends primarily upon meticulous attention to intensive care during the acute paralytic phase (Section 2.8) (Hughes et al. 2005). Feeding by naso-gastric tube should be instituted in those with bulbar dysfunction. Subcutaneous heparin and elastic stockings provide prophylaxis against deep venous thrombosis and pulmonary embolism. Vigilant electrocardiographic monitoring allows prompt recognition and treatment of cardiac arrhythmias which may be provoked by endotracheal suctioning or suxamethonium administration. Beta-blockers may be required for those with hypertensive crises. Patients with Guillain–Barré syndrome are particularly susceptible to hypotensive side effects of drugs, including thiopentone, frusemide, and morphine. Nursing care will prevent decubitus ulcers. Regular physiotherapy, and careful limb positioning will prevent muscle contractions in patients with prolonged paralysis. The gastrocnemius and soleus muscles are particularly prone to such contractures, which may lead to permanent walking disability even if muscle power returns.
Ventilation. Patients likely to deteriorate to the point of needing assisted ventilation should be alerted to this probability beforehand, whilst they can still ask questions, in a manner of calm planning. Endotracheal intubation and ventilation should be instituted without delay either if respiratory muscle failure is imminent or if paralysis of bulbar and laryngeal muscles places the patient at risk of choking. Assisted ventilation is usually required when the vital capacity has fallen to 15 ml/kg body weight; that is a vital capacity of approximately 1l for a 65 kg adult. Nasal endotracheal tubes are well tolerated by conscious patients and should be replaced by temporary tracheostomy if, as is usually the case, the period of ventilation is likely to exceed 1 week. Pulmonary atelectasis and infection are common in intubated patients and should be treated promptly with antibiotics and physiotherapy.
Steroids. Neither oral steroids nor intravenous high-dose steroids have a place in treating the Guillain–Barré syndrome (Guillain–Barré syndrome steroid trial group 1993). Addition of a 5-day course of 500 mg intravenous methylpredinisolone to standard IvIg therapy does not improve 4-week outcome (van Koningsveld et al. 2004).
Plasma exchange (Section 21.3.3). This shortens the time taken for patients with Guillain–Barré syndrome to start to improve, to regain functional abilities such as walking, and reduces their requirement for assisted ventilation (Winer 2002). Plasma exchange enables the median patient to walk independently at 53 days compared to 85 days for controls, and allows 82 per cent to walk independently at 6 months compared to 71 per cent of controls. It is unclear whether plasma exchange improves survival or reduces the number of patients unable to walk at 1 year. Subgroup analysis suggests that those patients with acute motor axonal forms associated with diarrhoea and Campylobacter infection have a better outcome following IvIg than plasma exchange (Visser et al. 1999). To be maximally effective, plasma exchange needs to be started within the first week of neurological symptoms. It is unlikely to be effective if given after 2 weeks of neurological symptoms. Plasma exchange is recommended for those patients approaching inability to walk or with impairment of bulbar or respiratory function. Plasma-exchange schedules vary, but four or five 4-l exchanges using a continuous-flow technique, given on sequential days, are recommended. The plasma may be replaced by either albumin or fresh frozen plasma; the risk of non-A, non-B hepatitis being greater with the latter. About 10 per cent of patients treated by plasma exchange will subsequently undergo a mild relapse between 5 and 42 days later, which may be treated by a further course of plasma exchange. The factors determining poor outcome, such as advanced age or low compound muscle action potential amplitudes, appear to be the same for those receiving plasma exchange as for those receiving conservative therapy.
Intravenous immunoglobulin, IvIg, (Section 21.3.3). This treatment, given at 0.4 g/kg body weight/day for 5 days is at least equally effective to plasma exchange (Plasma exchange/Sandoglobulin Guillain–Barré syndrome trial group 1997). IvIg has become the treatment of choice because it is immediately available, does not require cannulation of a major vessel, has fewer side effects than plasma exchange, and does not carry the same risks of exacerbating circulatory disturbances due to autonomic neuropathy. Also IvIg may be more effective than plasma exchange for the motor axonal subgroup resulting from diarrhoeal Campylobacter infections (Visser et al. 1999). There is concern that the easy availability of IvIg in district general hospitals may lead to Guillain–Barré syndrome being treated in intensive care units lacking expertise in the disease, with resultant increased death due to complications. As with plasma exchange, IvIg-treated patients may secondarily deteriorate within 2 weeks of treatment. It is unclear whether this simply reflects the natural history of underlying Guillain–Barré syndrome only temporarily modified by IvIg, or some specific IvIg effect, or indeed whether secondary deterioration is an indication for a second course of IvIg. Large scale trials of IvIg or plasma exchange have not been undertaken in children, but it seems logical to expect similar benefits to those seen in adults, with IvIg being preferable to plasma exchange, particularly given the problem of vascular access in small children.
Choice of immunotherapy. Plasma exchange and IvIg are equally effective. There is no additional benefit from combining the two or from giving plasma exchange and IvIg in sequence. Steroids have no place (Hughes et al. 2003). IvIg is the treatment of choice, particularly if it can be administered within 2 weeks of the first neurological symptoms. There is no evidence that plasma exchange or IvIg are at all effective if given more than 4 weeks after onset of neurological symptoms. Common sense suggests that the optimal benefit is to be gained by starting immunotherapy while the patient is still ambulant, although evidence for this is only available for plasma exchange.
Most patients with the Guillain–Barré syndrome will make a good spontaneous recovery if they receive competent supportive treatment. Even when general intensive care facilities are available, up to 10 per cent of patients may die in the acute phase of the disease. These patients are usually elderly and generally succumb to cardiac disease, pulmonary embolism, chest infection, or complications of intensive care or invasive procedures (Chio et al. 2003). The mortality is 4–5 per cent even for patients treated in specialist neurological units with plasma exchange or IvIg (Plasma Exchange/Sandoglobulin Guillain–Barré syndrome Trial Group 1997). Of the survivors, half make a full recovery but the others show some permanent residual symptoms and signs, usually weakness of distal leg muscles, absent ankle jerks, or distal sensory loss (Dornonville de la Cour and Jakobsen 2005). Even after IvIg or plasma exchange therapy, 16.5 per cent are unable to walk at 48 weeks (Plasma Exchange/Sandoglobulin Guillain–Barré syndrome Trial Group 1997). The factors predictive of poor outcome with slow recovery or permanent disability, include age over 60 years, a preceding diarrhoeal illness, development of severe paralysis within 5 days of the onset, respiratory failure requiring ventilation, and mean distal compound muscle action potentials of less than 20 per cent of normal.
21.10.2 Acute motor axonal neuropathy
Acute motor axonal neuropathy is a distinct subtype of Guillain–Barré syndrome which involves axonal degeneration or conduction block (Capasso et al. 2003) affecting motor fibres alone rather than the usual demyelination of both sensory and motor fibres. It was originally recognized in large summer epidemics in China, but is known to occur sporadically worldwide (Hafer-Macko et al. 1996). When compared to others with Guillain–Barré syndrome, acute motor axonal neuropathy patients have purely motor symptoms and signs, are more likely to have a more rapid evolution of limb weakness, plateau on average at 6 days compared to 9, have predominantly distal weakness, and are less likely to have cranial nerve involvement (Visser et al. 1996; Hiraga et al. 2003). Neurophysiology does not show the usual degree of motor slowing and prolongation of distal motor latencies, sensory nerve action potentials are generally preserved, motor nerves may be inexcitable, and electromyography often shows acute denervation changes. The differential diagnosis is similar to Guillain–Barré syndrome (Section 21.10.1) with particular consideration of poliomyelitis where that is still endemic. Subgroup analysis points to a better 6 months outcome if acute motor axonal neuropathy is treated with IvIg rather than plasma exchange (Visser et al. 1996 ; 1999). Acute motor axonal neuropathy is more likely to be associated with long-term or permanent disability. However many patients make substantial improvement in the early weeks after IvIg suggesting that reversible conduction block, rather than axonal degeneration, underlies much of the disability.
The pathogenesis of acute motor axonal neuropathy is of considerable interest given its clear association with preceding diarrhoeal illness caused by Campylobacter jejuni and the frequent development of anti-GMI gangliosides antibodies (Visser et al. 1996). Acute motor axonal neuropathy is particularly likely after infection with the Penner HS19 serotype of C. jejuni; Campylobacter lipopolysaccharides having ganglioside-like moieties raising the likelihood of antibodies cross-reacting with nerve (Koga et al. 2005; Kimoto et al. 2006). It is unknown whether some host susceptibility factor determines whether a Campylobacter-infected patient goes on to develop acute motor axonal neuropathy. This immunopathogenic mechanism is supported by demonstration of IgG and complement deposits on the axolemma at the nodes of Ranvier of motor fibres in fatal cases (Hafer-Macko et al. 1996).
21.10.3 Acute sensory neuropathy
Occasional patients with acute polyneuritis show profound limb sensory loss without weakness, particularly affecting joint, position, and vibration sensation, and with severe ataxia (Oh et al. 2001). Despite the lack of weakness, slowing of motor nerve conduction is usually demonstrable electrophysiologically. A high serum titre of anti-GD1b ganglioside antibody may be present (Pan et al. 2001). Patients show the same monophasic time course as for Guillain–Barré syndrome, and the same approach to treatment should be followed. Autopsies in such patients show lymphocytic infiltration and demyelination in the dorsal roots and sensory peripheral nerves.
This rare sensory form of polyneuritis should be distinguished from acute sensory neuronopathy, in which the limb sensory loss affects all modalities and often starts asymmetrically in the upper limbs, extends on to the trunk and face, there is no motor loss, recovery is unusual, and the pathology primarily involves loss of dorsal root ganglion neurones with lymphocytic infiltration (Hainfellner et al. 1996).
Rarely patients present acutely with symptoms of autonomic neuropathy. Their symptoms are varied and reflect failure of the sympathetic and parasympathetic systems: postural hypotension, blurred vision, ptosis, pupillary abnormalities, dry mouth and eyes, anhidrosis, erectile failure, and constipation. Some patients may have varying degrees of associated thermal and pain sensation disturbances in the limbs. Spontaneous neuropathic pain may be prominent. Peripheral neuropathy may not be suspected initially because the sparing of larger myelinated fibres results in preserved tendon reflexes and normal sensory nerve action potentials (Suarez et al. 1994). Spontaneous recovery is the rule but is often incomplete. Prompt response to IvIg has been recorded (Mericle and Triggs 1997).
Within this diagnostic group are occasional patients with acute or subacute onset of a pure autonomic syndrome, without a sensory disturbance. Such patients not only have orthostatic hypotension, but may also show prominent cholinergic dysautonomia, reflected by dry eyes and mouth, abnormal pupil-light responses, upper gastrointestinal symptoms, and neurogenic bladder. These patients often have high levels of antibody to the ganglionic acetylcholine receptor of the α3 nicotinic type present in autonomic ganglia (Klein et al. 2003; Sandroni et al. 2004). It seems reasonable to consider early immunomodulatory therapy for such patients. Subacute presentations of this pure autonomic disorder can be paraneoplastic.
21.10.5 Miller Fisher syndrome
This distinctive syndrome comprises total external ophthalmoplegia, severe ataxia, and generalized tendon areflexia which all develop over a few days (Fisher 1956). The spinal fluid protein is elevated and patients recover over a matter of weeks. Some patients have combined features of Guillain–Barré and Miller Fisher syndromes in which the oculomotor disturbance and limb weakness occur within a few days of one another. Serial neurophysiological studies have shown evidence of peripheral nerve involvement in the Miller Fisher syndrome, with prolonged peripheral conduction in the blink reflex arc and subsequent recovery of motor nerve and ‘F’-wave conduction velocities. The serum of over 90 per cent of patients contains antibodies against the GQ1b and GT1a gangliosides of both peripheral and central nervous systems (Willison and O’Hanlon 1999). Preceding infection with Campylobacter jejuni of the HS2 or HS4 serotypes is usual (Kimoto et al. 2006). The titre of this antibody tends to decline commensurate with clinical improvement. Some patients seem to respond promptly to either plasma exchange or intravenous immunoglobulin, but the overall impact of these treatments on eventual recovery is questioned (Mori et al. 2007).
There has been debate as to the existence of a central nervous system component to Miller Fisher syndrome. Indeed, some have considered the syndrome to be a form of brainstem encephalitis. Although brainstem encephalitis may present a similar clinical picture to the Miller Fisher syndrome, in addition it usually involves disturbed consciousness, extensor plantar responses, and MRI brain abnormalities, whilst tendon reflexes are preserved (Odaka et al. 2003). Some of these brainstem encephalitis patients have an axonal neuropathy too.
21.11 Chronic idiopathic polyneuropathies
21.11.1 The spectrum of disorders
Significant reversal of severe disability can be achieved with immunomodulatory treatment for many patients with this varied group of neuropathies. Although the sensorimotor demyelinating and axonal form is that most commonly encountered, the relative degrees of motor and sensory fibre involvement and the relative balance between demyelination, conduction block, and axonal degeneration, vary considerably in the different clinical subtypes. It is not known yet whether this reflects fundamentally different underlying pathogenic mechanisms, or whether the various clinical syndromes simply represent noteworthy peaks in a continuum. Clinical and electrophysiological distinction of these different syndromes is of practical importance because it influences the approach to treatment (Saperstein et al. 2001; Busby and Donaghy 2003). For instance steroids are usually highly effective in chronic inflammatory demyelinating sensorimotor polyneuropathy whereas they often cause deterioration, or at best are ineffective, in multifocal motor neuropathy with conduction block. As a general rule, intravenous immunoglobulin seems best effective when much of the disability is due to conduction block, whereas steroids and plasma exchange seem most effective when the disability is associated with histological demyelination as evidenced by slowed nerve conduction velocities.
21.11.2 Chronic inflammatory demyelinating polyneuropathy
This is a progressive, sometimes relapsing, steroid-dependent, demyelinating sensorimotor polyneuropathy primarily affecting the limbs. Usually it develops slowly, over months or years. Abrupt onset resembling Guillain–Barré syndrome can occur, yet with persistent symptoms (Mori et al. 2002). It is also known as chronic relapsing polyneuritis, chronic idiopathic demyelinating poly(radiculo)neuropathy, relapsing corticosteroid-dependent polyneuritis, or relapsing hypertrophic neuritis. Its recognition is of great importance because of the excellent response to immunomodulatory therapy in most patients.
Aetiology. The prevalence of chronic inflammatory demyelinating polyneuropathy increases with age from infancy to senescence with a mean of onset in the fifth decade. It is commoner in males. Accurate estimates of its incidence are not available, the overall prevalence is about 2 per 100 000, reaching 6.7/100 000 in the eighth decade in Australia (McLeod et al. 1999). Up to half the patients have a relapsing and remitting course, in which the initial deterioration can be rapid, resembling the Guillain–Barré syndrome. However, experience in Britain shows most patients to have stable or progressive neuropathy when one excludes fluctuation attributable to treatment changes. Unlike the Guillain–Barré syndrome, patients subsequently progress downhill over more than 2 months or undergo secondary deterioration some weeks after an initially satisfactory response to plasma exchange or intravenous immunoglobulin. The deterioration may be steady, or relapsing and remitting. In women, relapses are particularly associated with the third trimester of pregnancy or the immediate postpartum period. Up to a third of patients give a history of antecedent viral infection or vaccination. Serological evidence of previous cytomegalovirus infection is found in about half, although a directly causative relationship has not been established.
Various features point to an immunological mechanism for chronic inflammatory demyelinating polyneuropathy which might be considered as the chronic counterpart of Guillain–Barré syndrome. Nerve biopsies often show T-lymphocyte cell infiltrates, which may be slight, with early myelin stripping by macrophages. HLA antigen studies showed an increased frequency of the A3, B7, and DR2 antigens, and an association with specific GM haplotypes in a population of Australian patients (Feeney et al. 1990). An ubiquitous causative autoantibody has not been identified, although about 30 per cent have serum antibodies against myelin glycoprotein P0 which are capable of inducing conduction block and demyelination on injection into rat sciatic nerve (Yan et al. 2001). It remains unknown whether there are other target antigens in the other patients, or the extent to which cell-mediated immunity may be important.
Pathology. The histological features in sural nerve biopsies are often indistinguishable from those of the Guillain–Barré syndrome. Teased fibres show segmental demyelination and thinly remyelinated internodes. Inflammatory infiltrates may be found in the endoneurium. Axonal loss may particularly affect large myelinated fibre populations. This range of abnormalities overlaps with those seen in chronic idiopathic axonal polyneuropathy (Section 21.11.8), limiting the diagnostic specificity of nerve biopsy from that condition (Bosboom et al. 2001). Perivascular macrophage clustering may be a particular marker of chronic inflammatory demyelinating neuropathy (Sommer et al. 2005). Rarely nerve biopsies show hypertrophic ‘onion-bulb’ formations, raising difficulties in distinguishing chronic forms from Charcot–Marie–Tooth disease Type I (Section 21.4.4). Although sural nerve biopsy is frequently undertaken in suspected chronic inflammatory demyelinating neuropathy, it rarely adds diagnostic information in patients with a characteristic clinical and electrophysiological picture with raised spinal fluid protein.
Three-quarters of patients present with a mixed sensorimotor neuropathy which is relatively symmetrical. Less commonly asymmetrical, or predominantly motor or sensory forms are encountered. Paraesthesiae are a common early feature and may be uncomfortable. Loss of vibration and joint-position senses is usually demonstrable and Rombergism is a common early symptom. Limb weakness is generally distributed both proximally and distally. A predominantly distal subtype also occurs, often in older men and associated with IgM paraproteinaemia: distal acquired demyelinating symmetric polyneuropathy (Mygland and Monstad 2003). Usually, all the reflexes are lost. The rate of deterioration varies but progression over more than 8 weeks is a distinguishing criterion from the Guillain–Barré syndrome (McCombe et al. 1987b). The cranial nerves are affected in about 15 per cent of patients, usually to a mild degree. Dysphagia, dysarthria, weakness of facial or masticatory muscles, and diplopia are the commonest cranial nerve manifestations. Respiratory failure is rare (Henderson et al. 2005). Papilloedema occasionally occurs. A coarse irregular action tremor may occur, seemingly unrelated to the mild degrees of proprioceptive loss or weakness, and resembles that seen in patients with paraproteinaemic neuropathy. This may reflect mismatch of muscle spindle afferent information from agonist and antagonist muscles due to severely slowed peripheral nerve conduction (Busby et al. 2003). Limb muscle weakness or sensory ataxia are the usual causes of significant disability.
Central nervous system involvement. Some patients with chronic inflammatory demyelinating polyneuropathy also have a clinical history of a relapsing multifocal central nervous system disorder. Cerebral magnetic resonance imaging may show periventricular plaques of demyelination, and evoked responses may be prolonged. Subclinical abnormalities of the central nervous system are present in a third to a half of patients. These findings pose questions of overlap with multiple sclerosis. They also raise the possibility that tremor in some patients with chronic inflammatory demyelinating polyneuropathy could be due to associated central nervous system involvement (Koller et al. 2005).
Nerve conduction studies. The mainstay of diagnosis is the demonstration of slowed motor nerve conduction, often with a degree of conduction block, in a patient with a chronically or subacutely progressive acquired peripheral neuropathy. Electrophysiological criteria have been proposed for the diagnosis of chronic inflammatory demyelinating polyneuropathy (Section 3.5.3): motor conduction velocities of less than 75 per cent of the lower limit of normal, distal motor latencies exceeding 130 per cent of the upper limit of normal, temporal dispersion, or conduction block following proximal stimulation and prolonged F-wave latencies. Sensory nerve action potentials are usually diminished or lost. Diagnostic difficulty may arise in patients, usually with early and mild disease, in whom the motor conduction velocity is insufficiently slow to be sure that the neuropathy is primarily demyelinating. In such patients, motor conduction velocities only just below the normal range are not uncommon.
CSF. This protein is elevated above 0.6 g/l in 50–85 per cent (Busby and Donaghy 2003).
This most frequently causes difficulty in the distinction of chronic inflammatory demyelinating polyneuropathy from Charcot–Marie–Tooth disease Type I (Section 21.4.4), particularly if molecular genetic tests have been negative for the latter. Pointers favouring chronic inflammatory demyelinating polyneuropathy are a subacute rate of deterioration, relapsing-remitting progression of motor weakness, positive sensory symptoms such as paraesthesiae, raised spinal fluid protein, absence of a family history, and the absence of onion-bulb formations in a sural nerve biopsy. Motor nerve conduction studies tend to show multifocal slowing, conduction block, and dispersion of the distal compound muscle action potential in chronic inflammatory demyelinating polyneuropathy. By contrast the slowing is more uniform, without focal block, in Charcot–Marie–Tooth disease Type I. Associated deafness and pigmentary retinopathy should raise the possibility of Refsum disease, a rarely encountered possibility confirmable by blood phytanic acid measurement (Section 21.8.1). The mitochondrial disorder MNGIE (Section 21.7.6) should be considered in younger patients unresponsive to immunomodulatory treatment.
MRI-proven hypertrophy of cervical roots, brachial plexus, or the cauda equina may be noted in chronic inflammatory demyelinating polyneuropathy and Guillain–Barré syndrome (Duggins et al. 1999). Sometimes such MRI findings raise the question of a diffuse nerve root infiltrative process, but the presence of electrophysiologically proven demyelinating polyneuropathy is strong evidence against that, and should forestall nerve root biopsy. Similar cauda equine hypertrophy with leg neurological deficits occurs rarely in the absence of peripheral nerve conduction abnormalities (Burton et al. 2002). Hypertrophied roots and nerves may be more vulnerable to compression by stenosis of the lumbar spinal canal, in root exit foramina, and at common entrapment sites.
Chronic inflammatory demyelinating polyneuropathy is not usually a paraneoplastic phenomenon except in the sense of its common association with paraproteinaemias (Section 21.12.1). One should be suspicious of an underlying lymphoma, carcinoma (Section 21.13.2), or Castleman’s disease (Section 21.12.3) in two circumstances. First when the neuropathy evolves relatively rapidly, and there are unusual features such as extensive cranial nerve involvement or neuropathic pain. Second when the patient relentlessly deteriorates despite immunosuppressant therapy.
A proven diagnosis of chronic inflammatory demyelinating polyneuropathy means there is an excellent chance of recovery with immunomodulation therapy. Without treatment, chronic inflammatory demyelinating polyneuropathy is eventually fatal in up to 10 per cent of patients (Bouchard et al. 1999). Untreated, many of the remainder suffer protracted and serious disability. The degree of associated axonal loss may determine the chance of a good recovery, and may be lessened by prompt and early treatment.
Occasionally immunomodulatory treatment must be started in severe weakness to prevent further decline before it is clear whether the patient has Guillain–Barré syndrome, which would plateau by 4 weeks, subacute inflammatory demyelinating polyneuropathy progressing for up to 8 weeks, or chronic inflammatory demyelinating polyneuropathy, which should progress beyond 8 weeks. Usually it is preferable to give such patients a course of intravenous immunoglobulin or plasma exchange, rather than start steroids, since a secondary deterioration when the treatment effect wears off at 6–10 weeks will indicate that the underlying neuropathy continues to evolve, thus requiring more definitive long-term immunosuppressant therapy. An unusual intermediate form called subacute inflammatory demyelinating neuropathy evolving over 4–8 weeks is described (Oh et al. 2003).
Oral steroids. This therapy is the mainstay of treatment and often produces noteworthy improvements within 3 weeks. The results of therapy can be dramatic; bed-bound patients may regain almost normal motor function. Unfortunately not all patients respond to steroid therapy. It is elderly patients, or those with a significant degree of axonal degeneration, who tend to respond less well. Prednisolone administration schedules vary. An initial daily dosage of 60 mg is recommended, falling to 45 mg daily after 2 weeks, and converting to 45 mg on alternate days over the next 2–3 months. Steroid therapy may need to be continued for years and protection against osteoporosis should be prescribed (Section 21.3.3). Patients frequently relapse within a few months of withdrawing prednisolone or after reducing below the usual maintenance dose of 15–30 mg on alternate days.
Other immunosuppressant drugs are sometimes useful. Azathioprine is often added as a steroid-sparing agent, although there is no controlled evidence that it is beneficial in this condition. Nonetheless remission does seem to be maintainable by Azathioprine in some patients, particularly young women, who may relapse some months after this drug is stopped. Cyclosporin A can induce improvement in some steroid-resistant patients (Hodgkinson et al. 1990). Interferon-α 2A is effective in some patients resistant to other immunomodulatory therapy (Gorson et al. 1998), but conversely the neuropathy has been reported to develop during treatment with interferons-α or -β and with tumour-necrosis-factor-α blockers (Koller et al. 2005; Richez et al. 2005). Anecdotal reports suggest responses to treatment-resistant chronic inflammatory demyelinating neuropathy to methotrexate or high dose cyclophosphamide (Brannagan et al. 2002; Fialho et al. 2006).
Plasma exchange (Section 21.3.3). This produces substantial improvement in 80 per cent of patients with either progressive or relapsing forms of chronic inflammatory demyelinating polyneuropathy (Hahn et al. 1996a). The neuropathy relapses some 4–10 weeks after a successful course of plasma exchange, and definitive long-term therapy should be commenced simultaneously unless repeated plasma exchange is envisaged.
Intravenous immunoglobulin, IvIg (Section 21.3.3). This produces significant improvement in about 65 per cent of chronic inflammatory demyelinating neuropathy patients (Hahn et al. 1996b). It can improve conduction block in peripheral nerves. The benefit of a 5-day course usually lasts 4–10 weeks, and the general indications are identical to plasma exchange. Because it is easier to administer, it provides a better option for maintenance therapy. It is similarly effective to oral prednisolone (Hughes et al. 2001).
Strategies. Strategies for immunomodulatory treatment vary in different clinical situations. Some patients have such mild forms of chronic inflammatory demyelinating polyneuropathy that the risks of treatment far outweigh the small benefits which could accrue. Usually a patient can be maintained on Prednisolone 15–30mg on alternate days, often in conjunction with Azathioprine. For inadequate responses, Immunoglobulin then plasma exchange should be tried, and in last resort Cyclosporin, Interferon-α 2A, Cyclophosphamide, or Methotrexate. Infantile and childhood chronic inflammatory demyelinating neuropathy responds to steroids or immunoglobulin. The elderly can be slow to begin what may be an ultimately useful response and plasma exchange or immunoglobulin should be considered with steroids from the outset. Withdrawal of immunomodulatory treatment is only likely to be a prolonged success in those unusual patients who fully remit, often children, adolescents, or young women; Azathioprine offers the chance of maintaining steroid-free remission once a good response has been obtained. Relapses on stopping or reducing therapy should be treated promptly since such patients seem to become less completely responsive due to accumulated axonal damage.
Given that steroids remain the mainstay of treatment in most patients, plasma exchange or IvIg are recommended in the following circumstances:
♦ those who fail to respond promptly or adequately to steroids;
♦ those in whom high initial steroid dosages pose contraindications, such as steroid-induced psychosis or brittle diabetes;
♦ to ‘kick-start’ an improvement in the elderly who are notoriously slow responders to steroids;
♦ if there is severe disability at the outset; and
♦ to reverse a relapse promptly so as to avoid the need for reinstituting very high steroid dosages.
Objective monitoring of therapy is important to judging its effectiveness (Section 21.3.2). Velocity of nerve conduction is of little help in monitoring the ongoing severity of any patient’s neuropathy. Quantifiable foci of conduction block can provide useful guidance. Ultimately it is the clinical assessment of reliable parameters such as walking speeds, stair-climbing ability, manipulatory tasks such as buttons, Rombergism, and ability to stand on tiptoe or hop, which provides the best index of whether any patient’s response to treatment is useful.
21.11.3 Multifocal motor neuropathy with conduction block
Many patients with multifocal motor neuropathies used to be diagnosed as suffering from benign forms of motor neurone disease solely affecting lower motor neurones. These patients may present at any age in adult life with symptoms that may have progressed slowly for 20 years or more.
Clinical picture. This varies immensely. Weakness is usually maximal distally, is often notably asymmetrical, and is more likely to start and predominate in the arms than the legs. In retrospect, often the first symptom has been inability to fully extend a single finger (Fig. 21.17), probably reflecting the onset of conduction block in a terminal branch of the posterior interosseous nerve (Slee et al. 2007). Muscle atrophy occurs with time. Occasionally a weakened muscle may be hypertrophied (Fig. 21.18). Myokymia or coarse fasciculations are observed sometimes in weakened muscles, and occasionally in remote muscles. Cranial nerve involvement can occur, affecting bulbar muscles, causing difficulty in differentiation from amyotrophic lateral sclerosis. Reflex loss is usually restricted to the affected muscles, although it can be more generalized. The critical physical sign pointing to conduction block is a muscle which is markedly weakened despite being unwasted.
Motor nerve conduction studies show varying combinations of multifocal motor conduction block, prolonged or absent F-waves, prolonged distal latencies, reduced motor nerve conduction velocities, or motor axonal loss with electromyographic evidence of denervation. The crucial electrodiagnostic feature is conduction block restricted to a nerve’s motor fibres, at a site not vulnerable to compression (Fig. 21.19); unfortunately this often occurs in electrophysiologically inaccessible segments of an affected nerve, such as proximally. Pathophysiologically, these sites of conduction block seem associated with either depolarization or hyperpolarization (Kiernan et al. 2002; Priori et al. 2005). Despite inability to demonstrate conduction block electrophysiologically, some patients with the clinical phenotype typical of multifocal motor neuropathy respond well to IvIg (Delmont et al. 2006; Slee et al. 2007). Redefinition of the criteria for electrophysiological diagnosis of conduction block improves the diagnostic inclusion of IvIg responsive patients: removal of exclusions based on over-restrictive temporal dispersion, and allowing as little as 32 per cent reduction in compound muscle action potential following proximal stimulation (Ghosh et al. 2005a).
Serum antibodies to GM-1 gangliosides are present in approximately a third of patients with multifocal motor neuropathy with conduction block (Slee et al. 2007). It remains to be established whether anti-GM1 plays a pathogenic role in multifocal motor neuropathy (Willison and Yuki 2002). Interestingly neonatal motor neuropathy has been observed in a newborn from an α-GM1antibody-positive mother with multifocal motor neuropathy (Attarian et al. 2004). It binds to nodes of Ranvier in peripheral nerves (Santoro et al. 1990). Focal deposition of immunoglobulins, and demyelination associated with inflammation, have been observed in the motor roots (Oh et al. 1995). The spinal fluid is usually normal. Focal hypertrophy of nerves is often demonstrable, particularly in the brachial plexus (Beekman et al. 2005).
Sensory function. Usually there are no sensory symptoms and sensory nerve conduction is normal. A few patients report focal paraesthesiae but it is rare to demonstrate underlying abnormal sensory signs. Despite the purely motor features, minor involvement of sensory nerve fibres has been noted on biopsy.
Treatment. Untreated, multifocal motor neuropathy usually deteriorates steadily or in a stepwise fashion over many years. Occasionally it evolves subacutely causing severe disability within months. Some patients may stabilize with extremely minor degrees of motor involvement. It is uncertain whether true spontaneous remissions occur. Steroid treatment should be avoided since it is ineffective and often causes substantial motor deterioration (Busby and Donaghy 2003). Cyclophosphamide is effective but is not advisable as first-line therapy because of the serious side effect profile (Section 21.3.3). It is best reserved for patients unresponsive to, or intolerant of, immunoglobulin, or in those rare instances where it is helpful as adjunctive therapy when the beneficial effect of immunoglobulin alone only lasts two or three weeks.
Intravenous immunoglobulin, IvIg, is the mainstay of treatment, often producing a clear clinical response within 36 h, usually maximal at 10–14 days, and wearing off at 6–12 weeks (Federico et al. 2000). The first treatment with immunoglobulin should be designed to determine whether the response sufficiently reverses disability to make regular treatment worthwhile; up to a third of patients show poor responses. Objective neurophysiological improvement in conduction block may occur with IvIg, more often showing improved temporal dispersion than changes in amplitude of compound muscle action potentials (Ghosh et al. 2005b). Self-infused home therapy at 2–3 weekly intervals is effective, time saving, and convenient, and it can be scheduled to avoid treatment-related fluctuations (Slee et al. 2007). The long-term benefits of IvIg are unknown and cases of continued downhill deterioration do occur (Van den Berg-Vos et al. 2002). However many patients continue responding well to IvIg for over a decade with little or no evidence of background deterioration of the disorder once a regular programme of maintenance therapy has been established which avoids the intermittent relapses which may allow axonal damage to accumulate. Interferon-β1a may be effective if IvIg or cyclophosphamide treatment have failed (Van den Berg-Vos et al. 2000a).
21.11.4 Pure motor demyelinating neuropathy
Occasionally patients are encountered with purely motor polyneuropathy which is symmetrical. Although this may involve arms more than legs, usually all four limbs are affected to a similar extent, particularly the distal muscles. The weakness lacks the asymmetry normally associated with multifocal motor neuropathy (Sabatelli et al. 2001; Busby and Donaghy 2003). It tends to present with deterioration over weeks to months rather than the very slow deterioration normally occurring in typical multifocal motor neuropathy with conduction block. Motor conduction studies show widespread slowing with variable degrees of conduction block. Anti-GM1 antibodies may be associated. The implications for choice of treatment underline the importance of differentiating pure motor demyelinating neuropathy from sensori-motor demyelinating neuropathy. Pure motor demyelinating neuropathy often deteriorates with steroids, whereas it responds well to intravenous immunoglobulin (Busby and Donaghy 2003). The likelihood of eventual remission is unknown, although natural remission can be observed after patients with young onset pass through adolescence. Even in patients with a similar clinical picture and anti-GM1 antibodies, where the electrophysiological picture reflects axonal degeneration rather than demyelination or conduction block, strength may improve over 6–24 weeks following cyclophosphamide and plasma exchange therapy (Pestronk et al. 1994).
21.11.5 Chronic ataxic polyneuropathy
The onset of chronic relapsing polyneuropathy can be preceded by ocular palsies occurring several weeks earlier (Donaghy and Earl 1985). These ocular palsies may be unilateral or bilateral, usually consisting of partial paralysis of ocular abduction. The polyneuropathy may be asymmetrical, markedly ataxic, worse in the arms, and include dysphagia. Nerve conduction studies may point to a primarily demyelinating disorder but the electrophysiological abnormality can be remarkably mild in relation to the clinical severity. Ataxic neuropathy and eye movement disorder is often associated with anti-GQ1B, -GD1B, -GD3, or –GT1B antibodies, IgM paraproteins, and cold agglutinins (Willison et al. 2001). Rombergism and pseudoathetosis (Fig. 21.16) are prominent and often outweigh the degree of demonstrable joint position sense loss. Paraesthesiae are a less common symptom than ataxia. This syndrome has become known by the acronym CANOMAD, Chronic Ataxic Neuropathy with Ophthalmoplegia, M-proteins, cold Agglutinins, and anti-Disialated ganglioside antibodies. Many patients do not exhibit the full syndrome at presentation, although many or all of the missing features appear with time; however the anti-GQ1B antibody seems a reliable early marker. The eye movement disorder can be only intermittently symptomatic and manifest well after the initial neuropathic manifestations. Experience with immunomodulatory treatment shows that steroids are usually ineffective or may provoke deterioration whereas IvIg generally produces a response which is well maintained with long-term maintenance infusions (Busby and Donaghy 2003).
Chronic ataxia may be due occasionally to a purely sensory form of chronic inflammatory demyelinating polyneuropathy affecting large myelinated kinaesthetic fibres. Patients present with limb ataxia, and sometimes numbness or pain, and are found to have profound loss of proprioceptive sensation which may even affect proximal joints. Muscle strength is normal and there is generalized areflexia. Despite this, motor nerve conduction is often slowed. Sensory nerve action potentials are absent. Demyelination may be present on sural nerve biopsy. The spinal fluid protein can be raised. The condition usually deteriorates progressively over months or years. Improvement may follow a trial of immunomodulatory therapy, including intravenous immunoglobulin (van Dijk et al. 1996).
Differential diagnosis of chronic sensory neuropathy. Chronic idiopathic neuropathy with purely sensory symptoms presents a difficult differential diagnostic problem. If associated with an eye movement disorder and anti-GQ1B antibodies, the CANOMAD syndrome will be obvious. A syndrome of sensory ataxia with enlarged nerve roots on MRI, normal nerve conduction studies, somatosensory evoked potential abnormalities, and elevated CSF protein may respond to IvIg or steroids (Sinnreich et al. 2004). Paraneoplastic sensory neuropathy (Section 21.13.1) will be associated with small cell lung cancer or ovarian cancer, usually with subacute progression, involvement of all sensory fibre types, anti-Hu, antineuronal antibodies a mildly lymphocytic CSF, or other associated features of encephalomyelitis (Griffin et al. 1990; Graus et al. 1994). The sensory ganglionitis associated with Sjogren’s syndrome (Section 21.18.10) may or may not have clear-cut symptoms of dry eyes and mouth, usually occurs in women, ataxia due to large fibre loss predominates, and there may be autonomic symptoms including Adie’s pupil. An associated trigeminal neuropathy can occur, antinuclear antibody may be present, and the CSF is normal (Griffin et al. 1990; Sobue et al. 1993). A similar neurological picture may occur either acutely or chronically without Sjogren’s syndrome (Griffin et al. 1990). Vitamin E deficiency (Section 21.22.5) can also produce a sensory ataxic neuropathy. Purely sensory presentations of chronic idiopathic axonal polyneuropathy (Section 21.11.8) also occur, usually in late adulthood, often with troublesome pain (Wolfe et al. 1999).
21.11.6 Multifocal motor and sensory neuropathy
Also known by the acronym MADSAMN, this rare condition is also referred to as multifocal motor and sensory demyelinating neuropathy or the Lewis–Sumner syndrome. Patients are usually middle aged with motor and sensory loss multifocally distributed and often predominantly in the arm (Van den Berg-Vos et al. 2000b; Busby and Donaghy 2003). It may resemble multifocal motor neuropathy (Section 21.11.3) except with prominent additional sensory involvement. Neurophysiologically there is evidence of multifocal conduction block and demyelination, and inflammatory demyelinating changes in biopsied nerves (Oh et al. 2005). Patients are usually either unresponsive to, or deteriorate, with steroids, whereas IvIg is effective much as for multifocal motor neuropathy.
21.11.7 Chronic autonomic neuropathy
Autonomic failure of gradual onset and slow progression is also termed pure autonomic failure, or idiopathic orthostatic hypotension. Such chronic autonomic neuropathies involve postural hypotension and erectile failure; altered control of micturition or sweating are common too. Such patients segregate into two groups (Klein et al. 2003). One involves high titres of antibodies to the ganglionic acetyl-choline-receptor. Associated cholinergic features of dry eyes and mouth, pupil abnormalities, neurogenic bladder, and gastrointestinal dysfunction. It represents the chronic counterpart of acute autonomic neuropathy (Section 21.10.4) and can be paraneoplastic. These patients may respond to immunomodulation. The second group are less well defined, but have low antibody titres with few symptoms of cholinergic failure. Their idiopathic autonomic failure resembles that seen in association with Parkinson’s disease or multiple system atrophy, with prominent postural hypotension, often preceded by shoulder pain in a coat hanger distribution.
Presentation of hypotension in infancy, often coupled with hypotonia, hypothermia, and hypoglycaemia, and worsening during childhood and adolescence, should raise the possibility of dopamine-beta-hydroxylase deficiency. This very rare autosomal recessive disorder improves, with normalization of the low plasma noradrenaline levels, after administration of L-threodihydroxyphenyl serine, a precursor of noradrenaline (Senard and Rouet 2006).
21.11.8 Chronic idiopathic axonal polyneuropathy
This disorder usually starts in the sixth decade of life with clinical evidence of a mild sensorimotor, or less often a purely sensory, polyneuropathy, worse in the legs. It is a common polyneuropathy. All modalities of sensation may be impaired but paraesthesiae are uncommon. Neurophysiological and nerve biopsy studies point to axonal degeneration. Progression is slow, and eventual severe disability is rare. By definition an underlying cause is not discovered; a similar disorder in patients with paraproteinaemia tends to produce more severe arm involvement and worse disability (Notermans and Wokke 1996). Type 2 Charcot–Marie–Tooth disease (Section 21.4.5) can usually be differentiated by the positive family history, the predominance of motor involvement, the earlier age of onset, and the likelihood of pes cavus (Teunissen et al. 1997). The relationship to painful chronic cryptogenic sensory neuropathy with prominent pain (Wolfe et al. 1999) or to the painful burning foot syndrome (Periquet et al. 1999) is unclear. If abnormalities are limited to the legs, the potentially treatable lumbar canal stenosis syndrome should be sought by MRI. By definition, no cause can be found, although abnormal glucose tolerance tests are twice as common as in controls (Hughes et al. 2004; Hoffman-Snyder et al. 2006). There is no curative treatment for chronic idiopathic axonal polyneuropathy. A chronic relapsing axonal polyneuropathy with unusually severe motor involvement has responded promptly to intravenous immunoglobulin, presumably by reversal of widespread conduction failure (Katirji 1997) but this is not a likelihood in the majority of patients. Rapidly progressive axonal polyneuropathy, usually with subtle multifocal features, can occur occasionally in vasculitis (Section 21.15) (Vrancken et al. 2004).
21.12 Neuropathies associated with lymphoproliferative disorders
21.12.1 Benign paraproteinaemia
An increased incidence of peripheral neuropathy occurs in patients found to have monoclonal paraproteins on serum electrophoresis. Such paraproteins only have an incidence of 0.1 per cent in the third decade of life, rising to 3 per cent in the eighth decade, yet they are found in 10 per cent of patients with idiopathic peripheral neuropathy (Latov 1995). An underlying haematological malignancy is detected in about 8 per cent, and subsequent malignant transformation occurs at less than 3/100 patient years (Eurelings et al. 2005). Diverse neuropathies are encountered. Only a proportion of paraproteinaemic proteins are likely to be directly causative of neuropathy. Thus in many cases the paraprotein is merely a coincidental finding and a trial of treatment should be considered along the usual lines for the idiopathic equivalent of that particular type of neuropathy (Busby and Donaghy 2003). A wide variety of peripheral neuropathies are encountered, mostly demyelinating. Amyloid neuropathy (Section 21.9.2) may result from immunoglobulin light-chain deposition in patients with paraproteinaemia. Vasculitic neuropathy (Section 21.15) is occasionally associated with cryoglobulins containing monoclonal rheumatoid factors.
Chronic inflammatory demyelinating polyneuropathy types. Demyelinating neuropathies indistinguishable from idiopathic chronic inflammatory demyelinating polyneuropathy are usually associated with IgG or IgA paraproteins and may respond well to immunosuppressant drugs, plasma exchange, or intravenous immunoglobulin. As a group, these paraprotein-associated chronic inflammatory demyelinating polyneuropathy-like neuropathies are more likely to progress slowly, cause less severe disability, and have prominent sensory involvement than idiopathic chronic inflammatory demyelating polyneuropathy (Simmons et al. 1995). Paraproteinaemia or other lymphoproliferative disorders can develop, or at least become evident, after the initial diagnosis of chronic demyelinating polyneuropathy. Slowly progressive demyelinating polyneuropathy occurs in about 5 per cent of patients with Waldenström’s macroglobulinaemia, a disorder characterized by IgM hyperglobulinaemia, hyperviscosity, lymphadenopathy, hepatosplenomegaly, and lymphocytic infiltration of the bone marrow, and may antedate the systemic illness by some years.
Anti-myelin-associated glycoprotein activity. Some chronic sensorimotor demyelinating neuropathies are associated with IgM paraproteins possessing anti-myelin-associated glycoprotein, MAG, activity. Such patients usually develop sensory signs before motor, all go on to develop arm tremor and ataxia and usually stabilize at 2–5 years (Smith 1994). Nerve biopsies from such patients may show characteristic widely spaced myelin lamellae; similar morphological changes occurring in after passive transfer of the IgM paraprotein. Skin nerves show IgM on myelinated fibres, especially distally (Lombardi et al. 2005). The IgM paraproteins fix complement at the sites of separation of myelin lamellae. IgM paraproteinaemic demyelinating polyneuropathy with anti-MAG antibodies may show an unusually distal pattern of weakness (Katz et al. 2000). Unlike chronic inflammatory demyelinating polyneuropathy, such neuropathies normally respond poorly over the longer term to immunomodulation.
Anti-ganglioside activity. Purely motor neuropathies, often multifocal with conduction block, can be associated with paraproteins showing antibody activity against GM1 and GD1b gangliosides (Section 21.11.3). Predominantly sensory neuropathies due to combined axonal degeneration and demyelination are associated with paraproteins with antisulphatide activity (Ponsford et al. 2000). Chronic ataxic neuropathies associated with anti-GQ1B antibodies and intermittent ophthalmoplegia are often also associated with IgM paraproteinaemia, the CANOMAD syndrome (Section 21.11.5).
Anti-chondroitin sulphate activity. Predominantly sensory axonal degeneration neuropathy occasionally occurs in patients with IgM-k or IgM-λ paraproteins recognizing chondroitin sulphate. The first symptoms are usually peripheral numbness, paraesthesiae, or pain. Abnormalities of all modalities of sensation may be demonstrable. In some patients the disorder is associated with the skin condition, epidermolysis. In others there may be nerve thickening with features of focal entrapment neuropathy.
Treatment. The treatment of paraproteinaemic polyneuropathies can be difficult and relatively ineffective compared to idiopathic demyelinating neuropathies. Initially steroids, and plasma exchange or immunoglobulin, should be tried along the lines outlined for chronic inflammatory demyelinating polyneuropathy (Section 21.11.2). If this is insufficiently effective, the first decision concerns whether the patient has a sufficient degree of disability to warrant use of potentially dangerous chemotherapy. If so trials of the alkylating agents, cyclophosphamide or chlorambucil, fludarabine, cladribine, or Rituximab, can be considered.
21.12.2 Myelomatous neuropathy
Symptomatic neuropathies occur in about 5 per cent of patients with osteolytic multiple myeloma, although electrophysiological evidence of neuropathy may be present in up to 40 per cent of such patients. A wide range of neuropathies is encountered. The chronic demyelinating and amyloid neuropathies are probably a direct effect of paraproteins. A paraneoplastic sensory neuronopathy of the same type more usually associated with small-cell lung cancer can occur in myeloma. Conventional chemotherapy of the underlying myeloma has little effect on the amyloid neuropathy or the sensory neuronopathy. However, patients with demyelinating sensorimotor neuropathy can improve substantially with steroid therapy and plasma exchange given in addition to chemotherapy for their underlying myeloma. Pronounced improvement can occur after ablation therapy for a localized plasmacytoma.
Neuropathy is a common feature of osteosclerotic forms of myeloma, which are rare by comparison to osteolytic forms. The neuropathy associated with osteosclerotic myeloma, and the accompanying systemic illness, are identical to that seen in Castleman’s disease, the POEMS syndrome, and the Crow–Fukase syndrome (Section 21.12.3). If solitary, the osteosclerotic lesion may be treated by localized irradiation or resection, leading to substantial improvement in the neuropathy over subsequent months.
21.12.3 Castleman’s disease, POEMS syndrome
Progressively disabling, predominantly motor neuropathies may occur in association with elements of a characteristic syndrome: papilloedema, gynaecomastia, impotence, glucose intolerance, oedema, hepatosplenomegaly, and paraproteinaemia, usually IgA-λ. The skin changes are particularly characteristic and include diffuse cyanotic discolouration, poor capillary reperfusion after blanching, hypertrichosis, and diffuse non-dependent oedema. This constellation of features is particularly common in Japan where it is known as the Crow–Fukase syndrome. It is known otherwise by the acronymn POEMS syndrome, ‘Polyneuropathy, Organomegaly, Edema, M band, and Skin changes’. Either osteosclerotic myeloma, or angiofollicular lymph-node hyperplasia, Castleman’s disease, may underlie this clinical syndrome. The neuropathy may be predominantly motor with severely reduced conduction velocities, or it may be sensorimotor with evidence of both demyelination and axonal loss. Roughly half show a good neurological response some months after the initiation of cyclophosphamide and prednisolone therapy, or melphelan and prednisolone, or high-dose cyclophosphamide and autologous blood stem cell transplantation (Jaccard et al. 2002). The remainder are relatively unresponsive, and in some a remorseless downhill progression occurs with eventual death despite chemotherapy for the underlying lymphoproliferative disorder.
21.12.4 Lymphomatous neuropathy
Five distinct types of polyneuropathy occur as an occasional remote accompaniment of lymphoma. The Guillain–Barré syndrome and chronic relapsing inflammatory demyelinating neuropathy, probably reflect disordered immune regulation, and should be treated according to standard principles (Sections 21.10.1 and 21.11.2) (Vallat et al. 1995). Paraneoplastic sensory neuronopathy occasionally complicates lymphoma, although this is a rare association in comparison to its incidence in small-cell carcinoma of the lung (Section 21.13.1). A subacute motor neuropathy may complicate Hodgkin’s disease and other lymphomas and resolves spontaneously in most patients. Diffuse infiltration of nerves by non-Hodgkin’s lymphoma can produce a progressive, painful, asymmetric polyneuropathy (van den Bent et al. 1999).
21.13 Carcinomatous neuropathy
Three types of peripheral neuropathy may occur as remote, or paraneoplastic effects of carcinoma: sensory neuronopathy, sensorimotor polyneuropathy, and, less frequently, vasculitic neuropathy, neuromyopathy, and autonomic neuropathy. Small-cell carcinoma of the lung is the commonest tumour to underlie paraneoplastic neuropathy. Carcinoma of the breast, ovary, or gastrointestinal tract, myeloma, or lymphoma, occur less frequently. Patients frequently present with neuropathy before experiencing symptoms from the underlying cancer itself. Although symptomatic paraneoplastic neuropathy is relatively uncommon, prospective studies in patients with lung and breast cancer reveal clinical evidence of polyneuropathy in up to 5 per cent, with subclinical electrophysiological abnormalities in another 20 per cent (Hughes et al. 1996).
21.13.1 Paraneoplastic sensory neuronopathy
This sensory neuropathy occurs more commonly in women, usually preceding tumour symptoms by 6–15 months and occasionally as long as 3 years (Section 38.4.3). It usually develops subacutely over a period of weeks before stabilizing spontaneously (Camdessanche et al. 2002). Less often it continues to deteriorate inexorably. This distinctive neuropathy may predominate in the arms and can be asymmetrical. Patients develop sensory ataxia due to loss of kinaesthetic sensation and may experience uncomfortable paraesthesiae. All modalities of sensation are impaired. The gait ataxia may prevent walking. Sensory loss can extend to the trunk and may contribute to impaired sphincter function. Muscle weakness does not occur because motor fibres are spared. The reflexes are usually lost. Occasionally such paraneoplastic sensory neuropathy runs a slowly progressive course without severe disability. Other forms of paraneoplastic encephalomyelitis frequently coexist, particularly limbic encephalitis (Section 38.4.2). A similar neuropathy occurs in Sjogren’s syndrome (Section 21.18.10).
Nerve conduction studies show reduced or absent sensory nerve action potentials, while motor nerve conduction is normal. The spinal fluid is usually lymphocytic and proteinaceous. Neuropathologically there is profound loss of dorsal root ganglion neurones with lymphocytic infiltration; a ‘dorsal root ganglionitis’. The serum or spinal fluid may contain high titres of an autoantibody directed against neuronal nucleoproteins of molecular weight 35–40 kDa, known as anti-Hu antibodies (Section 3.7.3). Anti-Hu antibody also occurs in patients with other forms of paraneoplastic encephalomyelitis and in sensorimotor neuropathy (Camdessanche et al. 2002). It may also be detected in low titre in some patients with small-cell lung cancer who do not have an associated neurological disorder. Detection of this anti-Hu antibody should always provoke careful search for an underlying tumour, which should be repeated after an interval if initially negative. Neither treatment nor removal of the underlying tumour, nor immunosuppression, is known to reverse the sensory neuronopathy. However, the underlying carcinoma should be carefully staged in case of the rare possibility of curative treatment.
21.13.2 Paraneoplastic sensorimotor neuropathy
The presence of muscle weakness distinguishes this from the purely sensory neuronopathy described above. Such neuropathies are a heterogeneous collection; they can be acute, subacute, or chronic in presentation, and primarily demyelinating or axonal in nature. They are not usually associated with other paraneoplastic neurological disorders and they can be associated with a wide range of underlying carcinomas. They may precede or follow tumour symptoms. Mild sensorimotor neuropathy may be detected in up to a quarter of patients with lung cancer (Hughes et al. 1996). Most usually the onset is subacute with limb weakness, sensory disturbance, and areflexia. Nerve conduction studies and electromyography may reveal axonal degeneration, in which case attempts at treatment with steroids are likely to be unsuccessful. Demyelinating neuropathies are occasionally encountered, although more commonly with underlying lymphoma than with carcinoma. Typical Guillain–Barré syndrome or chronic inflammatory relapsing demyelinating polyneuritis may occur, and the latter is often steroid-responsive. Nerve biopsies show variable combinations of axonal loss, segmental demyelination and remyelination, and perivascular lymphocytic infiltration.
21.13.3 Paraneoplastic vasculitic neuropathy
Mononeuritis multiplex due to vasculitis occasionally occurs with cancer of the prostate or lung, or lymphoma. Neuropathic symptoms may precede those due to the underlying tumour. Nerve and muscle biopsies allow histological diagnosis of microvasculitis. Cyclophosphamide therapy may lead to stabilization or improvement of the neuropathy (Oh et al. 1991).
12.14 Neuropathy due to infections
Peripheral neuropathy is a central clinical feature of some infections: leprosy, diphtheria, human immunodeficiency virus or HIV infection, borreliosis and herpes zoster. This section does not cover those peripheral neuropathies, such as the Guillain–Barré syndrome, which are infrequent and indirect manifestations of common infections with a wide variety of viruses and bacteria, all of which may share the common property of disturbing immune regulation or evoking antibodies which cross-react with nerve (Section 21.10). Demyelinating neuropathy is a rare accompaniment of Creutzfeldt–Jakob disease, both in the sporadic and inherited forms (Niewiadomska et al. 2002).
Aetiology. Leprosy or Hansen’s disease, is due to infection of the skin, mucosal membranes, and peripheral nerves by Mycobacterium leprae, an acid-fast bacillus stainable by Ziehl–Neelsen’s method. Infection is only likely after prolonged contact with patients suffering from bacillus-rich forms of the disease, especially if shed in nasal secretions. The skin is the commonest portal of entry. Leprosy is common in the Asian subcontinent but may be encountered anywhere in the world. In the Western world it is usually encountered in migrants from endemic areas.
Pathology. The histopathological and clinical picture varies widely in different individuals. This reflects different degrees of cell-mediated immunity. Three general forms may be distinguished within what is, in reality, a continuum which can be subclassified further (Jacobson and Krahenbuhl 1999). Patients with high immunity develop tuberculoid leprosy, which is not progressive, and is usually associated with a single granulomatous skin lesion containing few bacilli and which may involve an underlying peripheral nerve. Patients with low or absent immunity develop lepromatous leprosy in which copious bacilli multiply extensively in the cooler tissues in the body, with progressive and extensive involvement of skin and nerves. Most commonly patients manifest the intermediate or dimorphous forms which occupy the borderland between the tuberculoid and lepromatous varieties.
The exact pathogenetic mechanisms underlying nerve damage in leprosy are not clear. The advanced nerve damage in established tuberculoid leprosy may reflect the compressive and ischaemic consequences of the infiltrating cells forming the granuloma. Nerves in advanced lepromatous leprosy contain vast accumulations of bacilli which may disrupt nerve fibres by virtue of their sheer size. It is unlikely that early leprous neuropathy reflects primary infection of Schwann cells, because segmental demyelination is not prominent. In early leprous neuropathy, the bacilli are most prominent in macrophages and Remak cells, the supporting cells of unmyelinated fibres.
Clinical features. Early diagnosis is crucial since antibiotic therapy will prevent further irreversible nerve damage. The combination of skin and peripheral-nerve lesions is the hallmark of leprosy. There are three cardinal signs for clinical diagnosis:
♦ anaesthetic skin lesions;
♦ peripheral nerve enlargement (Fig. 21.20); and
♦ acid-fast bacilli on skin smear.
In tuberculoid forms, sharply demarcated, hairless, anaesthetic erythematous plaques, or hypopigmented macules, are associated with sensory and motor loss in the distribution of one or two damaged peripheral nerves. The nerve is often palpably enlarged. The greater auricular and superficial peroneal nerves are the most commonly affected. Occasionally tuberculoid leprosy affects nerves without an associated skin lesion, and detection of M. leprae by polymerase chain reaction in nerve biopsies aids diagnosis (Jardim et al. 2003).
In lepromatous leprosy, there is extensive skin involvement with erythematous macules, papules, or nodes. Skin thickening produces the characteristic leonine faces, with thickening of the nose and ear lobes and eventual perforation of the nasal septum. Nerves are diffusely and progressively involved, leading to mononeuritis multiplex.
In dimorphous or intermediate forms of leprosy, the skin and neuropathic changes lie between the tuberculoid and lepromatous forms and poorly defined hypopigmented skin lesions are characteristic. Sensory loss in leprosy tends to spare warm areas of the body, such as the palms, and preferentially affects the skin of cold areas. Patients with advanced leprous neuropathy develop profound pain and temperature loss, leading to acromutilation with trophic ulcers, Charcot joints and autoamputations.
Diagnosis. The clinical picture is usually characteristic, and failure to prove the diagnosis histologically should not deter the physician from advising drug therapy. The simplest method of proving the diagnosis of leprosy is to take skin biopsies or smears from both the centre and edge of a lesion, and to demonstrate acid-fast bacilli by Ziehl–Neelsen staining. Bacilli are most prominent within dermal nerves. Nerve biopsy is particularly valuable in suspected cases without skin lesions and demonstrates bacilli or characteristic granulomatous reaction and inflammation (Chimelli et al. 1997). The lepromin skin test is only positive in tuberculoid forms.
Treatment. Leprosy is the world’s commonest treatable neuropathy. Adequate early therapy prevents the development of disfiguring disability but will not allow recovery of nerves which are already severely damaged. The following chemotherapeutic regimens are currently recommended for adults (Jacobson and Krahenbuhl 1999):
♦ Borderline and lepromatous leprosy should be treated for a minimum of 2 years until skin scrapings and biopsies are negative for bacilli. Daily self-administration of dapsone (100 mg) and clofazimine (50 mg) orally should be accompanied by supervised administration once-monthly of clofazimine (300 mg) and rifampicin (600 mg).
♦ Patients with tuberculoid leprosy should receive daily dapsone (100 mg) with supervised monthly rifampicin (600 mg) for 6 months; single-dose combination therapy of rifampicin, ofloxacin, and minocycline, ‘ROM’, may also be effective.
Some physicians recommend that rifampicin be administered daily, rather than monthly, for both multi-bacillary and paucibacillary leprosy. Following chemotherapy, nerve grafting may restore sensation in patients with severe mononeuritic sensory loss causing acrodystrophic changes. Steroids are recommended to prevent treatment reactions in patients with hypersensitivity phenomena, such as erythema nodosum or iritis. Steroids are advised if a silent neuropathy develops after the initiation of chemotherapy, whether or not associated with systemic evidence of a reaction; such nerve fibre impairments are most likely in multibacillary forms of disease (Croft et al. 2000). Vasculitic neuropathy can develop years after effective treatment in nerves containing persisting leprosy antigen; steroid treatment is effective (Bowen et al. 2000).
21.14.2 Human immunodeficiency virus
A wide spectrum of peripheral neuropathy occurs in HIV infection and AIDS. It includes the Guillain–Barré syndrome and chronic inflammatory demyelinating neuropathy developing early in the course of the disease. Later in the disease, the symmetrical distal sensory neuropathy of AIDS must be differentiated from that caused by antiretroviral therapy (Section 21.19.7). A rapidly progressive multifocal motor and sensory polyradiculopathy due to cytomegalovirus or infiltrative lymphocytosis may occur (Gherardi et al. 1998). Necrotizing arteritic neuropathy can also occur in HIV-infected patients (Bradley and Verma 1996). Possible underlying HIV infection must be considered in a patient with undiagnosed polyneuropathy.
Guillain–Barré Syndrome. Typical Guillain–Barré syndrome (Section 21.10.1) occurs early in the course of HIV infection, often around the time of primary infection. HIV antibodies may not be present, and P24 antigen assays may be required to diagnose the infection. A clue to underlying HIV infection comes from finding a spinal fluid pleocytosis, generally 20–30 cells/mm3. The usual treatment of the Guillain–Barré syndrome is recommended, including intravenous immunoglobulin administration, with particular care to avoid exposure to body fluids.
Chronic inflammatory demyelinating neuropathy. This regularly occurs in HIV-infected patients, often at a relatively early stage before the development of the acquired immunodeficiency syndrome. It should be treated in the usual way (Section 21.11.2). It should be recognized that steroid administration may augment the existing defect in cell-mediated immunity that occurs in HIV infection. Thus, immunoglobulin infusion may be particularly required in HIV-infected chronic inflammatory demyelinating polyneuropathy patients so as to minimize the use of immunosuppressive drugs.
Cytomegalovirus polyradiculoneuropathy. In patients with established HIV infection, cytomegalovirus causes a subacute polyradiculoneuropathy. Some patients may present with a sacral sensory loss and acute urinary retention, and progress to flaccid paraparesis within a few weeks (So and Olney 1994). Cytomegalovirus may be cultured from the spinal fluid and should be sought by polymerase chain reaction. Other patients develop a rapidly progressive multifocal sensory motor neuropathy affecting the limbs, in which dysaesthesiae and pain may be prominent from the outset. Cytomegalovirus may be detected by immunostaining within biopsied peripheral nerves or autopsied spinal-nerve roots. These nerves may contain gigantic cells with inclusions typical of cytomegalovirus infection. Without treatment, death soon follows the development of this neuropathy. Early therapy with ganciclovir or foscarnet can produce improvement.
Sensory polyneuropathy. A predominantly sensory, symmetrical polyneuropathy affects up to 30 per cent of patients with the acquired immunodeficiency syndrome. This neuropathy becomes increasingly common in the later stages of the illness and remains common despite the introduction of highly active antiretroviral therapy, or HAART (Simpson et al. 2003). The initial complaint is of painful paraesthesiae in the feet, and the ankle jerks are usually lost. Electrophysiology shows diminished or absent sensory nerve action potentials, without slowing of motor nerve conduction. The neuropathy progressively worsens in the feet. Lamotrigine is effective against the neuropathic pain (Simpson et al. 2003). It should be differentiated from the painful sensory neuropathy caused by ddI or ddC antiretroviral drugs (Section 21.19.7) which is likely to develop within months of starting the drug and then tends to deteriorate more rapidly.
Infection with the tick-borne spirochaete Borrelia burgdorferi causes Lyme disease, a multisystem disorder comprising a characteristic expanding annular skin lesion called erythema chronicum migrans, oligoarthritis, carditis, meningoencephalitis, cranial neuritis, polyradiculopathy, and peripheral neuropathy (Halperin et al. 1996). Incomplete forms of the disease are frequent and should be recognized because of their impressive response to antibiotic therapy. The differential diagnosis of the neurological disorder includes tick-borne encephalitis, transmitted by the same tick bite (Logina et al. 2006). Neurological features occur in about 15 per cent, starting a few weeks to several months after the tick bite. Human infection usually follows tick bites during the summer. It is commonest in patients who have been in woodland areas populated by rodents, squirrels, or deer, the animal reservoirs for Borrelia. Infection is frequent in North America and mainland Europe, and also occurs less frequently in Britain, Australia, and Asia. The Bannwarth syndrome of lymphocytic meningoradiculitis is a form of Lyme disease, described in Europe before it was recognized that there was an underlying Borrelia infection.
Cranial neuritis. Facial palsy of acute onset, either unilateral or bilateral, commonly occurs in the early weeks of Borrelia infection. About a quarter of cases of Bell’s palsy may be due to Borrelia infection in endemic areas (Halperin and Golightly 1992). The palsy is often incomplete and may be accompanied by subjective facial sensory disturbance. Facial nerve paralysis may be the only neurological feature of Lyme disease. It usually recovers without treatment but may be treated with oral antibiotics and a short course of oral prednisolone if seen within 24 h of onset.
Polyradiculopathy. Shooting pains in the territories of affected nerve roots are sometimes accompanied by reflex loss or sensorimotor abnormalities in the limbs. Sharp chest-wall pains reflect involvement of thoracic nerve roots. Half the patients with polyradiculopathy also have facial palsy. The polyradiculopathy of borreliosis may last some months, but usually resolves spontaneously.
Peripheral neuropathy. Mononeuritis multiplex, polyneuropathy, and acute brachial neuralgia may all occur in Lyme disease. Any of these neuropathies may accompany polyradiculitis and facial palsy. Mononeuritis multiplex and acute brachial plexus neuropathy tend to occur within the first few months of infection. Up to half of patients with untreated late Lyme disease develop a chronic polyneuropathy with intermittent limb paraesthesiae (Logigian and Steere 1992). Few neuropathic abnormalities are generally found on examination of such patients: mild distal gloveand-stocking sensory loss with preserved reflexes and motor function are the general rule. Nerve conduction studies show reduced and slowed sensory nerve action potentials, and, sometimes, increased distal motor latencies. Neurophysiological abnormalities are multifocal in nature, and there is no generalized motor slowing. Sural nerve biopsies may show mild axonal loss, with some perivascular lymphocytic infiltration; necrotizing vasculitis is not encountered.
Central nervous system involvement. This may be chronic and take a variety of forms resembling multiple sclerosis, other infective meningoencephalitides, stroke, or tumour (Oksi et al. 1996). MRI can show single or multiple enhancing brain lesions and pathologically these involve demyelination, lymphocytic blood vessel involvement, and detectable Borrelia DNA indicative of direct infection.
Investigations. The demonstration of elevated serum or spinal fluid IgM or IgG antibody titres to Borrelia burgdorferi has been the traditional diagnostic investigation. However antibody assays are of low diagnostic sensitivity early in infection, and do not discriminate between active and inactive infection later on. The spinal fluid contains a striking white cell pleocytosis of up to 700 cells/mm3 in patients with polyradiculitis, but may be normal if isolated facial palsy or peripheral neuropathy are the only neurological features. Borrelia may be cultured from about 50 per cent of skin lesions but only 5 per cent of CSF specimens. Amplification of small amounts of Borrelial DNA in CSF or urine by polymerase chain reaction holds promise as the most specific means to prove infection, but current tests are negative in up to 50 per cent of patients depending upon the particular clinical manifestations and the stage of the disease (Schmidt 1997).
Treatment. The peripheral neuropathy or radiculopathy of Lyme disease responds well to intravenous Benzyl penicillin (2.4 g 6 hourly for 10 days), or ceftriaxone (2 g per day for 14 days), or doxycycline (Halperin et al. 1987).
Polyneuropathy is the commonest and most important complication of diphtheria; the exotoxin of Corynebacterium diphtheriae has an affinity for peripheral nerves. Polyneuropathy is commoner in childhood rather than adult infections. Paralysis is more likely to follow severe local infections, which are usually faucial but may be extrafaucial. Antitoxin is given to reduce the incidence of paralysis, particularly in patients who can receive it early in the illness.
Palatal paralysis reflects the action of locally produced toxin upon the nerves to the bulbar musculature. Involvement of nerves by locally produced toxin accounts for localized paralysis following a cutaneous infection, the muscles paralysed being those supplied by the spinal segment from which the infected region is innervated. Localized neuropathy in one or more extremities was often seen after diphtheritic infection of limb wounds in the Middle East in the Second World War. Paralysis of accommodation, generalized polyneuropathy, and cardiac toxicity are due to blood-borne dissemination of the toxin to the ciliary muscles, peripheral nerves, and heart.
Diphtheria remains endemic in the Third World but is now rare in Western countries due to improved living conditions and childhood immunization programmes. Occasional outbreaks of clinical diphtheria do occur in previously immunized adults although the clinical severity is generally reduced. At least 10 per cent of adults vaccinated in childhood have insufficient residual immunity to protect against infection once Diphtheria returns to a population (Kjeldsen et al. 1985). This reduced immunity in adults resulted in a spectacular return of diphtheria to Russia and other eastern European countries after 1993 (Logina and Donaghy 1999; Piradov et al. 2001). Overall about 15 per cent of patients diagnosed with diphtheria develop polyneuropathy. Attenuated forms of diphtheritic polyneuropathy can occur in closed communities despite recent booster vaccination (Krumina et al. 2005).
Pathology. The primary lesion in the peripheral nerves is segmental demyelination accompanied by typical slowing of motor nerve conduction, which may persist for some time after clinical recovery. The neuropathic effects of the toxin are dose-dependent. Once bound to cells, the toxin becomes unavailable for inactivation by antitoxin.
Symptoms and signs. Paralysis of the palate is usually the earliest neurological symptom and appears a median of 10 days after the onset of localized throat Diphtheria, seen the typical palatal pseudomembrane. It is generally bilateral but may be unilateral. The voice becomes nasal, there is regurgitation of fluids through the nose on swallowing, and the larynx becomes paralysed, allowing inhalation and choking. The palatal reflex is usually lost. Twenty per cent develop ventilator-dependent respiratory failure. Improvement of bulbar symptoms occurs at median 30 days from onset. Secondary deterioration of bulbar function, sometimes enough to require ventilation for the first time, occurs in over a third at a median 40 days from initial onset (Logina and Donaghy 1999).
Paralysis of accommodation due to ciliary muscle involvement produces blurred vision for near objects. The pupillary reactions to light and on convergence are unimpaired. Paresis of the face or external ocular muscles may occur.
Generalized sensorimotor polyneuropathy affecting the limbs occurs in 90 per cent, at a median of 37 days from onset. It always occurs after the bulbar symptoms, and sometimes when the bulbar symptoms are already improving. About 50 per cent become unable to walk unaided; 30 per cent develop impaired bladder control. Blood pressure swings or cardiac arrhythmia reflect either autonomic neuropathy or cardiomyopathy (Logina and Donaghy 1999).
Diphtheritic hemiplegia is rare fortunately and is usually due to either embolism or thrombosis of a cerebral artery, or to acute post-infective encephalitis. Its effects are similar to those of other acquired forms of infantile hemiplegia. Meningism was once common in the acute stage with cervical rigidity or opisthotonos and rigidity of the limbs, so-called ‘spasmodic diphtheria’. The CSF in such cases of presumed encephalopathy is usually normal in composition. Permanent bulbar palsy is a rare sequel.
Diagnosis. The chief differential diagnosis of diphtheria is from Guillain–Barré syndrome, which is an ascending, rather than descending, polyneuropathy (Section 21.10.1). Diphtheria is favoured by the high prevalence of bulbar and respiratory dysfunction at a time of little or no limb involvement, by evolution for longer than 4 weeks, by the preceding sore throat rather than catarrhal illness, and by the simultaneous involvement of other organs, particularly the heart (Logina and Donaghy 1999). The CSF protein tends to be elevated in both conditions. Throat cultures are positive in 98 per cent of diphtheria, and 8 per cent have the highly toxic ‘bull-neck’ form of the disease (Rakhmanova et al. 1996).
Prognosis. The prognosis of the paralysis is usually good now that endotracheal intubation prevents death due to bulbar or respiratory muscle failure. Nevertheless some limb symptoms persist in 80 per cent at 1 year, while 6 per cent are still unable to walk. Sixteen per cent of diphtheria patients die, but usually from cardiac or other organ involvement rather than paralysis (Logina and Donaghy 1999). Hemiplegia is a serious complication especially in children, as it may not only be fatal, but in patients who survive, recovery is usually incomplete, and epilepsy and dementia may follow.
Treatment. The treatment of diphtheria includes antibiotic therapy and injection of adequate doses of antitoxin as early as possible. Benzyl penicillin 1.2 g 6 hourly intravenously, should be given for 14 days, converting to oral penicillin when the patient can swallow normally. Erythromycin 500 mg four times daily is an alternative for patients with penicillin allergy. Diphtheria antitoxin should be given intravenously or intramuscularly; serum sickness may occur in up to 10 per cent of patients. It is unclear for how long after onset of diphtheria that antitoxin will be beneficial. In the absence of any formal clinical trials, retrospective evidence suggests little benefit on the incidence of paralysis or death if antitoxin is administered after the second day of the throat infection (Logina and Donaghy 1999). The general nursing care, and indications for assisted ventilation, are similar to those in Guillain–Barré syndrome (Section 21.10.1). Tracheostomy may be required early if paralysis of the pharynx or larynx leads to choking while feeding or drinking.
21.14.5 Herpes zoster
Herpes zoster is a reactivation of varicella-zoster virus which had been primarily acquired during chickenpox infection. Zoster is particularly likely in the elderly and the immunosuppressed, and may affect a fifth of all adults at some time in life. Few patients have more than one attack. Following primary chickenpox infection, the varicella-zoster virus becomes latent in the sensory ganglia and motor neurones. During zoster eruptions there is inflammation and haemorrhagic necrosis destroying neurones of the affected dorsal root ganglion, with a shingles eruption in the skin of the corresponding dermatome.
Clinical features. An attack of shingles is usually heralded by tingling in the dermatome or lancinating pains. These generally precede the visible rash by 2 or 3 days. Occasionally rash never develops (Fox et al. 2001). Erythematous macules and papules rapidly become vesicular, and the lesions accumulate over 3–5 days. Scabbing occurs 3–7 days later, and then dry by two weeks. The intensity of the vesicular eruption varies immensely, from a few vesicles only in mildly affected patients, to a dense oedematous rash covering the entirety of one or more dermatomes in more severely affected patients (Fig. 21.21). When zoster affects the ophthalmic division of the trigeminal nerve, conjunctivitis and keratitis can occur, associated with peri-orbital oedema. Electromyographically detectable motor involvement is associated with the skin eruption in 50 per cent of patients, and sometimes produces clinically evident muscular paralysis affecting the diaphragm, limb muscles, external ocular, or facial muscles (Haanpaa et al. 1997). Zoster eruptions in sacral dermatomes may produce paralysis of the bladder with haemorrhagic cystitis, and bowel ileus confusable with an acute abdomen. Clinical evidence of meningoencephalitis is uncommon. However, subclinical evidence of brain stem or spinal cord involvement at the relevant level is evident on MRI in over 50 per cent, and the CSF is lymphocytic, often with detectable varicella-zoster virus DNA in 60 per cent (Haanpaa et al. 1998).
Although the diagnosis of shingles can be confirmed by isolation of the varicella-zoster virus from vesicular fluid, or immediate demonstration by electron microscopy, the rash is usually sufficiently characteristic to allow unequivocal clinical diagnosis. However, if seeing a patient after resolution of a rash attributed to zoster, it is advisable to take a clear history concerning the radicular distribution and vesicular character of the eruption, to confirm the likely diagnosis when a patient is seen after resolution of the rash. Sometimes patients will self-diagnose other skin disorders as being attacks of zoster.
Treatment. The treatment of the acute attack should be with analgesics sufficiently potent to relieve pain. Anti-viral drugs, acyclovir, valaciclovir, or famciclovir, speed resolution of the acute eruption and may reduce the risk of prolonged pain. Oral antiviral drugs are often prescribed for immunocompetent patients with uncomplicated zoster eruptions, although the extent of their value is unclear. Anti-viral drugs are clearly indicated in patients displaying clinical evidence of central nervous system involvement, or who are immunocompromised, and should be administered intravenously in more serious clinical situations (Cohen et al. 1999).
Post-herpetic neuralgia. This is the feared long-term complication of shingles. It is defined as pain persisting beyond 1 month. Quantification of sensory nerve fibres in skin biopsies from affected dermatomes show a more severe nerve fibre loss in those with post-herpetic neuralgia than in those without (Oaklander et al. 1998). Post-herpetic neuralgia is more likely in the elderly, those who have had a severe rash with significant pain, and those with ophthalmic involvement (Jung et al. 2004). Such patients merit anti-viral therapy during the acute zoster eruption so as to try and reduce the risk of subsequent post-herpetic neuralgia. Once established, post-herpetic neuralgia can be disturbingly resistant to local and systemic pain relieving measure. Amitriptyline may be beneficial, particularly if given from an early stage. Topical capsaicin ointment may relieve pain in some, but cause burning in others. Carbamazepine or gabapentin may be tried. Local measures may include topical lidocaine, regional nerve blocks, transcutaneous electrical stimulation, and acupuncture. Narcotic analgesics may be necessary if other measures fail.
21.15 Vasculopathic neuropathy
Ischaemia may produce focal damage to peripheral nerves, causing mononeuropathy or mononeuritis multiplex. This is most familiar in the context of necrotizing vasculitis or diabetic microvascular disease (Section 21.17.1) affecting the vasa nervorum. Patients with a possible diagnosis of vasculitic neuropathy should be investigated urgently so that treatment can be started to forestall further peripheral nerve damage.
21.15.1 Atherosclerosis and embolism
It is unusual for blockage of medium-sized arteries to cause obvious clinical features of neuropathy because of the rich longitudinal anastomosis of the peripheral nerve vasculature. Nonetheless, axonal loss is demonstrable histologically in nerves from limbs affected by chronic peripheral vascular disease (Nukada et al. 1982). In general, myelinated fibres seem more vulnerable to ischaemia than unmyelinated (Fujimura et al. 1991).
Acute embolic, thrombotic, or traumatic occlusion of a major artery to a limb may cause peripheral nerve dysfunction, but the neuropathic symptoms and signs are usually overshadowed by the prominent effects of associated acute ischaemia of skin and muscle. Prompt restoration of blood flow, for instance by embolectomy, may lead to full recovery of peripheral nerve function. Prolonged ischaemia leads to irreversible peripheral nerve damage which may be associated with ischaemic contractures of muscles. Multifocal neuropathy resembling vasculitis may occur in the cholesterol emboli syndrome which may be precipitated by arterial catheterization procedures; muscle or nerve biopsy may demonstrate cholesterol clefts within small arteries (Bendixen et al. 1992). The creation of arteriovenous fistulae in the arm for haemodialysis can cause a distal axonal neuropathy, probably due to a vascular steal syndrome.
21.15.2 Non-systemic vasculitis
In some patients, necrotizing vasculitis is confined to the peripheral nervous system (Collins et al. 2003). Most patients with non-systemic vasculitic neuropathy develop multiple mononeuropathies affecting the limbs, thoracic roots, or the cranial nerves. Each mononeuropathy evolves over a few hours or days, producing muscle weakness, paraesthesiae, and pain, and global sensory disturbance in the territory of the affected nerve. Tendon reflexes may not be lost if the damage is restricted to the more distal segments of nerves. A minority of patients present with a symmetrical or asymmetrical distal polyneuropathy which may be sensorimotor or purely sensory. Thus, the potentially treatable condition of vasculitic neuropathy should be considered in patients with a distal axonal polyneuropathy which progresses quickly and for which no satisfactory diagnosis is apparent. Vasculitic neuropathy may occur in patients infected with HIV.
The ESR is elevated in a minority. The spinal fluid is usually normal. Nerve conduction studies show focal axonal loss and denervation of muscles. Occasionally conduction block may be demonstrated. Nerve or muscle biopsy will show that the walls of epineurial, perineurial, or muscular arteries are infiltrated by polymorphonuclear cells, and there is fibrinoid necrosis, destruction of the internal elastic lamina, and occlusion of the vessel lumen (Fig. 21.22). The yield of nerve biopsy is greatest if an electrophysiologically abnormal sensory nerve is chosen and biopsied to full thickness. Nerve biopsy is positive in over half of patients, and muscle biopsy improves the diagnosis of arteritis by a quarter (Vital et al. 2006). Thus the recommended diagnostic procedure is full thickness biopsy of a sural or superficial radial nerve if electrophysiologically normal, and if not a muscle biopsy.
There have been no controlled studies comparing different therapies for neuropathy in non-systemic or systemic vasculitis. Many consider that prednisolone alone provides adequate therapy for non-systemic vasculitis restricted to the peripheral nervous system. There are no clear guidelines as to the duration of steroid therapy, whether alternate-day steroids are effective as maintenance therapy, and whether relapses are common on cessation of steroid therapy. If steroids incompletely suppress the underlying vasculitis thereby allowing worsening of the neuropathy, cyclophosphamide therapy should be considered (Mathew et al. 2007). If the neuropathy is rapidly progressive and destructive, cyclophosphamide should be considered from the outset, given either orally or as intravenous pulses. Given the potential side effects of immunosuppressive drugs, it is desirable to obtain unequivocal histological proof of vasculitis before starting therapy. The benefits of therapy are first to prevent further peripheral nerve damage and second to allow the moderate degree of recovery of neurological function which occurs during the year after suppressing the vasculitis.
21.15.3 Systemic vasculitis
The majority of patients with vasculitic neuropathy have underlying vasculitic involvement of systemic organs (Hawke et al. 1991). The neurological features resemble those of non-systemic vasculitic neuropathy, but often evolve more aggressively. The electrophysiological and nerve biopsy findings are identical to those in non-systemic vasculitic neuropathy (Section 21.15.2).
Neuropathy is a common feature of the systemic necrotizing vasculitides, which include polyarteritis nodosa, microscopic polyarteritis, Churg–Strauss syndrome, and Wegener’s Granulomatosis (Hawke et al. 1991; Hattori et al. 1999; de Groot et al. 2001). The various patterns of neuropathy which have been identified in the systemic necrotizing vasculitides include mononeuritis multiplex, involvement of small cutaneous sensory nerves in the fingers or feet, symmetrical distal sensorimotor neuropathy, brachial plexopathy, and radiculopathy. Anti-neutrophil cytoplasmic antibodies may present in serum early on in Wegener’s granulomatosis and polyarteritis nodosa. Often the choice of therapy is dictated by systemic manifestations such as renal involvement. Steroids alone are often effective in the Churg–Strauss syndrome, which is diagnosable by the distinctive eosinophilia and late-onset asthma. In patients with progressive vasculitic neuropathy, therapy should be instituted at the earliest opportunity to prevent the accumulation of irreversible nerve damage. Cyclophosphamide can produce dramatic remissions and cures in severe systemic necrotizing vasculitis to an extent that would be unlikely with steroids alone. However, considerable morbidity and mortality is associated with cyclophosphamide therapy, and it should be supervised by physicians familiar with the drug. It is recommended that cyclophosphamide should only be prescribed for patients with clear histological proof of systemic necrotizing vasculitis, or in whom the clinical syndrome is sufficiently distinctive to be beyond doubt. The rate of neurological relapses is greatly reduced by cyclophosphamide compared to prednisolone therapy, but probably at the cost of increased morbidity and mortality, attributable in part to cyclophosphamide side effects (Mathew et al. 2007).
Vasculitic neuropathy may occur in patients with nodular rheumatoid arthritis who may develop either mononeuritis multiplex, digital sensory neuropathy, or sensorimotor polyneuropathy. Vasculitic neuropathy also occurs in lupus erythematosus, Sjogren’s syndrome, scleroderma, and in up to 14 per cent of patients with giant cell arteritis (Stefurak et al. 1999). Multifocal axonal polyneuropathy can complicate coeliac disease, although vasculitis is unproven as the pathogenic mechanism (Chin et al. 2006).
Neuropathy occurs in over 50 per cent of patients with essential mixed cryoglobulinaemia (Gemignani et al. 1992). Symmetrical sensorimotor polyneuropathy is commoner than mononeuritis multiplex. Nerve biopsies may show necrotizing vasculitis but diffuse endoneurial vessel damage and non-specific axonal loss is a commoner pathological finding. Most often the neuropathy produces painful dyaesthesias and sensory loss in a stocking distribution with prominent symptoms of restless legs, burnings, or formication (Gemignani et al. 1992). Prominent vasculitic purpura and Raynaud’s phenomenon should suggest the possibility of cryoglobulinaemia. The diagnosis is proven by looking for immune precipitates in the serum of blood allowed to clot at 37°C. Plasma exchange, steroids, and cyclophosphamide have all been used therapeutically, with occasional success. Indeed, if a patient has been diagnosed with vasculitic neuropathy and continues to progress despite such treatment, the possibility of cryoglobulinaemia should be entertained. Hepatitis C infection commonly underlies essential mixed cryoglobulinaemia, and improvement in the neuropathy has been reported with interferon alpha therapy (Khella et al. 1995).
21.16 Sensory perineuritis and migrant sensory neuritis
21.16.1 Sensory perineuritis
This rare mononeuropathy causes pain and numbness in the territories of individual cutaneous nerves (Logigian et al. 1993). Patients may present with severe pain in the feet induced by standing or walking. Tinel’s sign may be produced by percussion along the course of affected nerves. Initially the disorder may be relapsing and remitting, but symmetrical distal sensory loss may eventually appear. Mixed motor and sensory nerve involvement has been described with perineuritis. Unlike the migrant sensory neuritis of Wartenberg, stretching of peripheral nerves does not produce electric shock sensations in sensory perineuritis. Biopsy of affected nerves shows a chronic inflammatory infiltrate in the perineurium surrounding some fascicles but not others. The differential diagnosis includes a rare purely sensory form of vasculitic neuropathy (Seo et al. 2004). Endoneurial blood vessels are spared. Similar histological findings have been described in the peripheral neuropathy of the Spanish toxic rapeseed oil syndrome. The disorder often responds to steroids.
21.16.2 Migrant sensory neuritis of Wartenberg
Patients with this disorder develop sudden pains in the territory of cutaneous nerves; the pain is induced by movements of a limb which stretch or distort the nerve. After repeated episodes of pain, cutaneous sensation may be lost in the nerve’s territory for about 6 weeks. The relapsing and remitting nature of the sensory disturbance may initially suggest multiple sclerosis. Migrant sensory neuritis is probably commoner than generally appreciated and usually affects patients in middle life (Matthews and Esiri 1983). It has occurred in members of a family with dominantly inherited brachial plexus neuropathy (Thomas and Ormerod 1993). Nerve conduction studies may show diminished sensory nerve action potentials in affected nerves. The condition follows a benign course.
21.17 Diabetic neuropathy
21.17.1 Range of disorders
Diabetes mellitus is one of the commonest causes of disabling polyneuropathy. Two types of polyneuropathy are recognized and may coexist: symmetrical sensorimotor and autonomic. Various focal neuropathies occur, including diabetic proximal neuropathy, mononeuropathies of cranial and peripheral nerves, and truncal neuropathies (Watkins 1990; Said 1996). Two or more of these neuropathies commonly coexist within the same patient. Furthermore, many patients with established insulin-dependent diabetes mellitus have subclinical or electrophysiological evidence of sensory or autonomic polyneuropathy, despite being asymptomatic. In a population-based cohort study neuropathy was present in 66 per cent of insulin-dependent diabetics: polyneuropathy 54 per cent, carpal tunnel syndrome 11 per cent, visceral autonomic 7 per cent, and in 59 per cent of non-insulin-dependent diabetics: polyneuropathy 45 per cent, carpal tunnel syndrome 6 per cent, visceral autonomic 5 per cent. However, only about 20 per cent of diabetics have symptoms, and only 6 per cent of insulin-dependent, and 1 per cent of non-insulin-dependent diabetics had more severe forms of neuropathy (Dyck et al. 1993b). Neuropathy is significantly associated with diabetic retinopathy or nephropathy. Impaired glucose tolerance, without frank diabetes mellitus, is associated with axonal polyneuropathy predominantly affecting small fibres (Sumner et al. 2003).
21.17.2 Diabetic polyneuropathy
This is most prevalent in insulin-dependent diabetics of more than 20 years standing, and in those with hypertension or poor glycaemic control. Sensory fibres are mainly involved, often accompanied by a variable degree of autonomic neuropathy.
Clinical features. Sensory symptoms usually commence in the legs. The common initial symptoms are paraesthesiae, and burning or lancinating pains. The sensory loss usually reflects abnormalities of unmyelinated fibres with impaired pain and temperature sensations in a stocking distribution. The hands are also involved in more severe cases. In established cases vibration and joint-position sensations are impaired at the toes. These patients may have a sensory gait ataxia and a positive Romberg’s sign. Tall diabetics are at greatest risk of sensory neuropathy, probably by virtue of their longer nerves. The ankle jerks are usually lost but generalized areflexia is less common. Involvement of autonomic fibres impairs sweating and prevents skin blood-flow regulation distally in the limbs, leading to a warm, dry foot with hard skin vulnerable to cracking. The combination of pain insensitivity and autonomic denervation predisposes the foot to skin ulceration. Neuropathic joints may develop. Motor loss is less common in diabetic polyneuropathy by comparison with the degree of sensory loss. Distal muscle weakness and wasting may be encountered in long-standing cases. However, marked motor involvement should provoke consideration of other possible contributing causes to the neuropathy apart from diabetes. Chronic inflammatory demyelinating polyneuropathy can occur in diabetics (Krendel et al. 1995). The diagnosis of sensory or autonomic polyneuropathy poses few difficulties in patients with recognized diabetes mellitus. The blood sugar should be checked in all patients presenting with sensory neuropathy since neuropathy may be the first symptom of diabetes.
Nerve conduction studies. These generally show diminished or absent sensory nerve action potentials with normal or only mildly impaired motor nerve conduction velocity. These electrophysiological findings occur in some diabetics before neuropathic symptoms develop. Electromyography often shows chronic denervation of distal muscles. Sensory nerve action potentials, which reflect conduction in large myelinated fibres, may be remarkably normal in those patients with selective loss of pain and temperature sensation.
Sural nerve biopsies. These usually show axonal loss and Wallerian degeneration affecting both myelinated and unmyelinated fibres. Less frequently diabetic nerves show segmental demyelination and remyelination, which is likely to be merely a secondary consequence of primary axonal atrophy (Said 1996). Painful forms of diabetic neuropathy show regenerative sprouting of unmyelinated fibres, possibly the pain results from abnormal discharges in the sprouts. Degeneration of the distal portions of dorsal column axons in the spinal cord is found at autopsy in patients with diabetic neuropathy. Thus both the central and peripheral branches of sensory neurones are vulnerable to hyperglycaemia. This observation, considered together with the greater vulnerability of sensory rather than motor neurones, suggests that it may be the perikarya of dorsal-root ganglion neurones rather than axons which are primarily affected by hyperglycaemia. Furthermore, because central nervous axonal branches of sensory neurones are unable to regenerate, full recovery of function is unlikely to result from treatments that merely promote peripheral nerve regeneration. Epineurial arteriolar walls may be thickened and endoneurial capillary lumens reduced in peripheral nerve, suggesting an ischaemic contribution to some cases of diabetic polyneuropathy. Morphometric examination of the entire length of nerves from elderly diabetics shows that multifocal ischaemic axonal loss may summate distally and contribute to the polyneuropathy (Dyck et al. 1986).
Pathophysiology. The abnormality of neuronal cell biology responsible for diabetic polyneuropathy is not known. It is likely that multiple pathogenetic mechanisms interact to varying degrees in producing a clinical picture of neuropathy which differs from patient to patient. Multifocal ischaemic neuropathy with distal summation of axonal loss may be a factor in elderly patients. However, it is likely that diffuse consequences of the metabolic disturbance are more prominent in causing the polyneuropathy of younger patients. Early trials of therapy were based on the notion that persistent hyperglycaemia may activate the polyol pathway in nerve causing sorbitol accumulation as a result of enhanced aldose reductase activity. The biochemical consequences of this for nerve conduction remain unproven and aldose reductase inhibitor therapy was unsuccessful in clinical trials. Insulin control does improve axonal excitability, with corresponding improvements in nerve conduction velocities (Kitano et al. 2004) but this is unlikely to be of direct relevance to the axonal degeneration of diabetic neuropathy. Accumulation of sugars can promote non-enzymatic glycosylation of peripheral-nerve proteins, probably altering their function and irreversibly cross-linking them by advanced glycosylation end-products (Ryle and Donaghy 1995). The slow phase of axonal transport of microtubule and neurofilament cytoskeletal proteins to the distal axon is reduced in experimental diabetes. This could alter the structural integrity of the distal axon and account for the axonal lengthrelated neuropathy of diabetes (Medori et al. 1988). The APOE genotypes 3/4 and 4/4 increase the risk of polyneuropathy, by a degree equivalent to 15 extra years of age or duration of diabetes (Bedlack et al. 2003).
Treatment. Strict control of glycaemia provides the best hope of reducing the occurrence and progression of diabetic polyneuropathy (Diabetes Control and Complications Trial Research Group 1993). Optimal control of glycaemia improves vibration sensation in diabetic polyneuropathy. Restoration of glycaemia by pancreas transplantation halts the downhill progression of diabetic neuropathy and a minor degree of recovery is apparent 3.5 years after transplantation (Kennedy et al. 1990). It should be noted that protracted or recurrent hypoglycaemia due to over-zealous insulin treatment may cause a predominantly motor peripheral neuropathy, which is distal and symmetrically distributed, and may particularly affect the arms. A similar motor neuropathy may be seen in the hyperinsulinism of islet cell tumours. Treatment of established diabetics with the aldose reductase inhibitor sorbinil does not significantly improve the clinical or electrophysiological outcome over more than 3-year follow up (Sorbinil Retinopathy Trial Research Group 1993).
Acutely painful diabetic polyneuropathy. This can be severely disabling and difficult to treat. It usually improves after some months of strict glycaemic control. In newly diagnosed diabetics, pain can be precipitated or augmented by insulin therapy. Carbamazepine, phenytoin, gabapentin, or sodium valproate therapy may help to relieve shooting or stabbing pains (Kochar et al. 2004). Constant deep aching pain may respond to amitriptyline within a few days, but this drug may exacerbate a coexisting autonomic neuropathy causing urinary hesitancy or erectile failure. Skin care is essential so as to prevent chronic ulceration; cuts and abrasions should be treated promptly. Regular advice should be sought from a chiropodist, and the insides of shoes inspected daily for small stones and other irregularities.
21.17.3 Diabetic proximal neuropathy
This disorder ranges from the familiar extreme of acute asymmetrical painful proximal leg muscle weakness developing over a few days or weeks, to the less familiar extreme of symmetrical painless proximal muscle weakness developing over many weeks or months. Diabetic proximal neuropathy has been termed diabetic radiculoplexus neuropathy, diabetic myelopathy, polyradiculopathy, amyotrophy, lumbar plexopathy, mononeuropathy multiplex, femoral neuropathy, myopathy, or neuropathic cachexia. It is commonest in non-insulin-dependent diabetics, generally in their sixth or seventh decade. Previously unrecognized diabetes may present with proximal neuropathy. Proximal neuropathy is seldom accompanied by diabetic retinopathy or nephropathy.
Anterior thigh muscle pain is the usual first symptom. Proximal leg muscle weakness, mainly involving the quadriceps muscle, develops over the next few days or weeks. The knee jerks are lost in most patients. Despite the unilateral onset, bilateral weakness eventually occurs in over half of all patients. Occasionally the plantar responses are extensor, hence the original term ‘diabetic myelopathy’. The neuropathy is usually accompanied by profound weight loss. Femoral nerve conduction is delayed. The spinal fluid protein is slightly elevated in most patients, indicating involvement of nerve roots.
Most patients improve neurologically after some months, and this is generally attributed to improved control of hyperglycaemia by insulin or oral hypoglycaemic agents (Coppack and Watkins 1991). Pain is the first symptom to resolve. The return of muscle power is usually substantial but is complete in only 20 per cent of patients. Recovery takes place over a period of 6–18 months. Up to one-fifth of patients may experience recurrence (Coppack and Watkins 1991). Although common sense requires that hyperglycaemia should be strictly treated in diabetic proximal neuropathy, there is no conclusive evidence that hypoglycaemic therapy promotes recovery over and above that which will occur spontaneously.
The pathogenetic mechanism responsible for diabetic proximal neuropathy remains unclear. The absence of associated diabetic retinopathy or glomerulopathy, the frequent bilaterality, and the relatively slow neurological deterioration in diabetic proximal neuropathy, have argued against vascular occlusion due to diabetic microangiopathy as the primary cause. Epineurial microvasculitis or inflammation is observed in some patients in biopsies of the intermediate cutaneous nerve of the thigh, a cutaneous branch of the femoral nerve (Said et al. 1994; Dyck et al. 1999). This raises the question of treating severe or enduring cases of diabetic proximal neuropathy with steroids or other immunomodulatory drugs (Krendel et al. 1995). The clinical features, pathology, and outcome of diabetic proximal neuropathy seem identical to those of non-diabetic radiculoplexus neuropathy (Section 22.6.1) (Dyck et al. 2001).
Attacks of truncal pain and sensory disturbance occur in diabetic patients. They may be recurrent, of variable severity, and may affect more than one thoracic nerve root territory. Truncal neuropathy typically affects non-insulin-dependent diabetics in their fifth to seventh decades. It is often accompanied by considerable weight loss, similar to that occurring in diabetic proximal neuropathy. The pain may not be strictly localized to the territory of a discrete dermatome. A sensory deficit is usually demonstrable on the trunk and can be restricted to the territory of a single anterior or posterior ramus. Abdominal protuberance may result from focal paralysis of abdominal wall muscles. Electromyography often shows denervation of paraspinal muscles. Skin nerve fibres are reduced in biopsies from affected compared to unaffected sensory territories (Lauria et al. 1998). The differential diagnosis includes multiple sclerosis and lesions affecting vertebral bones. Spontaneous recovery is usual but may take some months. Carbamazepine or amitriptyline can control the pain.
21.17.5 Diabetic autonomic neuropathy
Abnormal autonomic function is detectable in a sixth of all patients with insulin-dependent diabetes, although symptoms of autonomic peripheral neuropathy occur only in relatively few. Autonomic neuropathy usually coexists with a small fibre sensory peripheral neuropathy. The main symptoms are abnormal sweating or diarrhoea. Less frequently patients are troubled by postural hypotension, vomiting from gastroparesis, micturition difficulties, bladder infection due to atony, sexual impotence, and retrograde ejaculation. Symptomatic autonomic neuropathy predisposes patients to sudden death during anaesthesia, to cardiac arrhythmias, and it may reduce awareness of hypoglycaemia due to failure of catecholamine release. Although notably intermittent in severity, symptoms of autonomic disturbance tend to continue with little change in severity for many years. A wide variety of autonomic function abnormalities may be measured in diabetic patients (Said 1996). Dry warm feet, miosis, reduced pupil light reflexes, and ptosis may be observed. Iritis is associated with autonomic neuropathy in diabetics (Watkins 1990). The simplest reliable bedside tests consist of measuring postural hypotension, which reflects failure of sympathetic fibres, and measuring variability of the heart rate during deep breathing, this represents the sinus arrhythmia, in turn reflecting the parasympathetic innervation of the heart. Tight control of glycaemia by continuous subcutaneous insulin infusion or pancreatic transplantation produces only minor improvements in autonomic function (Kennedy et al. 1990). Diarrhoea can be particularly troublesome at night and may respond to codeine phosphate, clonidine, or one or two doses of tetracycline. Oral erythromycin can improve gastric emptying, possibly by mimicking the effects of motilin on gastrointestinal motility, and can be tried in patients disabled by serious vomiting due to diabetic gastroparesis (Janssens et al. 1990).
21.17.6 Diabetic mononeuropathy
Diabetics are particularly vulnerable to a wide range of mononeuropathies affecting peripheral or cranial nerves. Nerves vulnerable to compression are most commonly affected, such as the median in the carpal tunnel, the ulnar in the cubital groove, the radial at the humerus, the common peroneal at the fibular head, and the lateral cutaneous nerve of the thigh at the inguinal ligament. Painful oculomotor nerve palsies, often sparing the pupil, are common in older diabetics and resolve spontaneously. It is likely that pre-existing diabetic microvascular disease makes nerves unusually vulnerable to compression, although the utility of surgical decompression remains unproven (Chaudhry et al. 2006). These mononeuropathies may improve spontaneously, or with surgical release if at sites of compression. However, permanent residual abnormalities are common.
Some diabetics, usually elderly, develop a progressive and painful multifocal mononeuritis with necrotizing vasculitis found on nerve biopsy (Kelkar and Parry 2003; Said et al. 2003). Steroids seem effective in such patients.
21.17.7 Chronic inflammatory demyelinating polyneuropathy in diabetics
Diabetics seem to be ten-fold more vulnerable to chronic inflammatory demyelinating polyneuropathy (Section 21.11.2) than non-diabetics. Type 1, insulin-dependent, and Type 2, non-insulin-dependent, diabetics are equally vulnerable (Sharma et al. 2002a). This disorder can be differentiated from the normal diabetic polyneuropathy (Section 21.17.2) by the subacute development of weakness, including proximally, the large fibre sensory loss, and evidence of demyelination electrophysiologically (Uncini et al. 1999). The disorder is normally responsive to immunomodulation, including IvIg (Sharma et al. 2002b). When the occurrence of chronic inflammatory demyelinating polyneuropathy is suspected in a diabetic patient, it is advisable to give a trial of IvIg treatment (Section 21.3.3) to prove that the neuropathy is reversible. If so, long-term treatment should either continue with IvIg, or using oral prednisolone with adjustment of the patient’s hypoglycaemic medication to offset the diabetogenic effect of steroids.
21.18 Neuropathy due to systemic medical disorders
21.18.1 Chronic renal failure
Clinical or electrophysiological evidence of polyneuropathy is detectable in over 50 per cent of patients with end-stage renal disease. Symptomatic polyneuropathy was much commoner before the era of widespread and earlier introduction of renal replacement therapy. Uraemic neuropathy develops very gradually and is uncommon if the glomerular filtration rate exceeds 10 ml/min. Although uraemia itself is responsible for the neuropathy in many patients with chronic renal failure, it should be recognized that neuropathy may be an independent feature of the underlying disease which has caused the chronic renal failure: diabetes mellitus, systemic vasculitis, myelomatosis, amyloidosis, and systemic lupus erythematosus. The neuropathies caused by these diseases are often focal or demyelinating in nature, unlike the axonal degeneration polyneuropathy of uraemia.
A restless leg syndrome is the commonest early symptom of uraemic polyneuropathy: crawling, pricking, and itching sensations occur at night. Burning paraesthesiae may develop. Muscle cramps and fatigability are followed by distal weakness and muscle atrophy. An autonomic neuropathy may cause sexual impotence and contribute to difficulties in intravascular fluid volume regulation, making postural hypotension a particular problem following fluid removal by dialysis. The earliest physical signs are loss of vibration sensation at the toes and absent ankle jerks. A mixed motor, autonomic, and multimodal sensory neuropathy eventually develops.
Nerve conduction studies reflect axonal degeneration of motor and sensory fibres. Nerve excitability is reduced; this axonal depolarization correlates with hyperkalaemia and improves with dialysis (Krishnan et al. 2006). Nerve biopsy shows loss of all sizes of nerve fibres, particularly large myelinated fibres. Less commonly, there is evidence of segmental demyelination or remyelination which may be secondary to axonal changes. Autopsy studies show degeneration of the dorsal columns of the spinal cord, representing the central axons of dorsal root ganglion cells. It is presumed that uraemic polyneuropathy results from the accumulation of neurotoxic waste products, but the causative compounds have not been identified.
Renal replacement therapy normally prevents the neuropathy from deteriorating and may allow considerable recovery. The greatest improvement occurs in patients receiving renal transplants rather than those maintained by dialysis. Following successful renal transplantation, clinical and electrophysiological improvement starts after some months and continues slowly. However, full recovery of the neuropathy is unusual unless it was initially mild. A carpal tunnel syndrome may develop in patients receiving long-term dialysis, due to deposition of β2-microglobulin amyloid in the flexor retinaculum. Acute or subacute neuropathy has occurred occasionally in patients treated by peritoneal dialysis. Such patients may have coexisting diabetes mellitus, the neuropathy has demyelinating features, and sometimes improves (Ropper 1993).
Paraesthesiae, lancinating limb pains, or muscle cramps occur in half of all patients with established myxoedema. Sensory symptoms in the limbs may be the presenting feature of hypothyroidism. There are few neuropathic signs on examination; minor distal sensory changes are usually the only abnormalities. Distal spontaneous and evoked pains either before or after thyroid replacement therapy, reflects a small fibre neuropathy or central sensitization (Ørstavik et al. 2006). Although characteristically slowly relaxing, the tendon reflexes are usually retained. Nerve biopsies may show segmental demyelination. The sensory symptoms may resolve on thyroid hormone replacement therapy. Carpal tunnel syndrome is common, and tarsal tunnel syndrome less common, in myxoedema. Acroparaesthesiae due to the former often resolve with thyroid hormone replacement therapy, but if not, surgical decompression may be required.
Both polyneuropathy and the carpal tunnel syndrome are common in patients with acromegaly and are not thought to be due to the associated diabetes mellitus. The polyneuropathy is of insidious onset, causing distal paraesthesiae, depressed reflexes, distal muscle weakness and multimodal sensory disturbance. The peripheral nerves may be clinically enlarged. Nerve conduction is slightly slowed. Nerve biopsies show axonal loss with some demyelination and remyelination. The fascicular cross-sectional area is increased with accumulation of tissue subperineurially and endoneurially. It is unclear whether the neuropathy improves significantly with treatment of the underlying growth hormone excess. Symptomatic carpal tunnel syndrome should be treated by surgical decompression.
21.18.4 Primary biliary cirrhosis
A distal sensory polyneuropathy may develop in patients with primary biliary cirrhosis. Sural nerve biopsy shows perineurial xanthomatous deposits distorting the normal architecture.
21.18.5 Systemic lupus erythematosus
A wide variety of peripheral neuropathies occur in systemic lupus erythematosus and should be treated according to principles already outlined. Some evidence of polyneuropathy occurs in 20 per cent, although often mild or even asymptomatic (Omdal et al. 1991). Demyelinating neuropathies of the acute Guillain–Barré type (Section 21.10.1) or steroid-responsive chronic inflammatory demyelinating polyneuropathy (Section 21.11.2) may occur. Chronic sensorimotor axonal degeneration neuropathies may be encountered. Focal neuropathy due to necrotizing arteritis, or carpal tunnel syndrome may be the presenting feature of systemic lupus erythematosus (Stefurak et al. 1999). A small fibre sensory neuropathy may be demonstrated at skin biopsy by reduced numbers of intradermal nerve fibres (Gøransson et al. 2006).
A small proportion of patients with sarcoidosis have peripheral neuropathy. Neuropathy can be the presenting feature of sarcoidosis. Cranial nerve palsies are most often encountered; these are often multiple, of variable severity, and particularly affecting the facial nerve. Mononeuropathy may affect any peripheral nerve, including the sensory nerves of the trunk. Sensorimotor polyneuropathy is less common and may take acute multifocal or purely sensory forms. Sensorimotor polyneuropathy may be associated with multiple small granulomas within biopsied nerves or muscles, with associated inflammatory or vasculitic features in some (Said et al. 2002). The response to steroids is usually good.
21.18.7 Eosinophilia–myalgia syndrome
This disorder followed months or years after ingestion of contaminated l-tryptophan, a component of some body building food supplements. There was associated eosinophilia and brawny induration of the skin. Some patients developed a painful inflammatory myopathy. Sensorimotor axonal degeneration neuropathies or multifocal neuropathies may occur. The combination of neuropathy and myopathy could result in respiratory failure requiring ventilation (Smith and Dyck 1990). A more chronic demyelinating neuropathy has also occurred (Freimer et al. 1992). The neuropathy of the eosinophilia–myalgia syndrome should be distinguished from other neuropathies associated with eosinophilia: hypereosinophilic syndrome (Section 21.18.8), necrotizing arteritis of the Churg–Strauss type (Section 21.15.3), and Hodgkin’s disease (Section 21.12.4).
21.18.8 Hypereosinophilic syndrome
Symmetrical sensorimotor peripheral neuropathy due to axonal degeneration occurs in about one-tenth of patients with idiopathic hypereosinophilia (Monaco et al. 1988). Increased numbers of degranulated eosinophils are found in the blood. The systemic disorder may include a restrictive cardiomyopathy due to endomyocardial fibrosis.
Sensorimotor polyneuropathy can develop in patients being ventilated for cardiorespiratory disease who develop multi-organ failure or sepsis. Prospective electrophysiological examination of patients with severe sepsis shows that abnormalities are common at the time of admission to intensive care, and predict subsequent development of critical illness neuropathy and myopathy (Khan et al. 2006). The compound muscle action potentials and sensory nerve action potentials are reduced in amplitude, and needle electrodes show evidence of limb muscle denervation. This neuropathy usually comes to light when patients fail to wean from the ventilator. The mortality in such patients is high, but those who recover neurologically do so over 3–6 months. This rapidity of recovery is faster than might be expected from a dense axonal degeneration polyneuropathy and suggests a degree of potentially reversible conduction failure. The disorder should be distinguished from Guillain–Barré syndrome by normal spinal fluid protein levels and the electrophysiological characteristic of axonal degeneration rather than demyelination. In a critically ill patient in the intensive care setting, the principal differential diagnosis is a critical illness myopathy, occurring most commonly in acute respiratory disorder such as asthma treated with non-depolarizing neuromuscular-blocking agents or high-dose steroids. Critical illness polyneuropathy and myopathy may coexist, and given that the creatine kinase level often remains normal, muscle biopsy is the only reliable way to diagnose the myopathy (Gutmann and Gutmann 1999).
21.18.10 Sjogren’s syndrome
A sensory neuronopathy similar to the paraneoplastic disorder (Section 21.13.1) may occur in Sjogren’s syndrome or the isolated sicca complex of dry eyes and dry mouth (Mori et al. 2005). This disorder can develop in patients without underlying cancer or Sjogren’s syndrome and can be associated with Adie’s pupil. The cases associated with Sjogren’s syndrome usually have predominantly kinaesthetic sensory loss, may have neuropathic pain, dry eyes on Schirmer testing, a positive antinuclear factor, and they lack other features of paraneoplastic encephalomyelitis. Their sensory disturbance may stabilize or improve slightly. T2-weighted MRI shows high signal intensity in the posterior columns cervically. No treatment is invariably effective in these sensory neuropathy syndromes, although there are reported benefits of IvIg in the ataxic neuropathy (Takahashi et al. 2003).
21.18.11 Gastrointestinal disease
Patients with inflammatory bowel disease can develop a range of demyelinating and axonal sensorimotor polyneuropathies and small fibre sensory neuropathies (Gondim et al. 2005). Immunomodulatory agents usually lead to improvement in those with demyelinating neuropathies. Approximately a quarter of patients with coeliac disease have a detectable chronic axonal neuropathy (Luostarinen et al. 2003). A range of neuropathies, usually axonal, is reported up to three times as frequently in patients with gluten sensitivity associated with antigliadin antibodies as in controls (Hadjivassiliou et al. 2006).
21.19 Drug-induced polyneuropathy
Proving that a drug causes peripheral neuropathy can be difficult unless prospective monitoring of patients has been carried out within a clinical trial, as is usually the case for cancer and HIV chemotherapy. Tinglings are a common medication side effect, but often reflect a physiological effect of the drug, rather than a degenerative peripheral neuropathy. Patients with pre-existing peripheral neuropathy, especially Charcot–Marie–Tooth disease seem unusually vulnerable to normally non-toxic doses of neuropathic drugs, such as Vincristine (Chaudhry et al. 2003; Weimer and Podwall 2006).
Alcoholics may develop either polyneuropathy or focal compressive peripheral nerve lesions. Pressure palsies often follow periods of stuporous immobility and generally affect the radial, ulnar, or common peroneal nerves. Polyneuropathy may develop insidiously in long-standing alcoholics. It usually presents with symmetrical burning dysaesthesiae or paraesthesiae distally, or with sensory ataxia. Physical signs of a symmetrical sensorimotor polyneuropathy are often restricted to the legs. Nerve conduction studies reflect axonal degeneration predominantly affecting sensory axons. Autonomic neuropathy may be present, and is associated with an increased risk of cardiovascular death. Alcoholic polyneuropathy may be caused either by direct toxicity of ethanol and its metabolites or by nutritional deficiency. Alcoholic neuropathy tends to be sensory dominant and slowly progressive, whereas thiamine deficiency produces marked motor involvement and subacute progression (Koike et al. 2003). Nutritional deficiency polyneuropathies are common in patients with associated Wernicke–Korsakoff syndrome (Section 34.5) and particularly reflect deficiency of vitamin B1, thiamine. Ethanol, or its metabolites such as acetaldehyde, may have direct neurotoxic effects; this mechanism may be a particularly important cause of neuropathy in those alcoholics who are not malnourished.
Neuropathy is often ascribed erroneously to alcohol in any patients with moderately high consumption. In practice neuropathy is unlikely until a lifetime of alcohol consumption of 15 kg ethanol per kg body weight is reached; this equates for a 70 kg man to 300 ml whisky daily for 25 years (Monforte et al. 1995). Occasionally rapidly progressive polyneuropathy resembling Guillain–Barré syndrome, but without raised CSF protein or slowed nerve conduction, has occurred in alcoholics (Wohrle et al. 1998). Vitamin B1 replacement therapy should be given to all patients with alcoholic polyneuropathy. Gradual improvement in the clinical and electrophysiological aspects of peripheral neuropathy occurs in those alcoholics who achieve long-term abstinence. Disulfiram, Antabuse, therapy may itself produce neuropathy in alcoholics (Section 21.19.8).
This iodine-containing antiarrhythmic drug increases two-fold the occurrence of symmetrical distal sensorimotor polyneuropathy after prolonged administration (Vorperian et al. 1997). The neuropathy develops some months after starting treatment, can produce severe weakness, and is often associated with a raised spinal fluid protein level. Sural nerve biopsies show loss of myelinated fibres with lipid-laden lysosomes in Schwann cells; demyelination rather than axonal degeneration is thought to be the primary event (Pellissier et al. 1984). Approximately 70 per cent of patients taking 800 mg of amiodarone daily develop a reversible syndrome of tremor and ataxia which occurs independently of peripheral neuropathy.
Chloroquine is used to treat malaria, amoebiasis, and chronic discoid lupus erythematosus. A combination of sensorimotor peripheral neuropathy with myopathy, or myopathy alone, may occur in patients taking doses of at least 500 mg daily for a year or more (Whisnant et al. 1963). The neuromyopathy improves steadily on stopping the drug.
Cisplatin, carboplatin, and oxaloplatin are important drugs in treating ovarian, testicular, and bladder tumours. A predominantly sensory peripheral neuropathy, characterized by distal paraesthesiae, develops in almost all patients given a cumulative dose of 300–600 mg/m2 cisplatin, often accompanied by Adriamycin (LoMonaco et al. 1992). Sensory ataxia may be severe. Sensory nerve conduction is abnormal, motor conduction is normal. Symptoms of neuropathy may start some weeks after the last dose of cisplatin has been administered, and may subsequently worsen for a few months. This phenomenon is known as coasting. Partial or complete recovery of the neuropathy may occur after cessation of cisplatin therapy, usually taking more than a year. Oxaloplatin differs in producing sensory symptoms within an hour of infusion and eventually almost all patients receiving a cumulative dosage of >540 mg/m2 develop neuropathy (Quasthoff and Hartung 2002).
Mild neuromyopathy may be common in patients receiving colchicine as treatment for gout (Kuncl et al. 1987). Neuromyopathy is particularly likely to occur if there is associated mild chronic renal impairment. The myopathic element may involve severe proximal muscle weakness, electromyographic features resembling those of polymyositis, elevated serum creatine kinase levels, and electron microscopic evidence of accumulation of lysosomes and autophagic vacuoles in biopsies of proximal muscles. Creatine kinase levels return to normal within days of stopping colchicine, and proximal muscle strength improves over subsequent weeks. The neuropathic element is less pronounced than the myopathy, with distal limb sensory loss, tendon areflexia, and evidence of axonal degeneration on nerve conduction studies and sural nerve biopsies.
Motor neuropathy may complicate long-term therapy with 200–500 mg of dapsone daily (Gutmann et al. 1976). Such doses are generally used for the treatment of dermatological conditions, usually dermatitis herpetiformis, and dapsone neuropathy is less likely to complicate leprosy treatment. Weakness and wasting is most prominent distally in the limbs. Motor conduction velocities are normal or only slightly slowed and evoked muscle action potentials reduced. Tendon reflexes tend to be preserved although hypoactive. Muscle strength improves following withdrawal of dapsone.
21.19.7 Didanosine and antiretroviral drugs
Polyneuropathy occurs regularly in patients with HIV infection treated by the nucleoside analogue drugs didanosine, ddI, zalcidabine, ddC, lamuvidine, 3TC, stavudine, d4T, and fialuridine reverse transcriptase inhibitor, FIAV, and is a dose-limiting side effect (Dalakas 2001). This neuropathy is painful, purely or predominantly sensory, and often of explosive onset. The commonest signs are hyporeflexia of the ankle jerk, impaired pinprick and vibration sensation in the feet, and gait unsteadiness. The chance of neuropathy is dosage dependant, and it develops on average 8 weeks after starting high-dose therapy but develops later with contemporary lower dose therapy. After stopping the drug, the neuropathy may ‘coast’ with worsening symptoms, before stabilizing and improving. It can be difficult to differentiate this toxic neuropathy from the painful sensory neuropathy which occurs in patients with established HIV infection (Section 21.14.2). However these drug-toxic neuropathies differ in that they occur during the months after starting therapy, the painful symptoms usually evolve abruptly, and the hands are uninvolved. If in doubt, the drug should be withdrawn for some months to see if improvement occurs.
An axonal degeneration sensorimotor neuropathy may develop after disulfiram, Antabuse, therapy for alcoholism. Symptoms improve after stopping the drug. Axonal neurofilament accumulations can be found in the sural nerve on electron microscopy. It is noteworthy that disulfiram is enzymatically converted to carbon disulphide which itself is known to cause a distal axonopathy with neurofilament accumulations (Section 21.21.2) (Ansbacher et al. 1982). Prospective studies suggest that peripheral nerve damage occurs at disulfiram doses of 250 mg/day, but not at 125 mg/day (Palliyath et al. 1990).
Predominantly sensory neuropathy is an occasional consequence of treatment with the antituberculous drug ethambutol (Nair et al. 1980). Optic neuropathy is a commoner complication of long-term ethambutol administration.
Acute or subacute sensorimotor neuropathy can occur in patients some months after commencing gold therapy for rheumatoid arthritis (Katrak et al. 1980). Partial recovery occurs over the months following cessation of gold administration. Myokymia of limb muscles is a distinctive finding. Gold neuropathy should be distinguished from the mononeuritis multiplex that can occur in patients with aggressive rheumatoid disease with vasculitic features (Section 21.15.3).
Patients with inherited slow drug-acetylation status may develop peripheral neuropathy when they receive long-term isoniazid therapy. Paraesthesiae and numbness are the initial symptoms and neuropathic pain may be prominent. Muscle weakness usually only appears in the later stages. Hyperalgesia and muscle cramping are distinctive features in many patients (Ochoa 1970). Isoniazid antagonizes the actions of vitamin B6, or pyridoxine, and the neuropathy can be prevented by simultaneous administration of pyridoxine during isoniazid therapy. In patients who develop neuropathy, isoniazid therapy may be interrupted, vitamin B6 given parenterally at 100–200 mg/day, and other antituberculous drugs continued. Variable degrees of improvement in the neuropathy follow these measures.
A predominantly sensory and axonal degeneration polyneuropathy has been noted in patients treated with Leflunomide for rheumatoid arthritis (Bonnel and Graham 2004). The mean time of onset was after 6 months of therapy and early discontinuation led to some improvement.
Occasional cases of peripheral neuropathy have been associated with lithium carbonate therapy for depression. Toxic levels of lithium were deemed responsible for a severe generalized sensorimotor neuropathy which shows electrophysiological and nerve biopsy evidence of axonal loss. Recovery can occur following drug cessation (Vanhooren et al. 1990).
Sensory neuropathy may follow prolonged administration of the antibacterial drug metronidazole (Coxon and Pallis 1976). Paraesthesiae or numbness of the toes have usually been recorded only in patients who have received a total dose of at least 30 g. Sensory nerve action potentials are diminished in amplitude but of normal latency. Neuropathic symptoms resolve during the months after stopping the drug. Occasionally convulsions, encephalopathy, and cerebellar ataxia have been associated with metronidazole therapy.
An axonal degeneration sensory neuropathy may follow administration of large doses of the antibiotic, nitrofurantoin. Total dosages usually exceed 20 g, although neuropathy can occur after lower dosage in patients with impaired renal excretion (Lindholm 1967). Partial recovery may follow cessation of the drug.
Peripheral neuropathy is demonstrable in up to 20 per cent of epileptic patients on long-term anticonvulsant therapy. It is usually relatively mild, involving sensory diminution in a stocking distribution and reduced ankle tendon reflexes. Although commonly attributed to phenytoin, the evidence relates this neuropathy to a wide range of anticonvulsants. It is commonest in patients receiving multiple drugs (Swift et al. 1981).
Sensory neuropathy with prominent ataxia may follow self-medication with megadoses of pyridoxine, vitamin B6. The normal human daily pyridoxine requirement is approximately 0.004 g. Sensory neuropathy has usually followed daily oral ingestion of 2–6 g of pyridoxine or single massive parenteral doses (2 g/kg) in the treatment of mushroom poisoning (Albin et al. 1987). Neuropathy has also been recorded following long-term chronic consumption of lower doses (0.2 g daily) (Parry and Bredesen 1985). The rate of onset of symptoms is proportional to the magnitude of the daily dosage. The sensory neuropathy probably reflects damage to dorsal root ganglion neurones, with little potential for recovery.
A pharmacoepidemiologic database study reported an increased incidence of predominantly sensory and axonal polyneuropathy in patients receiving long-term statin treatment (Gaist et al. 2002). The neuropathy tends to be mild, with pain, paraesthesiae, numbness, and absent tendon reflexes in half of the cases.
Either distal axonal, or subacute demyelinating, sensorimotor polyneuropathies have been noted in more than 80 per cent of patients receiving suramin doses sufficient to achieve plasma levels 350 µg ml–1 during attempted treatment of hormone-refractory metastatic prostate cancer (Chaudhry et al. 1996).
Subacute demyelinating sensorimotor polyneuropathy has been noted 2 weeks to 6 months after starting tacrolimus, FK506, immunosuppression in transplant recipients (Bronster et al. 1995). It resembles chronic inflammatory demyelinating polyneuropathy and responds to plasma exchange or IvIg treatment. Recovery has been reported following substitution of tacrolimus by cyclosporin.
The drugs docetaxel and paclitaxel, derived from yew tree needles, promote microtubule polymerization. They are valuable antitumour drugs but peripheral neuropathy is a dose-limiting side effect. Sensory neuropathy can occur in humans within days of high-dose paclitaxel therapy or more slowly at lower dosage regimens. Neuropathy seems more likely when the cumulative dose exceeds 600 mg/m2 (Hilkens et al. 1996). Initially tingling and numbness affect the feet before spreading to the hands. Limb weakness can be present both distally and proximally. Nerve conduction studies show features of both axonal degeneration and demyelination. Symptoms and signs can progressively ‘coast’ after stopping taxols, but recovery usually starts by 8 weeks (New et al. 1996).
Sensory neuropathy, with prominent paraesthesiae and muscle cramps, followed the use of thalidomide as a hypnotic in the 1960s before it was withdrawn for teratogenicity. Since its reintroduction for a variety of medical disorders, including graft versus host disease and erythema nodosum leprosum, thalidomide’s capacity to cause a predominantly sensory neuropathy is regarded by many as being dose limiting. The neuropathy seems more likely with cumulative doses exceeding 20 g (Cavaletti et al. 2004).
21.19.23 Tumour necrosis factor inhibitors
Therapeutic monoclonal antibodies blocking tumour necrosis factor-α, enteracept and infliximab, have been associated with reports of chronic inflammatory demyelinating polyneuropathy and acute motor neuropathy with conduction block (Richez et al. 2005; Singer et al. 2004).
21.19.24 Vinca alkaloids
Vincristine and other vinca alkaloids disrupt microtubules and are used chiefly for treating lymphoma or leukaemia. The peripheral neuropathy initially develops after cumulative dosage of 4–19 mg/m2 and causes paraesthesiae, areflexia, and mild autonomic symptoms. Modern drug administration schedules show early neuropathic symptoms to be more severe at higher dosage intensities, such as 1.33 mg/week (Verstappen et al. 2005). If the drug is continued, severe muscle weakness and sensory loss develop. Autonomic neuropathy may be severe, with paralytic ileus, features of acute abdomen, impotence, or postural hypotension. Laryngeal nerve palsies have been attributed to vincristine therapy. Nerve conduction studies point to a dying back axonal degeneration neuropathy (Quasthoff and Hartung 2002). Mild neurotoxicity inevitably occurs with therapeutically effective doses of vincristine. When patients develop numbness or mild manipulatory difficulties, it should be a warning to reduce or stop the drug. Vincristine should be stopped immediately if significant weakness or paralytic ileus develop. Functional recovery is usual if the drug is stopped before the advent of significant toxicity. Coasting, or off-therapy worsening, of the neuropathy occurs in over a quarter after stopping therapy (Verstappen et al. 2005). Permanently absent ankle tendon jerks are commonly noted in otherwise asymptomatic patients who have received courses of vincristine therapy. Patients with hereditary motor and sensory neuropathy may be unusually sensitive to vincristine neuropathy (Weimer and Podwall 2006).
21.20 Metal-poisoning polyneuropathy
This section considers peripheral neuropathies attributable to arsenic, lead, mercury, and thallium poisoning. Neuropathies due to therapy with cisplatin, lithium, and gold are considered in Section 21.19.
Neuropathy due to inorganic arsenic poisoning may develop insidiously in arsenic smelting workers. If it occurs acutely after single-dose poisonings, it develops 2–3 weeks later in victims who survive the initial shock and gastrointestinal disturbance of acute intoxication (Ratnaike 2003). Numbness and paraesthesiae are the initial symptoms, and abnormalities of vibration and position sensation are demonstrable. Distal leg muscle weakness may develop subsequently. The ankle tendon reflexes are invariably lost, those at the knee are sometimes lost, and the arm reflexes are generally preserved. White lines across the nails, Mee’s lines, develop later. Sensory nerve action potentials are absent and motor conduction is mildly slowed initially before electrophysiological features of axonal degeneration supervene (Donofrio et al. 1987). Sural nerve biopsies show axonal degeneration. Slow improvement occurs over a period of years but permanent abnormalities are usual.
Chronic arsenical exposure in industrial workers may produce an asymptomatic sensorimotor neuropathy, detectable only by nerve conduction studies and unaccompanied by neuropathic signs on examination (Feldman et al. 1979). The arsenic level may be elevated in the blood, urine, or hair, depending upon the recency of exposure. Hyperkeratosis of the hands and feet may be noted. Gastrointestinal symptoms are not usually a feature of chronic arsenical poisoning. Chronic poisoning may cause anaemia with basophilic stippling of erythrocytes. Chelation therapy may be indicated, particularly in patients seen soon after the ingestion of a single dose.
Peripheral neuropathy due to inorganic lead poisoning usually occurs in metal smelting or battery manufacturing workers. Organic lead intoxication has not been associated clearly to peripheral neuropathy. Lead neuropathy takes two forms, an acute or subacute predominantly motor disorder, and a chronic sensory disorder (Rubens et al. 2001). The blood lead level tends to reflect recent exposure.
Classically a purely motor peripheral neuropathy develops, particularly affecting much-used muscles, such as the wrist extensors of manual workers. Abdominal crampings are a common initial manifestation. Prominent wrist or foot drop are characteristic. Muscle weakness can be profound, causing respiratory failure. The degree of tendon reflex loss varies. Sensory loss is unusual. Children with lead neuropathy frequently have an associated encephalopathy (Section 5.7.3). Motor nerve conduction velocities may be slowed. Sural nerve biopsies show loss of the large myelinated axons with noteworthy paranodal demyelination. Lead interferes with porphyrin metabolism, which may explain the similarity between the symptoms of lead poisoning and those of porphyric neuropathy (Section 21.8.6): abdominal pain, motor neuropathy, and behavioural disturbance occur in both. In addition there is a rare inherited condition known as plumboporphyria, due to δ-aminolaevulinic acid dehydratase deficiency, in which porphyric neuropathy may be precipitated by occupational exposure to lead within accepted safety limits (Dyer et al. 1993).
Chronic lead intoxication can cause sensory polyneuropathy independently of its provocation of porphyria (Rubens et al. 2001). Distal sensory disturbance, reduced reflexes and autonomic vasomotor or sudomotor abnormalities are characteristic. Such patients do not have motor involvement. Delayed and reduced sensory nerve action potentials are found electrophysiologically. It is noteworthy that sensory features, which are absent in classical descriptions of lead neuropathy, are prominent in all other polyneuropathies caused by heavy metal poisoning. The free erythrocyte protoporphyrin level is the best guide to chronic lead exposure. Basophilic stippling of erythrocytes is seen on blood smear. Treatment involves identifying and removing the source of exposure, and using the chelating agents.
Chronic exposure to inorganic or elemental mercury produces a mild peripheral neuropathy. Mild sensorimotor neuropathy has been noted following long-term exposure of industrial workers to inorganic mercury vapour and in dentists using mercury amalgam. Previously asymptomatic polyneuropathy may be demonstrable many years after occupational elemental mercury exposure (Albers et al. 1988). Elemental mercury poisoning occasionally resembles motor neurone disease (Adams et al. 1983).
Organic mercury poisoning typically causes the combination of paraesthesiae, sensory ataxia, and visual-field constriction (Section 5.7.5). Organic mercury poisoning has occurred after exposure to methyl mercury dust, after eating seafood which has accumulated methyl mercury from industrial effluent, Minamata disease, and after inadvertent consumption of seed grain treated with mercurial fungicides. Patients with mercurial neuropathy develop paraesthesiae in and around the mouth and in the fingers and the toes. Nerve conduction studies may be normal in patients with organic mercury toxicity, suggesting that the sensory loss can be due to central nervous system involvement. Extensive cerebellar involvement is evident at autopsy (Nierenberg et al. 1998).
The diagnosis of mercury poisoning may be confirmed by measuring blood, urine, and hair levels, which are differentially elevated depending upon the type and rate of exposure. The treatment involves identification and elimination of the source of exposure. Chelating agents such as dimercaprol or penicillamine are mainly effective against inorganic and elemental, rather than organic, mercury poisoning. It is unlikely that chelating agents remove mercury that is already bound to neural tissue.
Polyneuropathy due to thallium normally follows suicidal or homicidal poisoning attempts with this tasteless, colourless rodenticide. High doses cause shock due to gastroenteritis and dehydration. If the victim survives, sensorimotor neuropathy becomes evident within a few days. Sensory symptoms occur first and consist of painful paraesthesiae, particularly affecting the feet (Kuo et al. 2005). The neuropathy may progress rapidly to involve the respiratory and bulbar muscles, thus resembling the Guillain–Barré syndrome. An associated autonomic neuropathy can result in tachycardia and hypertension. Central nervous system involvement occurs in severe poisoning, producing ataxia, optic neuropathy, confusional psychoses, and involuntary movements. Systemic features include dark pigmentation at the hair roots (Fig. 21.23) followed by alopecia, dry scaly skin, and Mee’s lines on the nails. Neuropathological studies show axonal degeneration of fibres in peripheral nerves and dorsal columns. Electron microscopy reveals swollen axons containing large vacuoles and distended mitochondria. Although the neuropathy may eventually recover partially, permanent abnormalities are the rule unless the patient is seen early enough to undertake effective gastric decontamination. Chelating agents have not been effective. Haemoperfusion has been recommended for severe poisoning. Oral Berliner–Blue may promote faecal excretion of thallium.
21.21 Polyneuropathy due to industrial and agricultural chemicals
Acrylamide monomer is catalytically polymerized in order to stabilize soil during mining and other earthworkings. The monomer is neurotoxic. High-dose intoxication, as may occur after drinking contaminated well-water, causes a subacute encephalopathy followed some days later by signs of mild polyneuropathy (Igisu et al. 1975). Chronic low-dose intoxication generally occurs in construction workers following skin and inhalational exposure. Polyneuropathy may occur following exposure for as little as 4 weeks. The neuropathy involves both sensory and motor fibres. Positive sensory symptoms, such as paraesthesiae, are unusual. Diffuse areflexia is an early finding. Ataxia may be prominent. Contact dermatitis, blistering, and hyperhidrosis of the palms and soles may occur. Sensory nerve action potentials are small or absent and only a mild degree of motor slowing occurs. Sural nerve biopsy shows degeneration and regeneration of axons. Electron microscopy shows accumulations of disorganized neurofilaments in occasional axons, but giant axonal swellings are not seen (Davenport et al. 1976). In mild or subclinical cases, good recovery follows removal from exposure. Only partial recovery occurs from the more severe neuropathies.
21.21.2 Carbon disulphide
Peripheral neuropathy has been noted in workers using carbon disulphide in poorly ventilated conditions, in the rubber vulcanization or viscose rayon manufacturing industries. Distal sensorimotor loss and areflexia is usually restricted to the legs, but may involve the arms in severe cases. Electrophysiologically, the neuropathy is due to axonal degeneration (Vasilescu 1976). It is sometimes accompanied by encephalopathy with psychotic features.
Dimethylaminopropionitrile was used as a catalyst in the manufacture of polyurethane. Exposed workers developed an axonal degeneration sensorimotor neuropathy with noteworthy involvement of bladder control and sexual dysfunction. The initial symptoms were generally urinary hesitancy and impotence (Keogh et al. 1980).
21.21.4 Diethylene glycol
A rapidly ascending paralysis involving cranial muscles has been noted to start 8 days after diethylene glycol ingestion after initial manifestations of confusion and renal failure treated with haemodialysis (Rollins et al. 2002).
21.21.4 Ethylene oxide
Ethylene oxide gas is used both as a precursor for industrial chemicals and for sterilizing heat-sensitive devices used in healthcare. Industrial exposure to the gas has caused both encephalopathy and sensorimotor polyneuropathy (Gross et al. 1979).
Peripheral neuropathy has followed intense or repeated skin exposure to derivatives of the weed killer 2,4-D, 2,4-dichlorophenoxyacetic acid. Nausea, vomiting, and diarrhoea occur during the days immediately following exposure. First symptoms of peripheral neuropathy develop some days later and consist of painful paraesthesiae in the fingers and toes. Severe motor and sensory disability develop subsequently and recover incompletely. Once the neuropathy is established, motor nerve conduction velocities are moderately slowed (Goldstein et al. 1959).
n-Hexane and methyl n-butyl ketone ‘MNBK’ are used as solvents in glues and in flexographic printing. They are metabolized to the neurotoxic compound 2,5-hexanedione. Sensorimotor neuropathy has occurred in workers using such glues in shoe or furniture manufacture and following inhalational solvent abuse, ‘glue-sniffing’, (Altenkirch et al. 1977). The neurotoxic potency of hexacarbons is enhanced by simultaneous exposure to methylethylketone, which is often present in solvent mixtures but is not in itself neurotoxic. The peripheral neuropathy starts with numbness of the digits and may develop into severe symmetrical distal sensory and motor loss. Severe weakness may develop subacutely in ‘glue-sniffers’ and be misdiagnosed as the Guillain–Barré syndrome. Even after removal from exposure to the toxin, the neuropathy may continue to worsen for 2 or 3 months before stabilization and partial recovery take place. Electron microscopic examination of nerve biopsies shows giant axonal profiles swollen by accumulations of disorganized neurofilaments. Motor nerve conduction velocities are substantially slowed once the neuropathy is established. This may reflect the marked paranodal demyelination and myelin thinning that occur in relation to giant axonal change; since the neuropathy is not primarily demyelinating in nature.
Sensorimotor peripheral neuropathy has been reported following chronic low-dose intoxication with methylbromide, a gas used as a fumigant and in fire extinguishers (Kantarjian and Shaheen 1963). Complete recovery of the neuropathy was reported within a year of removal from exposure.
Peripheral neuropathy has occurred following exposure to both organophosphorous and carbamate pesticides. In both cases, the symptoms of peripheral neuropathy develop after a delay of a few days or weeks following a single exposure. This delayed onset of neuropathy follows the earlier cholinergic phase of poisoning, in which acute paralysis, overwhelming bronchial secretions, bradycardia, and seizures may occur (Section 5.8.1).
In organophosphorous poisoning, symptoms of a predominantly motor neuropathy have been reported 1–3 weeks after acute exposure to the pesticides tricresylphosphate, mipafox, leptophos, trichlorphon, trichlornate, and methamidophos (Senanayake and Johnson 1982; Lotti et al. 1984). Not all organophosphates induce delayed peripheral neuropathy and it has been proposed that this capacity relates to their propensity to inhibit neurotoxic esterase (Lotti et al. 1984). It is uncertain whether neuropathy can follow chronic low-dose pesticide exposure, or whether it might follow acute intoxication by nerve gases intended for warfare. The initial symptoms of neuropathy consist of cramping in distal leg muscles accompanied by distal paraesthesiae and numbness. Progressive distal leg muscle weakness and hyporeflexia develop, followed by similar weakness of the arms. The severity varies, but severe quadriplegia may occur. Demonstrable sensory signs are mild or absent. Superimposed pyramidal tract abnormalities may be seen. Nerve conduction studies show denervation of muscles with little or no slowing of conduction velocity. Although the peripheral neuropathy recovers to some degree, the associated pyramidal tract abnormalities contribute to substantial long-term disability (Morgan and Penovich 1978).
Acute ingestion of carbamate pesticides may also produce delayed onset of peripheral neuropathy (Umehara et al. 1991). In comparison to organophosphorous poisoning, carbamate toxicity produces more prominent sensory signs and the degree of recovery is greater.
The solvent and degreasing agent trichloroethylene can cause selective numbness of the facial skin, or polyneuritis cranialis in severe exposures (Feldman et al. 1992).
This rodenticide is related to streptozotocin, a diabetogenic toxin. The acute onset of diabetes mellitus and severe autonomic failure, and a glove and stocking disturbance of pinprick sensation have been recorded after suicidal consumption of vacor (Pont et al. 1979). The autonomic failure is permanent with prominent disturbance of blood pressure and bladder control.
21.22 Vitamin deficiency polyneuropathy
21.22.1 The burning feet syndrome
Many nutritional neuropathies reflect the multiple vitamin deficiencies that occur during malnutrition due to starvation, chronic gastrointestinal disease, malnourished alcoholism, and contemporary bariatric surgery for morbid obesity (Thaisetthawatkul et al. 2004). Such patients often develop neurological illnesses which do not conform to the classic descriptions of dry beriberi due to thiamine deficiency or pellagra due to pyridoxine deficiency. Multiple vitamin deficiencies may produce the combination of predominantly sensory peripheral neuropathy with burning feet, amblyopia, sensorineural deafness, dizziness, myelopathy, and orogenital dermatitis, which is sometimes known as Strachan’s syndrome. During the past century, this state has been described in malnourished native West Indians, jail inmates, sugar plantation labourers, and prisoners of war, particularly those held captive in the Far East during the Second World War (Cockerell and Ormerod 1993). Although the symptoms recover in some patients, they are permanent in many despite reinstitution of a balanced diet. The ‘burning feet syndrome’ is another permanent sequel of nutritional deprivation.
21.22.2 Vitamin B1 deficiency
Dry or neuropathic beriberi results from thiamine deficiency in malnourished alcoholics, after gastrectomy or in patients receiving a diet of milled rice without vitamin B supplementation (Koike et al. 2001). The latter group of patients are often physically active and consuming large amounts of carbohydrate. Sensorimotor polyneuropathy, leg oedema, and cardiomegaly usually develop simultaneously. The neuropathy is predominantly motor, initially affecting distal leg muscles, and may prevent walking. Neuropathic limb pains or paraethesiae may occur. The neuropathy can follow a relapsing course prior to the institution of vitamin B1 replacement therapy after which it may improve within two weeks (Ishibashi et al. 2003). Sural nerve biopsies from established cases show axonal degeneration predominantly affecting the larger myelinated fibres with a degree of secondary demyelination (Ohnishi et al. 1980). Motor nerve conduction is mildly slowed and sensory nerve action potentials diminished. Measurement of blood or urine thiamine levels is of limited value in making the diagnosis. The red cell transketolase activity is a more sensitive index, but does not distinguish between acute and chronic thiamine deficiency. After supplementation with vitamin B1, strength and motor nerve conduction steadily improve and nerve biopsies show extensive regenerative activity.
21.22.3 Vitamin B6 deficiency
The full-blown syndrome of pellagra is only rarely encountered. It consists of a red-brown hyperkeratotic rash affecting exposed skin, gastrointestinal symptoms, neuropsychiatric features, and peripheral neuropathy. Approximately 50 per cent of pellagrins have sensorimotor peripheral neuropathy with noteworthy paraesthesiae, pain, and tenderness of distal leg muscles (Bomb et al. 1977). The peripheral neuropathy associated with isoniazid therapy is due to this drug’s antagonism of vitamin B6 (Section 21.19.11).
21.22.4 Vitamin B12 deficiency
Sensory peripheral neuropathy is occasionally encountered as the sole neurological manifestation of vitamin B12 deficiency, usually caused by underlying pernicious anaemia. It is normally overshadowed by the associated spinal-cord lesion known as subacute combined degeneration (Hemmer et al. 1998). The peripheral neuropathy contributes to paraesthesiae in the feet and distal loss of all modalities of sensation. The ankle jerks are absent and this physical sign correlates with the finding of reduced vitamin B12 levels in the elderly (Hin et al. 2006). Nerve conduction studies show diminished or absent sensory nerve action potentials. Motor nerve conduction studies generally show axonal neuropathy, but demyelinating features can occur. Symptoms improve little following initiation of vitamin B12 replacement injections (Saperstein et al. 2003).
21.22.5 Vitamin E deficiency
Long-standing vitamin E deficiency causes a sensory peripheral neuropathy associated with prominent ataxia, resembling a spinocerebellar degeneration (Chapter 39). Vitamin E deficiency occurs in patients with fat malabsorption due to cholestatic liver disease, short-bowel syndrome, or cystic fibrosis, and in abetalipoproteinaemia (Brin et al. 1986). Familial vitamin E deficiency is due to mutations of the α-Tocopherol transfer protein (Hentati et al. 1996). Chronic vitamin E deficiency can also cause a pigmentary retinopathy. Abnormalities of somatosensory-evoked potentials indicate an abnormality of central nervous system axons in the dorsal columns of the spinal cord. The diagnosis is proven by demonstrating a plasma tocopherol level reduced out of proportion to any reduction in plasma lipoprotein levels. The vitamin E content of the sural nerve is reduced, and this deficiency may precede the development of peripheral neuropathy (Traber et al. 1987). Vitamin E supplementation prevents further downhill progression of the neurological disorder (Sokol et al. 1985).
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