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Paraneoplastic neurological syndromes 

Paraneoplastic neurological syndromes
Chapter:
Paraneoplastic neurological syndromes
Author(s):

Jeremy Rees

and Angela Vincent

DOI:
10.1093/med/9780199204854.003.2421_update_001

Update:

Recent incidence data.

Onconeural antibody associated disorders and NMDAR antibody encephalitis.

Further reading updated.

Other minor changes.

A relevant case history from Neurological Case Histories: Case Histories in Acute Neurology and the Neurology of General Medicine has been added to this chapter.

Updated on 28 November 2012. The previous version of this content can be found here.
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Essentials

Paraneoplastic neurological syndromes are disorders caused by the presence of an underlying tumour, but not due to either direct or metastatic invasion, or to recognized metabolic or endocrine complications. They are thought to arise from an autoimmune response to onconeural tumour antigens which are also expressed by cells of the central or peripheral nervous system.

Paraneoplastic syndromes are rare but important because (1) they often develop before the cancer has been identified, (2) serological testing for specific anti-neuronal (onconeural) antibodies may identify a neurological disorder as paraneoplastic and the results may suggest the location of the underlying tumour and/or predicts its prognosis. In some cases, the identity of the antibody predicts an immunotherapy-responsive disease.

Epidemiology—the most common tumours associated with paraneoplastic syndromes are lung (both small-cell lung cancer (SCLC) and non-SCLC), ovary, breast, thymus, lymph nodes (Hodgkin’s disease and non-Hodgkin’s lymphoma) and testis.

Treatment—a few paraneoplastic syndromes respond to immunosuppression or to treatment of the underlying cancer, particularly when they are associated with antibodies to neuronal cell-surface proteins and germ cell tumours, but treatment is unrewarding for most and the patients remain with stable but often severe neurological disability even if the cancer is cured.

Specific syndromes

Paraneoplastic neurological syndromes A 32 yr old man presenting with drowsiness and confusion.

Brain and nerves—(1) cerebellar degeneration—most common with lung cancer (especially SCLC), breast and gynaecological cancer, and Hodgkin’s disease; (2) opsoclonus/myoclonus; (3) limbic encephalitis (see Chapter 24.22); (4) brainstem encephalitis; (5) cancer-associated retinopathy.

Spinal cord, dorsal root ganglia and peripheral nerves—(1) necrotizing myelopathy; (2) motor neurone disease (some cases); (3) myelitis; (4) sensory neuronopathy; (5) peripheral neuropathies.

Neuromuscular junction and muscle (see also Chapter 24.23)—(1) Lambert–Eaton myasthenic syndrome—typically associated with SCLC; (2) myasthenia gravis—occurs in 30% of patients with thymomas; (3) polymyositis/dermatomyositis; (4) neuromyotonia.

Incidence

Paraneoplastic neurological syndromesThe most frequent peripheral syndromes are the Lambert–Eaton myasthenic syndrome (LEMS), which affects about 2 to 3% of patients with small-cell lung cancer (SCLC), and thymoma-associated myasthenia gravis (Chapter 24.22). By contrast, the central paraneoplastic neurological syndromes (PNS) are very rare, probably affecting fewer than 1% of patients with cancers of all types. In one series of almost 1500 patients with tumours, only 3 had paraneoplastic cerebellar degeneration, and none had subacute sensory neuronopathy. In a surveillance study of all PNS from the United Kingdom, 50 cases were identified in one year; the female:male ratio was greater than 3:1, the median age of onset of PNS was 66 years and only 11% of patients were less than 50 years of age at presentation. The PNS preceded the diagnosis of cancer in 84% of patients. In a recent European multicentre study of more than 900 patients, predominantly with central nervous system involvement, cerebellar degeneration was the most frequent (24%) followed by limbic encephalitis (10%).

Despite their low incidence, paraneoplastic syndromes are important for several reasons.

  • They often develop before the cancer has been identified and so their presence may lead to the detection of small and potentially curable cancers.

  • The presence of specific antibodies in the serum of patients with a PNS identifies the neurological disorder as paraneoplastic and may strongly suggest the location of the underlying tumour.

  • The PNS is often more disabling than the cancer and, in some instances, may be the cause of death.

  • A PNS or an antibody associated with a PNS (see below) may predict a less aggressive course for the cancer.

  • Paraneoplastic antibodies identify proteins normally restricted to neurons that are of importance in the development and maintenance of the nervous system (see ‘Further reading’).

The syndromes

The clinical syndromes may be focal or diffuse involving single or multiple parts of the nervous system. The most well-characterized syndromes (termed ‘classical’ by Graus et al.) are those that should always arouse suspicion of an associated cancer, and are listed in Table 24.21.1. These syndromes are commonly, but not always, associated with antibodies to certain onconeural antigens which point to the most likely tumours (Table 24.21.2), and will be described in detail below. The exception is limbic encephalitis that is often non-paraneoplastic (Chapter 24.22).

Paraneoplastic neurological syndromesTable 24.21.1 Classical paraneoplastic neurological syndromes*

Example(s)

Area most affected

Encephalomyelitis

Limbic system, brainstem, spinal cord

Limbic encephalitis

Limbic system

Cerebellar degeneration

Cerebellum

Opsoclonus–myoclonus

Brainstem

Carcinoma-associated retinopathy

Retina

Sensory neuronopathy

Dorsal root ganglia

Chronic gastrointestinal pseudo-obstruction

Myenteric plexus

Lambert–Eaton myasthenic syndrome

Neuromuscular junction

Dermatomyositis

Muscle

Paraneoplastic neurological syndromesTable 24.21.2 Onconeural antibody associated paraneoplastic disorders

Antibody to

Neuronal reactivity

Cloned genes

Tumour

Clinical syndromes

Hu

Nucleus>cytoplasm (all neuron)

HuD, HuC

SCLC, neuroblastoma, sarcoma, prostate

PEM, PSN, PCD, autonomic neuropathy

Yo

Cytoplasm, Purkinje cells

CDR34, CDR62

Ovary, breast, lung

PCD

Ri

Nucleus>cytoplasm (CNS neurons)

Nova

Breast, gynaecological cancer, lung, bladder

Ataxia/opsoclonus

Tr

Cytoplasm, Purkinje cells

Not known

Hodgkin’s disease

PCD

VGCC

Presynaptic neuromuscular junction

P/Q type VGCC

VGCC, SCLC

LEMS

VGKC-complex

Presynaptic: neuromuscular junction and CNS neurons

VGKCs and VGKC-complex protein CASPR2

Thymoma, SCLC

Neuromyotonia, antonomic, limbic encephalitis or combinations of these (Morvan’s syndrome)

Retinal

Photoreceptor, ganglion cells

Recoverin and others

SCLC, melanoma, gynaecological

CAR, MAR

Amphiphysin

Presynaptic

Amphiphysin

Breast, SCLC

Stiff person syndrome, PEM

CRMP5 (Anti- CV2)

Oligodendrocytes cytoplasm,

CRMP5 (POP66)

SCLC, thymoma

PEM, PCD, chorea, sensory neuropathy, autonomic neuropathy

Ma1

Neurons (subnucleus)

Ma1

Lung, others

Brainstem, PCD

Ma2

Neurons (subnucleus)

Ma2

Testis

Limbic/brainstem encephalitis

NMDAR

Surface membrane of hippocampal and other neurons

NR1 subunit

Ovarian teratoma

Limbic encephalitis with prominent neuropsychiatric features progressing to movement disorders, fall in consciousness and autonomic instability

AMPA receptor

Surface of hippocampal and other neurons

GluR1/2

Lung, breast, thymoma

Rare form of limbic encephalitis

GABA(B) receptor

Surface of hippocampal and other neurons

GABA(B1) or GABA(B2)

Lung

Rare form of limbic encephalitis

Glycine receptor

Inhibitory synapses on neurons

GlyRα‎1 and others

Thymoma, lymphomas

Rare form of stiff person syndrome often with dysautonomia and brainstem involvement

Ganglionic form of nAChR

Ganglionic synapses

Ganglionic AChR

SCLC, thymoma

Form of autoimmune dysautonomia

AChR, acetylcholine receptor; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channels. For other abbreviations, see text.

Onconeural antibodies

These antibodies help to diagnose the syndrome as being paraneoplastic and may point to a specific underlying tumour. For example, a patient with paraneoplastic cerebellar degeneration (PCD) who has serum anti-Yo antibodies will almost always have a breast, ovarian, or other gynaecological cancer. Patients with PCD associated with nongynaecological cancers have other antibodies that react with Purkinje cells or do not have antibodies identifiable by current techniques. The main antigens (Table 24.21.2) are not described here, but most are cytoplasmic or nuclear proteins although some, e.g. voltage-gated calcium channels, N-methyl-D-aspartate (NMDA) receptors, are membrane proteins that are accessible to circulating antibodies.

Some autoantibodies are associated with specific tumours but widely varying paraneoplastic syndromes. For example, the anti-Hu antibody (Fig. 24.21.1) is almost always associated with SCLC (occasionally neuroblastoma or prostate cancer), but may be found in several different clinical syndromes usually encompassed by the term ‘encephalomyelitis’. The clinical abnormalities include limbic encephalitis, PCD, brainstem encephalitis, sensory neuronopathy, and autonomic failure. Some or all of these clinical abnormalities may be found in the same patient.

Fig. 24.21.1 Anti-Hu antibodies: serum immunoreactivity with rat brainstem counterstained showing strong nuclear staining (solid arrow) and weaker cytoplasmic staining (dashed arrow) typical of anti-Hu (anti ANNA 1) antibodies (DAB-peroxidase counterstained with haematoxylin and eosin). Western blot shows a ‘ladder’ pattern of bands between 35 and 40 kDa. The patient was a woman with subacute cerebellar degeneration who was subsequently found to have lung cancer.

Fig. 24.21.1
Anti-Hu antibodies: serum immunoreactivity with rat brainstem counterstained showing strong nuclear staining (solid arrow) and weaker cytoplasmic staining (dashed arrow) typical of anti-Hu (anti ANNA 1) antibodies (DAB-peroxidase counterstained with haematoxylin and eosin). Western blot shows a ‘ladder’ pattern of bands between 35 and 40 kDa. The patient was a woman with subacute cerebellar degeneration who was subsequently found to have lung cancer.

(Courtesy of Elizabeth Amyes Msc, University of Oxford.)

Not all patients with a classical syndrome and associated tumour have onconeural antibodies. Thus the absence of a positive antibody should not be taken as evidence that the patient has a nonparaneoplastic form of disease. In some conditions, there are no identified antibodies. A good example is opsoclonus–myoclonus associated with neuroblastoma in children. Most observers believe that this paraneoplastic disorder is immune-mediated. The failure to find a disease- or tumour- specific antibody does not mean that one is not present, only that current techniques have not identified it. As techniques improve, new antibodies are regularly being reported; of particular interest is the recent discovery of antibodies directed against N-methyl-D-aspartate receptors (NMDAR) on hippocampal neurons in young female patients and children with a progressive encephalopathy, patients with including some associated with ovarian teratomas (see ‘Further reading’).

Tumours associated with PNS

The most common tumours associated with PNS are found in lung (both SCLC and non-SCLC), ovary, breast, thymus, lymph nodes (both Hodgkin’s disease and non-Hodgkin’s lymphoma), and testis. In a recent European survey, other tumours were also identified suggesting that whole-body scanning is appropriate in the diagnostic work-up of patients with suspected PNS.

Diagnosis

Certain clinical clues suggest that a neurological disorder may be a PNS. The onset is subacute or even acute; in some cases the symptoms develop overnight so that a stroke is initially suspected. Most PNS are progressive initially then stabilize after weeks to months, although more slowly progressive syndromes may occur. Recovery is rare in most of the CNS syndromes, probably because of irreversible neuronal loss and degeneration, although spontaneous resolution and improvement after oncological treatment have been reported.

The neurological disorders are usually severe. Most patients have substantial disability by the time they first consult a physician. Mild or waxing and waning neurological symptoms are rarely paraneoplastic. For example, the patient with PCD is usually unable to walk or sit unsupported, unable to write, and sometimes, because of the oscillopsia associated with nystagmus, unable to read.

The neurological findings are often characteristic. A subacutely developing pancerebellar disorder, the rapid development of opsoclonus (see below), or the development of LEMS strongly suggests cancer as the underlying cause. However, none of these syndromes, even the most characteristic, is invariably associated with cancer. Thus, only about one-half of patients with LEMS have cancer and only about 10% of patients with myasthenia gravis have a tumour (almost always thymoma). Probably about one-half of the patients with subacute cerebellar degeneration have cancer. Limbic encephalitis was thought of as paraneoplastic but it is now clear that nonparaneoplastic forms can be identified, and are more common (Chapter 24.22).

Imaging in suspected PNS is often not informative. Indeed, one of the clues to the presence of a PNS is the relative normality of imaging in a patient with such severe clinical symptoms and signs. Occasionally MRI may show high signal within one or both medial temporal lobes (limbic encephalitis) or brainstem (brainstem encephalitis) and very rarely diffuse oedema of the cerebellum (PCD). The cerebrospinal fluid may show pleocytosis (30–40 cells), elevated protein, increased IgG, and oligoclonal bands particularly early in the course of disease which then settles within a few weeks of onset. The immunoglobulin abnormalities usually persist. In a patient with a known cancer, the diagnosis of PNS should usually only be made after exclusion of the more common neurological complications of cancer, unless an onconeural antibody is found in the serum.

In a patient without a known cancer, particularly when conventional imaging studies (radiography, CT, ultrasonography, and mammography) are negative, the appropriate use of whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) may show a FDG-avid ‘hot spot’ suggestive of an occult malignancy (Fig. 24.21.2). Blood tumour markers are rarely helpful in this clinical context. If an onconeural antibody is present and the search for an underlying cancer is negative, the physician is obliged to follow the patient carefully, searching periodically for a cancer.

Fig. 24.21.2 Axial T2W MRI brain of patient with limbic encephalitis showing high signal in left medial temporal lobe (arrow).

Fig. 24.21.2
Axial T2W MRI brain of patient with limbic encephalitis showing high signal in left medial temporal lobe (arrow).

The difficulties of defining and hence diagnosing PND have been carefully considered by an international panel of neurological experts who have established guidelines for more rigorous diagnostic criteria. The aim of these guidelines has been to facilitate diagnosis, classification, and collaborative research. They rely on the definition of ‘classical’ paraneoplastic syndromes and ‘well-characterized’ onconeural autoantibodies. On this basis a condition could be diagnosed as paraneoplastic based on a descending hierarchy of factors: (1) presence or absence of ‘classical’ syndrome; (2) presence or absence of cancer; (3) presence or absence of ‘well-characterized’ antineuronal antibodies, and (4) exclusion of other possible causes of a similar neurological syndrome particularly malignant meningitis. On the basis of combinations of these criteria, the diagnosis of a PND is now either ‘definite’ or ‘possible’. (See ‘Further reading’.)

Pathogenesis

Current evidence suggests that PNS result from an autoimmune reaction to ‘onconeural’ antigens in the tumour. These antigens are those that are normally restricted to the nervous system (or the testis, which is also an immunologically privileged site). The immune system therefore recognizes the antigen as foreign and some patients mount an immune response. The immune response may have the beneficial effect of slowing tumour growth but it can also damage those parts of the nervous system that express the antigen. Although many PNS are associated with specific neuronal autoantibodies, there is limited evidence that those directed against cytoplasmic or nuclear antigens are pathogenic. T lymphocytes recognizing these or other onconeural antigens, and other cellular immune mechanisms, are the likely pathogenic agents in these conditions. In contrast, antibodies directed against membrane ion channels or receptors for neurotransmitters (e.g. voltage gated calcium and potassium channels, NMDA and AMPA forms of glutamate receptors) are pathogenic but are also often present in nonparaneoplastic forms of the disease.

Treatment

Some PNS, such as LEMS, MG and the central diseases associated with antibodies to the neuronal surface proteins (NMDAR, AMPAR, GABA(B)R, CASPR2), respond to immunosuppression or to treatment of the underlying cancer (Table 24.21.3) and many are not paraneoplastic. Some syndromes, such as opsoclonus–myoclonus, may remit spontaneously, but for most PNS treatment is unrewarding and the patients remain with severe neurological disability even if the cancer is cured. Treatments usually involve immunosuppression with plasma exchange, intravenous immunoglobulin, steroids, or cytotoxics particularly for those syndromes associated with onconeural autoantibodies. It is possible that the rapid onset of the syndromes does not allow sufficient time for accurate early diagnosis and for treatment to begin before irreversible neural damage has occurred. With earlier diagnosis, therapy may be more successful. However, as mentioned above, a number of the ‘classical’ paraneoplastic conditions appear to exist in nonparaneoplastic forms (e.g. limbic encephalitis with potassium channel antibodies) and may respond to immunotherapies; therefore, if onconeural antibodies are absent, and no cancer is found, a trial of immunotherapy should be considered. There has been recent interest in rituximab (anti-CD20 monoclonal Ab) which has shown modest benefit in a small open trial of patients with PNS.

Paraneoplastic neurological syndromesTable 24.21.3 Treatable paraneoplastic neurological syndromes

Syndrome

Treatment

Completely responsive

Lambert–Eaton myasthenic syndrome (LEMS)

Tumour therapy, plasma exchange, intravenous immunoglobulin, 3,4 diaminopyridine

Myasthenia gravis

Tumour therapy, plasma exchange, intravenous immunoglobulin, steroids, immunosuppressants, thymectomy, anticholinesterases

Dermatomyositis

Steroids, immunosuppressants, intravenous immunoglobulin

Opsoclonus–myoclonus (children)

Steroids, ACTH, tumour therapy

Limbic encephalitis or other syndromes with antibodies to cell surface antigens, eg. VGKC, NMDAR, AMPAR, GABA(B)R, GlyR

Tumour therapy, plasma exchange, intravenous immunoglobulin, immunosuppressants

Neuromyotonia

Anti-epileptics, steroids, plasma exchance, tumour therapy

Demyelinating neuropathy (osteosclerotic myeloma)

Tumour therapy, radiation, bevacizumab

Partially responsive

Opsoclonus–myoclonus (adults)

Steroids, tumour therapy, clonazepam, diazepam, baclofen

Paraneoplastic cerebellar ataxia (Hodgkin’s disease)

Tumour therapy

Opsoclonus/ataxia (anti-Ri)

Steroids, cyclophosphamide

Specific syndromes

Brain and cranial nerves

(Box 24.21.1)

Paraneoplastic cerebellar degeneration (PCD)

PCD may complicate any malignant tumour but is most common with lung cancer (especially SCLC), breast and gynaecological cancer, and Hodgkin’s disease. Males and females are both affected and the age incidence reflects the age distribution of the underlying cancer. Neurological manifestations precede detection of the associated tumour in over one-half of patients, rarely by more than five years, or PCD may develop after diagnosis of the neoplasm. In some instances, the tumour is not found until autopsy. Typically, the disorder begins as gait ataxia that progresses over a few days to weeks to severe truncal and appendicular ataxia with dysarthria and nystagmus. The nystagmus is frequently downbeating. Vertigo with or without nausea and vomiting is common and many patients complain of diplopia. The cerebellar signs are bilateral but may be asymmetrical. The cerebellar deficit usually stabilizes but, by then, the patient is often incapacitated. Spontaneous improvement sometimes occurs, particularly when associated with Hodgkin’s disease. Some patients will also be found to be mildly cognitively impaired and demonstrate extensor plantar reflexes or sensory changes suggesting a more widespread encephalomyelitis.

The cerebrospinal fluid may be normal, but there is usually a pleocytosis within the first few months, and raised protein and oligoclonal bands may also be present. Cytological examination of the cerebrospinal fluid and contrast-enhanced MRI of the neuraxis rule out leptomeningeal metastases. MRI scans typically are normal early, but later show signs of progressive cerebellar atrophy with prominent cerebellar folia and a dilated fourth ventricle.

The pathological hallmark of paraneoplastic cerebellar degeneration is loss of Purkinje cells, affecting all parts of the cerebellum. Less striking changes in the cerebellar cortex may include thinning of the molecular layer with microglial proliferation and astrocytic gliosis, proliferation of Bergmann glia, and slight thinning of the granular layer with decreased numbers of granule cells.

When typical, the clinical picture of PCD is almost pathognomonic. When atypical, the disorder must be distinguished from a cerebellar tumour (primary or metastatic) and from leptomeningeal metastases (by MRI and cerebrospinal fluid examination, respectively), from late-onset, nonparaneoplastic cerebellar degenerations, cerebellar haemorrhage and infarction, abscess, prion diseases, cerebellar ataxia related to 5-fluorouracil or high-dose cytarabine, and metabolic disorders, especially alcoholic cerebellar degeneration.

There have been occasional reports of a partial or near-complete remission of paraneoplastic cerebellar degeneration following treatment of the primary tumour. This is very unusual, however, and most patients do not improve even when treatment is begun early in the illness, before Purkinje cells are irreversibly damaged. Plasmapheresis, corticosteroids, immunosuppressive drugs and, more recently, intravenous immune globlulin (IVIG) and rituximab have all been tried and may lead to mild symptomatic improvement in the ataxia. PCD may occasionally be associated with LEMS, both associated with SCLC. Recognition and treatment of the peripheral symptoms can lead to overall clinical benefits. In the future, non-paraneoplastic potentially treatable forms may be identified.

Opsoclonus–myoclonus

Opsoclonus is a disorder of eye movements consisting of almost continuous chaotic, multidirectional, involuntary, high-amplitude conjugate saccades that are often accompanied by synchronous blinking of the lids. It is usually considered to be a paraneoplastic syndrome complicating 2% of childhood neuroblastoma (dancing eyes syndrome) or a variety of tumours in adults, particularly breast cancer and SCLC, but there are cases that appear to be nonparaneoplastic and self-limiting (see below).

Opsoclonus may be an isolated neurological sign, but is often accompanied by myoclonus of the trunk, limbs, head, diaphragm, larynx, pharynx, and palate, and ataxia, hence the term opsoclonus–myoclonus or opsoclonus–myoclonus ataxia. Neurological symptoms precede identification of the neuroblastoma in at least 50% of patients, and the tumour may be missed by abdominal examination; thus, recognition of the neurological syndrome is an important clue to the presence of a neuroblastoma. There are preliminary reports of antibodies to neuroblastoma cell lines but no specific antigen has been defined. When a neuroblastoma is associated with opsoclonus–myoclonus, there is a higher than expected incidence of intrathoracic tumours and of tumours with a benign histology. The prognosis of the neuroblastoma is better if opsoclonus–myoclonus is associated than when there is no neurological complication, an observation not explained by earlier diagnosis when neurological symptoms are present. The neurological disorder responds to ACTH and to intravenous immunoglobulin but not to prednisone. However, most patients suffer residual neurological damage, usually cognitive.

Opsoclonus–myoclonus is less common in adults, and in younger adults is often nonparaneoplastic. Nevertheless, about 20% of adult patients reported with opsoclonus–myoclonus have an underlying cancer. The neurological symptoms usually precede diagnosis of the tumour and commonly progress over several weeks, although more rapid or slower progression may be observed. The cerebrospinal fluid may show a mild pleocytosis and an elevated protein. The MRI is usually normal. Neuropathological findings have been variable. In some patients there are no identifiable abnormalities. In others, the changes resembled those of PCD with a loss of Purkinje cells, inflammatory infiltrates in the brainstem, Bergmann gliosis, and loss of cells from the granular layer of the cerebellum.

The prognosis for recovery or partial remission of the neurological disorder is better for opsoclonus–myoclonus than it is for PCD. Improvement may follow treatment of the underlying tumour, and spontaneous partial remissions occur. Differential diagnosis includes nonparaneoplastic conditions such as viral inections, postinfectious encephalitis, hydrocephalus, thalamic haemorrhage, and toxic encephalopathies from thallium or lithium, amitriptyline overdose, and diabetic hyperosmolar coma.

Limbic encephalitis

Limbic encephalitis may occur as an isolated finding initially but the paraneoplastic forms frequently progress to a more extensive encephalomyelitis. The neurological symptoms often precede diagnosis of the tumour by up to 2 years; sometimes the cancer is not detected until autopsy. Symptoms usually progress over several weeks but the course may be more insidious. Anxiety and depression are common early symptoms, but the most striking feature is a severe impairment of episodic memory. Other manifestations include agitation, confusion, hallucinations, and partial or generalized seizures. The symptoms may spread to include other brain functions, e.g. the hypothalamus, with changes in appetite or sleep, e.g. hypersomnia. Progressive dementia usually occurs, but occasionally there may be a spontaneous remission; more and more of these cases are now known to be non paraneoplastic associated with antibodies to voltage-gated potassium channel complex proteins (Chapter 24.22). Indeed this test should now be sent off in any patient presenting with a rapidly progressive amnesic syndrome, as it is treatable. The cerebrospinal fluid commonly shows a pleocytosis and an elevated protein concentration in PNS cases. MR scans are usually normal but medial temporal abnormalities have been reported (Fig. 24.21.3).

Fig. 24.21.3 Whole body FDG-PET scan showing two hot spots in right middle lobe (arrow) from patient with cerebellar degeneration and anti-Hu antibodies in whom chest radiography and CT of the thorax were both negative. Subsequent biopsy confirmed small-cell lung cancer.

Fig. 24.21.3
Whole body FDG-PET scan showing two hot spots in right middle lobe (arrow) from patient with cerebellar degeneration and anti-Hu antibodies in whom chest radiography and CT of the thorax were both negative. Subsequent biopsy confirmed small-cell lung cancer.

Inflammatory pathological changes affect the grey matter of the hippocampus, cingulate gyrus, pyriform cortex, orbital surfaces of the frontal lobes, insula, and the amygdala. No treatment has proved uniformly beneficial although spontaneous remissions have been reported and some patients have improved after treatment of the underlying tumour. If onconeural antibodies are negative and there is no evidence of a tumour, immunosuppression should be considered as recent studies have identified antibodies against novel cell-surface antigens (VGKC complex proteins, LGI1, CASPR2, or NMDARs) which are associated with a favourable prognosis.

Paraneoplastic neurological syndromesNMDAR antibody encephalitis

This condition, recently described, has proved to be relatively common particularly in younger adults and children. Patients present with neuropsychiatric features, sometimes following a viral illness, and usually within 2 weeks progress to a severe encephalopathy with seizures, movement disorders, autonomic instability, and reduced consciousness. Despite the severity of the disease, the MRI is often normal or changes nonspecific, but the CSF often shows pleocytosis during the first days. Oligoclonal bands tend to appear later. Ovarian teratomas or cysts are found in up to 50% of the adult females, but tumours are less common in males or the increasing number of children identified, even within the first year of life. Removal of the ovary(s) and multiple symptomatic treatments are required combined with immunotherapies with steroids, plasma exchange, and intravenous immunoglobulins; benefits may be evident within a few weeks but if not, rituximab and cyclophosphamide are recommended (see ‘Further reading’). Although many patients require intensive care for weeks or months, the long-term prognosis is positive with a proportion returning to normal life particularly if identified and treated early. The ovarian tumours express NMDARs. Experimental results suggest that the antibodies reduce the number of hippocampal NMDARs in a reversible manner.

Brainstem encephalitis

Paraneoplastic brainstem encephalitis is often associated with clinical and pathological evidence of encephalomyelitis elsewhere within the central and peripheral nervous systems, but may occur as the dominant or an isolated clinical finding. It is commonly associated with SCLC, but an identical clinicopathological syndrome may be seen in the absence of a malignancy.

The clinical features vary according to the brainstem structures involved in the pathological process. Common manifestations include vertigo, ataxia, nystagmus, vomiting, bulbar palsy, oculomotor disorders, and corticospinal tract dysfunction. Less common clinical features include deafness, myoclonus of the branchial musculature, central alveolar hypoventilation presenting with respiratory failure. Basal ganglia involvement produces movement disorders including chorea or Parkinson’s syndrome, these being more commonly seen in patients with anti-CV2 antibodies.

Neurological symptoms may develop before or after discovery of the malignancy. The pathological changes are identical to those observed in other forms of paraneoplastic encephalomyelitis.

Visual loss

PNS can affect retinal photoreceptors, either rods or cones or both. They can cause a retinal vasculitis or optic neuropathy. Paraneoplastic retinal degeneration, also called cancer-associated retinopathy (CAR), usually occurs in association with SCLC, melanoma, and gynaecological tumours. Typically, the visual symptoms include episodic visual obscurations, night blindness, light-induced glare, photosensitivity, and impaired colour vision. Visual symptoms usually precede the diagnosis of cancer. The symptoms progress to painless visual loss. They may begin unilaterally but usually become bilateral. Visual testing demonstrates peripheral and ring scotomas and loss of acuity. Fundoscopic examination may reveal arteriolar narrowing and abnormal mottling of the retinal pigment epithelium. The electroretinogram is abnormal. Cerebrospinal fluid is typically normal, although elevated immunoglobulin levels have been reported. Inflammatory cells are sometimes seen in the vitreous by slit-lamp examination. Retinal antibodies (e.g. recoverin), although well recognized, are not routinely available in most countries.

Pathologically, CAR is associated with a loss of photoreceptors and ganglion cells with inflammatory infiltrates and macrophages. The other parts of the optic pathway are preserved, although a loss of myelin and lymphocytic infiltration of the optic nerve may occur.

Treatment of CAR is usually unsuccessful although a recent report describes improvement in some patients with the use of intravenous immunoglobulin. The condition is not recognized very frequently, and there may be nonparaneoplastic forms that are difficult to distinguish.

Spinal cord and dorsal root ganglia

(Box 24.21.2)

Necrotizing myelopathy

This is an extremely rare PNS. The initial symptoms of muscle weakness and sensory loss in the arms and legs may be asymmetrical, but eventually signs become bilateral and symmetrical. Back or radicular pain may precede other neurological signs. Cerebrospinal fluid abnormalities may include an elevated level of protein and a mild pleocytosis. Swelling of the spinal cord may be apparent on MRI. Typically, the neurological deficit progresses rapidly over days or a few weeks, ultimately leading to respiratory failure and death. There is no effective treatment.

Pathologically, there is widespread necrosis of the spinal cord, often most marked in the thoracic segments. The necrosis involves all components of the spinal cord with white matter usually more affected than grey matter.

Motor neuron disease (amyotrophic lateral sclerosis)

There is controversy as to whether motor neuron disease (MND) can be regarded as a classical PNS. It is likely to be paraneoplastic in three distinct groups of patients; the first with a rapidly progressive amyotrophic lateral sclerosis picture associated with anti-Hu antibodies; the second with primary lateral sclerosis and breast cancer; and the third with a subacute motor neuronopathy associated with lymphoma. Classical MND in a patient with a previous history of cancer is probably not paraneoplastic, merely reflecting the occurrence of two reasonably common diseases of older age in the same patient separated in time.

Myelitis

Paraneoplastic myelitis is usually a part of the encephalomyelitis syndrome with inflammatory lesions elsewhere in the brain and dorsal root ganglia as well as the spinal cord. The clinical picture is dominated by the radicular element of a myeloradiculitis and is characterized by patchy wasting and weakness of muscles, sometimes combined with fasciculations. The upper extremities are often more severely affected than the legs, reflecting predominant involvement of the cervical spinal cord. There may be striking weakness of neck and intercostal muscles, resulting in respiratory failure. Sensory symptoms and autonomic dysfunction may be present.

Sensory neuronopathy

Paraneoplastic sensory neuronopathy is most commonly associated with SCLC. Symptoms typically begin before the cancer is identified, with dysaesthetic pain and numbness in the legs or occasionally in the arm(s), face, or trunk. The symptoms may be asymmetrical at onset but progress over days to several weeks to involve the limbs, trunk, and sometimes the face, causing a severe sensory ataxia. All sensory modalities are affected. Deep tendon reflexes are lost but motor function is preserved. Occasional patients have a mild and indolent neuropathy. The cerebrospinal fluid is typically inflammatory.

Early pathological changes are limited mostly to the dorsal root ganglia, in which both a loss of neurons and the presence of lymphocytic inflammatory infiltrates are noted (Fig. 24.21.4). About 50% of patients with paraneoplastic sensory neuronopathy have pathological changes that may be clinically inapparent in other regions of the nervous system. As with other PND, this disorder rarely responds to treatment.

Fig. 24.21.4 Sensory ganglionitis: dorsal root ganglion with hypercellular nodules marking the site of ganglion cell degeneration. Another ganglion cell (dashed arrow) is in the process of degenerating. A healthy ganglion cell is shown in the bottom left-hand corner of the plate.

Fig. 24.21.4
Sensory ganglionitis: dorsal root ganglion with hypercellular nodules marking the site of ganglion cell degeneration. Another ganglion cell (dashed arrow) is in the process of degenerating. A healthy ganglion cell is shown in the bottom left-hand corner of the plate.

Peripheral nerves

(Box 24.21.3)

Sensory and sensorimotor neuropathy

Peripheral neuropathies, particularly mild distal sensorimotor neuropathies, are common in patients with cancer and may be due to the metabolic or nutritional effects of late cancer, or associated with certain drugs, e.g. cisplatin.

Some patients not known to have cancer, and who are not evidently systemically ill, present to the neurologist with a peripheral neuropathy that may be quite severe and disabling. It is estimated that about 10% of those patients whose initial evaluations do not reveal an obvious cause (such as vitamin B12 deficiency, alcohol or diabetes), will eventually prove to have cancer as the underlying reason for the peripheral neuropathy. Paraneoplastic peripheral neuropathy may take several clinical and pathological forms. The most common is the distal, symmetrical, subacutely developing, sensory neuropathy which may be either axonal or demyelinating. A relatively pure sensory neuropathy, a mononeuritis multiplex due to microvasculitis, an acute polyradiculopathy, a focal neuropathy such as brachial neuritis, or an autonomic neuropathy may also be paraneoplastic. Most of these neuropathies are not associated with autoantibodies and the diagnosis is often one of exclusion.

Neuromuscular junction and muscle

(Box 24.21.4)

Paraneoplastic disorders of the neuromuscular junction include the Lambert–Eaton myasthenic syndrome, myasthenia gravis and acquired neuromyotoia. These disorders have a common pathogenetic mechanism—they are caused by antibodies against ion channels and, whether paraneoplastic or not, they respond to immunological treatment. They are described in more detail in Chapter 24.22. Finally, because of its similarity to neuromyotonia, the stiff person syndrome is also included in this section. Whereas the more common non-paraneoplastic form is associated with antbodies to glutamic acid decarboxylase, the presence of amphiphysin or other onconeural antibodies should raise the suspicion of a tumour.

Lambert–Eaton myasthenic syndrome (LEMS)

LEMS results from a reduced release of acetylcholine at presynaptic nerve terminals. The same P/Q-type voltage-gated calcium channels are found in small-cell lung cancers. Interestingly, the richest source of P/Q-type voltage-gated calcium channels is the cerebellum, perhaps explaining the occasional relationship of PCD and LEMS.

LEMS can be treated either by immune suppression or by treatment of the underlying cancer when present. Patients with SCLC associated with LEMS have a better prognosis than patients with SCLC who do not develop a paraneoplastic disorder, but this could be partly due to earlier diagnosis.

Myasthenia gravis

Myasthenia gravis occurs in 30% of patients with thymomas, and approximately 10% of patients with myasthenia gravis are found to have a thymoma. Usually the two are diagnosed synchronously but rarely myasthenia may develop many years after the thymoma, sometimes in association with other autoimmune diseases, e.g. red-cell aplasia.

Polymyositis and dermatomyositis

Only a minority of patients, usually older people, with polymyositis or dermatomyositis have an underlying malignancy as the cause. Dermatomyositis with typical cutaneous changes is more likely to be paraneoplastic than polymyositis. Females and males are affected in approximately equal numbers. Symptoms of muscle weakness generally precede identification of the cancer. The tumour may be at any site, but breast, lung, ovarian, and gastric malignancies are the most common.

Corticosteroids, ciclosporin, and other immunosuppressants have been used successfully. Other reports suggest that high-dose IVIG is useful in patients unresponsive to other forms of immunosuppression.

Neuromyotonia and stiff person syndrome

Muscle cramps are a common complication of cancer, sometimes related to electrolyte imbalance or induced by chemotherapy. A much rarer but clinically significant PNS is acquired neuromyotonia. The disorder is characterized by muscle stiffness, cramps, and obviously rippling and twitching muscles, sometimes leading to sustained abnormal postures. Relaxation after voluntary contraction is delayed. Symptoms persist during sleep (and are abolished by curare). Sudden prolonged bursts of high-frequency, involuntary, repetitive muscle action potentials are seen on electromyography.

The muscle spasms and rigidity are sometimes precipitated by activity, forcing patients to become sedentary. The disorder arises from peripheral nerves and is sometimes a part of the encephalomyelitis syndrome. The disorder is usually nonparaneoplastic, but may be associated with cancer including thymomas and SCLC. Antibodies against voltage-gated potassium channels are often positive (Chapter 24.22). Plasma exchange improves the patient’s condition; but they often respond to anticonvulsants alone. Injection of IgG from affected patients into experimental animals can reproduce evidence of peripheral nerve hyperexcitability.

The stiff person syndrome may superficially resemble neuromyotonia, but has a central origin and is usually not paraneoplastic. This rare disorder is clinically characterized by stiffness and rigidity, with episodic spasms of axial muscles. A variant of the syndrome affects the limbs. Painful reflex spasms can occur in response to tactile stimuli or startle. Muscle action potentials are normal on electromyography but the activity is continuous and excessive and increased by voluntary activity. The disorder is usually autoimmune, associated with antibodies against glutamic acid dehydroxylase; since this antibody is also important in type 1 diabetes, the assay is widely available. When paraneoplastic, it can be associated with lung or breast tumours often with the appropriate onconeural antibody. Recently antibodies to glycine receptors have been recognized in patients with stiff person syndrome or a form of progressive encephalomyelitis with rigidity and myoclonus.

Further reading

Candler PM, et al. (2004). A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry, 75, 1411–15.Find this resource:

    Dalmau J, Rosenfeld MR (2008). Paraneoplastic syndromes of the CNS. Lancet Neurol, 7, 327–40. Review.Find this resource:

      Dalmau J, et al. (2011). Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol, 10, 63–74.Find this resource:

        Giometto B, et al. (2010). Paraneoplastic neurologic syndromes in the PNS Euronetwork Database. A European study from 20 centers. Arch Neurol, 67, 330–5.Find this resource:

          Graus F, et al. (2004). Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 75, 1135–40.Find this resource:

            Vedeler CA, et al. (2006). Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol, 13, 682–90.Find this resource:

              Vincent A, et al. (2011). Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol, 10, 759–72.Find this resource: