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Miscellaneous movement disorders 

Miscellaneous movement disorders
Chapter:
Miscellaneous movement disorders
Author(s):

Ivan Donaldson

, C. David Marsden

, Susanne A. Schneider

, and Kailash P. Bhatia

DOI:
10.1093/med/9780192619112.003.1192
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Introduction

This chapter deals with a number of conditions that do not fit easily into the major categories of movement disorders. Some, such as stereotypies, can be seen in a variety of the diseases that have been covered in the preceding chapters, while others are again mentioned to put them into a broader context. Thus, neuroleptic malignant syndrome can be considered as a drug-induced akinetic–rigid syndrome, and hence has been covered in Chapter 13, but also has features of catatonia, and is thus also briefly mentioned here.

By its very nature, this chapter deals with a number of unrelated disorders. Some are very important because of their frequency, e.g. drop attacks and hemifacial spasm.

Drop attacks

The term ‘drop attack’ was introduced into the medical literature by Sheldon in 1948 in an investigation into the impact of old age. It has now become an ‘umbrella label’ for a wide range of aetiological different attacks, many of which were well described in the medical literature well prior to that date (see Table 1 in the Introduction to Episodic Movement Disorders – Section 11). For example, Hunt called epileptic drop attacks ‘static seizures’ as early as 1922. Not only are the causes heterogeneous but also there is no universally accepted definition of a drop attack and what are called such in the literature are frequently not clearly described. This makes any review of the topic imprecise.

Table 52.1 Causes of drop attacks due to neuromuscular and neurodegenerative disorders.

Neuromuscular diseases associated with weak legs

Muscular dystrophy

Inclusion body myositis

Myasthenia gravis

Polymyositis

Neurogenic atrophy

Neurodegenerative diseases

Idiopathic Parkinson's disease

Multiple system atrophy

Progressive supranuclear palsy

Corticobasal degeneration

Huntington's disease

Alzheimer's disease

One of the major points of disagreement relates to the retention of consciousness. Some authors exclude attacks in which there is loss of consciousness (Brust et al. 1979, Meissner et al. 1986) whereas others not only accept this but include bouts of unconscious for 1–2 minutes followed by brief confusion (Pazzaglia et al. 1985). If loss of consciousness is disallowed this would eliminate some epileptic seizures, cardiac dysrhythmias, and faints due to orthostatic hypotension, which have been called drop attacks (Pfammater et al. 1995). There is no clear answer to this dilemma, which is perhaps best exemplified by epilepsy. Suspension of awareness may momentarily occur during a burst of generalized spike and wave activity in the electroencephalography (EEG) associated with a fall. In most cases, such as during a large generalized myoclonic jerk, it is impossible to determine whether the patient has lost consciousness for such a brief period. On the other hand, an atonic epileptic seizure associated with falling and prolonged unconsciousness would not generally be regarded as a drop attack. Similarly, fainting due to a simple vasovagal syncope would normally not be included. For the purposes of our discussion, we will generally exclude bouts in which the patient is aware of loss of consciousness or it has been prolonged for more than a few seconds.

We will also disregard patients who have prolonged signs following a drop attack, unless these are the result of injuries sustained in the fall. Thus, a brainstem transient ischaemic attack followed by motor or sensory signs that gradually resolve over an hour or so would not qualify. The question is to what extent falls resulting from pre-existing physical disability, such as weak limbs or impaired balance mechanisms, should be included. Neuromuscular disorders, spinal cord lesions, and the like may result in collapse due to reduced lower limb power, and a variety of neurodegenerative disorders may interfere with postural control. For example, quadriceps myopathy and progressive supranuclear palsy may present with unexplained falls. While accepting they may have a legitimate claim to be considered as drop attacks we have not discussed them in detail here, although they are outlined in Table 52.1. Occasionally drop attacks have been secondary to a metabolic disturbance, such as hypothyroidism (Kramer and Achiron 1993), but in such cases weakness or myopathy may have been the underlying reason for the collapse. In addition, a significant proportion of what have been called ‘drop attacks’ in the geriatric literature really consists of falls due to a variety of mechanisms (Table 52.2). These are not reviewed extensively, although they need to be kept in mind.

Table 52.2 Falls in old age

Causes of falls

Number

Accidental falls

171

Drop attacks

125

Trips

53

Vertigo

37

CNS lesions

27

Extension of neck

20

Postural syncope

18

Leg weakness

16

Falls out of bed or chair

10

Uncertain

23

Based on 500 falls in 202 people aged 50–90 years: 59 falls resulted in a fractured femur; drop attacks (125 of the 500 falls) occurred in 58 individuals; 26 of these 58 patients sustained fractures or dislocations; 51 of the 58 patients had more than one fall.

CNS= central nervous system.

Reproduced with permission from Sheldon JH. On the natural history of falls in old age. Br Med J 1960; 2:1685–1690. © BMJ Publishing Group.

We will thus define drop attacks as sudden falls that occur without warning or post-ictal symptoms in which the subject is unaware of losing consciousness or such loss of consciousness is brief, and it is possible to get up straight away unless injury prevents this. In our discussion, however, we have included some cases that do not completely fulfil these criteria and we have attempted to make it clear where we have done this.

Most drop attacks are caused by a sudden brief disturbance of postural mechanisms, without vertigo or dizziness. This can have many different aetiologies, which are very age dependent. Thus, drop attacks starting in young children are particularly likely to be epileptic whereas this is less often the case in adults. In the elderly cardiovascular causes tend to predominate. In a retrospective computerized search of drop attacks seen at the Mayo Clinic between 1976 and 1983, 108 cases were identified. Patients with loss of awareness or consciousness were excluded (Table 52.3). From subsequent examinations, patient questionnaires, telephone interviews, and death certificates it was felt the cause was established in 39. The likely aetiology was cardiac in 12%, cerebrovascular insufficiency in 8%, combined cardiac and cerebrovascular disease in 7%, seizures in 5%, vestibular disturbance in 3%, and psychogenic in 1%. In all the patients who were under 40 years of age epileptic seizures were felt to be the cause. In 64% no cause could be established but there were a number of associated medical conditions, which may have been relevant. Cardiovascular problems predominated, including hypertension and heart disease.

Table 52.3 The causes and associations of drop attacks

Percentage of drop attacks

Causes (39/108 cases)

Cardiac disease

12

Cerebrovascular disease

8

Combined cardiac and cerebrovascular disease

7

Seizures

5

Vestibular disease

3

Psychogenic

1

Unknown

64

Unknown causes (69/108 cases)

Hypertension

41

Cardiac disease

25

Migraine

25

Diabetes

6

Alcohol

3

Cataplexy

1

Cervical spondylosis

19

Based on 166 patients seen at the Mayo Clinic from 1976 to 1983. Fifty-eight patients were excluded, most because of cardiogenic causes with changes in consciousness. One hundred and eight patients (76 women and 32 men) met the definition of ‘a falling spell occurring without warning or post-ictal symptoms, with immediate righting, and without loss of awareness or consciousness’. Mean age was 70 years (most patients over the age of 60); follow-up was 6–7 years. Ninety-two of the 108 were alive at follow-up. Eight-four percent of 58 untreated patients were asymptomatic. Stroke rate was 0.5 per year, similar to the controls rate.

Reproduced with permission from Lee MS, Marsden CD. Drop attacks. In: Negative Motor Phenomena (Advances in Neurology,Vol. 67). Eds Fahn S, Hallett M, Luders HO, Marsden CD. Lippincott Williams & Wilkins, 1995; 67:41–52. © Lippincott Williams & Wilkins.

In 35 consecutive elderly referrals with drop attacks reported by Dey et al. (1997) the diagnosis was felt to be uncertain in only 29%. The cause was considered to be due to carotid sinus syncope in 51%, orthostatic hypertension in 14%, and imbalance of gait in 3%. In 21% more than one of these diagnoses were present. This marked predominance of cardiovascular causes may have resulted from referral bias as the study was carried out in a cardiovascular investigation unit. The authors provided only sketchy detail of the testing and none of the criteria used to establish the diagnosis. Nonetheless, it is in keeping with the hypothesis that cardiovascular abnormalities are the commonest cause of drop attacks in elderly people.

The natural history and prognosis of drop attacks clearly depends on their underlying cause. In the series of Meissner et al. (1986) 54% of patients received no treatment. Similar percentages of treated (82%) and untreated (84%) cases were symptom free at follow-up. They also found that the stroke rate in the overall group was approximately 0.5% per annum. This was not significantly different from that in a normal age – and sex – matched population. There are many specific types of drop attacks for which the outcome is much less favourable. These are mentioned below but include epileptic drop attacks.

Systemic hypotension

A systemic fall in blood pressure caused by a change in cardiac rhythm or orthostatic hypotension can result in falling. While symptoms of faintness, dizziness, or loss of consciousness probably occur during the majority of such bouts this is not invariably the case (Dey et al. 1997). A definite diagnosis of cardiac dysrhythmia really requires Holter monitoring during the event, but presumptive evidence can be derived from associated disturbances in interictal cardiac rhythm or precipitatory manoeuvres. One manoeuvre is carotid sinus massage which may reveal a hypersensitive carotid sinus. This is probably more frequent in the elderly and has been said to occur in up to 25% of such patients who have unexplained falls, dizziness, or syncope (Kenny and Traynor 1991, Richardson et al. 1997). While the associated symptoms of faintness, giddiness, and presyncope would exclude many such patients from consideration here a small number may present with drop attacks. In these cases precipitation by head movement or vagal stimuli may give a clue to the aetiology (Kenny and Traynor 1991). These episodes and drop attacks resulting from other causes of cardiac dysrhythmia may be able to be controlled by cardiac pacing.

While drop attacks due to cardiovascular disorders are more common in the elderly they can occur at any age, including in the paediatric age group. Long-QT syndrome (Romano-Ward syndrome) seems a particularly likely cause of cardiac drop attacks in the paediatric age group (Pfammatter et al. 1995). In most children these episodes are accompanied by recognizable loss of consciousness. Therapy consists of beta blockers. An implantable cardioverter defibrillator or left cervicothoracic sympathetic denervation are therapeutic options in patients who remain symptomatic despite beta-blocker therapy [for review of the long QT syndrome see Goldenberg and Moss (2008) and Roden (2008)].

Focal cerebral transient attacks

Episodes of transient brainstem ischaemia may cause falls associated with other features of vertebrobasilar territory dysfunction, including visual disturbance, tinnitus, deafness, vertigo, vomiting, dysarthria, dysphagia, incoordination, unsteadiness, and long tract symptoms or signs. It is probably uncommon, however, for transient ischaemia to produce drop attacks unaccompanied by some of these or by recognizable loss of consciousness. Some authors consider that drop attacks do not occur due to focal episodes of transient cerebral ischaemia unless there are other localizing symptoms (Fisher 1958, Baker et al. 1966, 1968, Friedman et al. 1969). Others, however, disagree (Millikan and Siekert et al. 1955, Klee and Mordhorst 1961, Williams and Wilson 1962, Lund 1963, Gortvai 1964, Kameyama 1965, Russo 1979). Brust et al. (1979) published the case of a 65-year-old man who had several attacks of transient limb weakness with falling, some of which were unaccompanied by loss of consciousness and rapid recovery occurred. Neurological examination within 5 minutes of one such attack was said to be normal. Within days the patient developed more sustained evidence of a brainstem lesion and at autopsy was shown to have infarction in the pons and medulla, which particularly involved the corticospinal tracts. There was also damage to the reticular formation nuclei and their rostral projections. The authors felt that at least some of the drop attacks resulted from transient ischaemia of the corticospinal tracts. In the absence of demonstrable brainstem lesions or symptoms the aetiological association between focal ischaemia and drop attacks is often based on the demonstration of cerebrovascular disease in those suffering falls. By and large, this is an unsatisfactory way of establishing causality. Demonstration of vascular disease within the vertebrobasilar territory is more convincing and relief of symptoms by therapy provides the most compelling evidence. A number of studies have reported abolition of drop attacks in subclavian steal syndrome by bypass surgery (Edwards and Mulherin 1983, Vitti et al. 1994, Ciocca et al. 1995) or by angioplasty (Imparato et al. 1981). Although such patients have been reported to have such drop attacks, the precise details of the bouts have usually been sketchy.

In addition to the possibility that brainstem ischaemia can cause drop attacks it has also been reported that episodic lapses of postural control which typify asterixis can result from ischaemic damage to the mesencephalic reticular formation. It has been proposed that these might represent a segmental form of drop attack (Bril et al. 1979). Whether bouts of transient ischaemia within the carotid territory can cause drop attacks is a moot point. Hemiparesis or paralysis of a leg resulting in falling would not normally be considered a drop attack. It has been postulated that if both anterior cerebral arteries are supplied by one carotid, which becomes transiently blocked, leg weakness and drop attack might follow (Meissner et al. 1986). This remains speculative.

Although focal brainstem ischaemia can undoubtedly result in falling, associated loss of consciousness, other brainstem symptoms and signs, and the more prolonged nature of the event usually serve to differentiate this from the typical drop attack as we have defined above. We thus consider it as a rare cause of ‘pure’ drop attack.

Epilepsy

As mentioned above, Hunt (1922) was the first to describe epileptic drop attacks. He regarded them as being due to ‘sudden losses of postural control’ with ‘falling to the ground’ and ‘rising almost immediately’. He felt there should be ‘very slight’ or no loss of consciousness. They have subsequently been known by a variety of other names, including ‘astatic’, ‘akinetic’, and ‘inhibitory seizures’. Brief falling due to epilepsy can result from several different abnormalities of postural control and from a variety of types of epilepsy. Thus, the falls may be triggered by tonic seizures, a clonic jerk, or atonia. Sometimes a myoclonic jerk may proceed atonia. The exact mechanism depends on the seizure type.

Perhaps the best known form of epileptic drop attacks is that which is found in Lennox-Gastaut syndrome (Lennox 1960, Gastaut and Regis 1961, Gastaut et al. 1966, Gastaut et al. 1974) in which falls are usually associated with absence seizures and myoclonus. Onset is typically in childhood, frequently between 3 and 6 years of age. Attacks can occur spontaneously or be provoked by photic stimulation. The drop attacks usually only last seconds. Lennox-Gastaut syndrome can be cryptogenic or symptomatic of other disorders, with about 70% falling into the latter group in many series. About half of the symptomatic group may have West's syndrome (Oguni et al. 1996). In addition to the common childhood form of Lennox-Gastaut syndrome, a so-called late variant has been described in which onset is usually in the teens (Oller Daurella 1970, Lipinski 1977, Bauer et al. 1983).

Gastaut and Broughton (1972) demonstrated that drop attacks were accompanied by generalized bilaterally synchronous spike and wave discharges lasting 1–3 seconds, which were rapidly replaced by generalized slow wave activity. They considered the brief attacks to be due to intense inhibition of the motor centres maintaining posture. Thus, drop attacks in Lennox-Gastaut syndrome come to be thought of as resulting from a sudden loss of muscle tone, but in about half they may actually result from generalized tonic seizures or spasms, which seem more likely to occur in those who have had West's syndrome (Oguni et al. 1996). Simultaneous video-EEG monitoring has shown that these tonic seizures are a type of brief axial flexor tonic spasm in which the head and trunk are suddenly bent forwards. In somewhat less than a quarter of drop attacks there is a myoclonic jerk followed by a period of atonia (myoclonic-atonic), while in a similar or smaller number there is a true atonic seizure (Egli et al. 1985, Ikeno et al. 1985). Long-term follow-up of Lennox-Gastaut syndrome has shown a poor outcome with intellectual deterioration, worsening gait, and persisting seizures in the majority even with treatment. Drop attacks may become very disabling in almost half, especially over 10 years of age and, along with the gait disturbance, result in many patients being chair bound (Oguni et al. 1996).

In 1985 Doose described a variety of childhood epilepsy which has become known as myoclonic-astatic epilepsy of early childhood. Epilepsy starts between the ages of 1 and 6 years and is characterized by myoclonic, myoclonic-astatic, and astatic seizures which often cause the patient to fall. Development prior to onset of epilepsy is normal and there is a genetic predisposition. The EEG usually shows a 4–7Hz rhythm which is accentuated in the parietal region. Drop attacks in this condition can be due to sudden myoclonus causing flexion of the head and trunk, an initial myoclonic jerk, followed by an atonic period or by sudden atonia (Oguni et al. 1992). Some of the episodes that appear to be purely atonic may be preceded by subtle myoclonic twitching, which is really only visible with combined video/EEG monitoring (Oguni et al. 1997). In these atonic attacks children collapse straight on to their buttocks and they are usually able to get up again almost immediately (Fig. 52.1). There is sudden interruption of electromyography (EMG) in the postural or antigravity muscles lasting up to 400 msec. This coincides with the slow wave phase of generalized spike and wave complexes on EEG and the intensity of the seizures seems to parallel the slow wave amplitude (Oguni et al. 1992).

Fig. 52.1 Simultaneous video (A) and polygraphic findings (B) of intense atonic epileptic drop attacks in a boy aged 3 years 10 months with cryptogenic epilepsy. A: Before the seizure the patient was standing in front of a desk and manipulating a toy (1). He suddenly collapsed straight down, landing on his buttocks (2–5). Semiflexion is apparent at the knees (3). The arms also dropped down (3–4). He had already regained consciousness by the time he landed on the floor (5). B: The electromyographic (EMG) potentials preceding the interrupted EMG potentials were apparent polygraphically at forearm flexor and quadriceps muscles. The EMG discharges of the quadriceps and biceps femoris muscles were restored during the late phase of falling, suggesting that the bodily collapse was probably due not only to global atonia but also to gravity, so that he immediately recovered once on the floor. Numbers in the photograph corresponded to those of the EEG.

Fig. 52.1
Simultaneous video (A) and polygraphic findings (B) of intense atonic epileptic drop attacks in a boy aged 3 years 10 months with cryptogenic epilepsy. A: Before the seizure the patient was standing in front of a desk and manipulating a toy (1). He suddenly collapsed straight down, landing on his buttocks (2–5). Semiflexion is apparent at the knees (3). The arms also dropped down (3–4). He had already regained consciousness by the time he landed on the floor (5). B: The electromyographic (EMG) potentials preceding the interrupted EMG potentials were apparent polygraphically at forearm flexor and quadriceps muscles. The EMG discharges of the quadriceps and biceps femoris muscles were restored during the late phase of falling, suggesting that the bodily collapse was probably due not only to global atonia but also to gravity, so that he immediately recovered once on the floor. Numbers in the photograph corresponded to those of the EEG.

Reproduced with permission from Oguni H, Uehara T, Imai K, Osawa M. Atonic epileptic drop attacks associated with generalised spike-and-slow wave complexes: video-polygraphic study in two patients. Epilepsia 1997; 38:813–818. © John Wiley & Sons.

Drop attacks can also occur in juvenile myoclonic epilepsy. In these a large generalized myoclonic jerk is usually followed by a degree of atonia. Sometimes this cessation of muscle contraction is brief and can only be detected by use of concomitant EMG, but on other occasions it results in loss of posture (Oguni et al. 1994).

Migrational disorders are a potent cause of epilepsy and seem particularly likely to produce drop attacks (Palmini et al. 1991). In this context, there is polymicrogyria which is characterized by an excessive number of small and prominent brain gyri, separated by shallow sulci. In congenital bilateral perisylvian polymicrogyria, seizures usually commence between 4 and 12 years of age and include atypical absence, atonic/tonic, and generalized tonic-clonic seizures. The disorder has been linked to the X chromosome (Villard et al. 2002). Kuzniecky et al. (1994) found 73% in a series of 31 patients had experienced atonic or tonic drop attacks. Multilobar polymicrogyria may also be associated with frequent atonic drop attacks, many of which seem to cease spontaneously in later childhood (Guerrini et al. 1998[b]).

In 1950 Ethelberg described five patients with drop attacks, which he called ‘chalastic fits’ or ‘symptomatic cataplexy’, which resulted from structural lesions of the frontal cortex. Falls have subsequently been reported to be the main ictal manifestation of frontal lobe lesions, occurring in about 80% of patients (Geier et al. 1977). About 70% of cases with drop attacks due to partial epilepsy have the focus in the frontal region (Tinuper et al. 1998) (Fig. 52.2). Temporal lobe lesions are perhaps the next most common site, making up about 16% (Jacome 1989, Gambardella et al. 1994, Tinuper et al. 1998). They can, however, arise due to a focus in other areas, including the parietal lobes (Smith 1983). The pathologies underlying these drop attacks have been quite varied.

Fig. 52.2 Video-polygraphic recording of a drop seizure in a 35-year-old man with partial epilepsy due to a right frontal focus. A: Clinical sequence of the seizure. (1) The patient is standing up. He wears a safety jacket to prevent him hitting the floor. (2) A tonic contraction of the facial, axial, and upper limb muscles appears. The patient bends his head and trunk slightly forward (3–5). One second later he begins to drop. The tonic posture is still evident (6–7). The patient remains unresponsive, motionless, for 31 seconds (8). He begins to get up without help (9). The seizure is over. The seizure lasted 51 seconds. B: Simultaneous polygraphic recording. The numbers indcate the sequence of the photographs in (A).

Fig. 52.2
Video-polygraphic recording of a drop seizure in a 35-year-old man with partial epilepsy due to a right frontal focus. A: Clinical sequence of the seizure. (1) The patient is standing up. He wears a safety jacket to prevent him hitting the floor. (2) A tonic contraction of the facial, axial, and upper limb muscles appears. The patient bends his head and trunk slightly forward (3–5). One second later he begins to drop. The tonic posture is still evident (6–7). The patient remains unresponsive, motionless, for 31 seconds (8). He begins to get up without help (9). The seizure is over. The seizure lasted 51 seconds. B: Simultaneous polygraphic recording. The numbers indcate the sequence of the photographs in (A).

Reproduced with permission from Tinuper P, Cerullo A, Marini C, et al. Epileptic drop attacks in partial epilepsy: clinical features, evolution, and prognosis Journal of Neurology, Neurosurgery, & Psychiatry 1998; 64: 231–7. © BMJ Publishing Group.

While some authors have postulated a focal discharge via the cortico-reticular pathways into the pontine reticular formation (Smith 1983, Gambardella et al. 1994), it seems likely that most drop attacks are caused by secondary bilateral synchrony resulting from rapid spread of the focal ictal discharge via the corpus callosum and/or hippocampal commisure to the contralateral hemisphere. In one series 74% of such drop attacks showed the EEG pattern of secondary bilateral synchrony during their revolution and it has been suggested this discharge either activates (tonic) or inhibits (atonic) centres controlling postural tone (Tinuper et al. 1998).

Drop attacks occurring in partial epilepsy are usually a late manifestation, arising some years after the onset of seizures. There is usually unconsciousness for a minute or two followed by a brief period of confusion. The prognosis for seizure control with anticonvulsants is poor (Pazzaglia et al. 1985, Gambardella et al. 1994, Tinuper et al. 1998). About three quarters of patients have a bad outlook, with mental retardation in almost a half and continuing drop attacks in a similar proportion.

Gelastic or laughing seizures are the best known manifestation of hypothalamic hamartomas, but a variety of other seizures including drop attacks may occur (Cascino et al. 1993). Other lesions around the third ventricle may also cause drop attacks (see later) and, while the mechanism related to these is uncertain, it seems likely that those due to hamartomas are epileptic, not only because of their association with other seizure types but also because of their response to callosotomy.

Another type of epileptic drop attack that has been described is that which arises from stimulus sensitive seizures in which a sudden unexpected somatosensory stimulus can cause tonic posturing with falling. This can be associated with infantile hemiplegia (Oguni et al. 1998).

The response of epileptic drop attacks to medication depends on the underlying disorder. Juvenile myoclonic epilepsy is usually well controlled with valproate, but most other forms of drop attack are relatively resistant to anticonvulsant medication. Thus, the falling episodes seen in Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, hypothalamic hamartomas, and focal cortical lesions tend to respond poorly to phenytoin, carbamazepine, and valproate. Felbamate (The Felbamate Study Group 1993, Burdette and Sackellares 1994), lamotrigine (Motte et al. 1977), and to a lesser extent benzodiazepines such as clobazam, clonazepam, and nitrazepam (Peterson 1967, Geller and Christoff 1971, Hansen and Menkes 1972, Canadian Clobazam Cooperative Group 1991, Dichter and Brodie 1996) may be helpful in generalized seizures causing drop attacks, particularly in Lennox-Gastaut syndrome. Topiramate also holds promise (Langtry et al. 1997). The tricyclic imipramine has occasionally been reported to be helpful in children (Hurst 1986).

The response to surgery has been reasonable. On occasions removal of an epileptogenic focus has been helpful (Gambardella et al. 1994, Lipinsky 1997). Extripation of a hypothalamic hamartoma has infrequently been reported to help drop attacks (Nishio et al. 1994) but is normally ineffective (Cascino et al. 1993). On the other hand, sectioning of the corpus callosum may be worthwhile, although other types of seizures associated with these hamartomas are unlikely to respond (Cascino et al. 1993). Callostomy, even in its anterior half to two thirds (Mamelak et al. 1993), has been found to be helpful in a range of drop attacks due to both cryptogenic epilepsy and focal cortical lesions. Significant improvement in attacks has been noted in between 50 and 85% of cases. In Lennox-Gastaut syndrome atonic seizures respond best and axial spasms the worst (Carmant and Holmes 1994, Phillips and Sakas 1996, Papo et al. 1997, Rougier et al. 1997). Good results in drop attacks associated with partial epilepsy have been published by a number of different groups (Wilson et al. 1982, Gates et al. 1984, 1987, Spencer et al. 1985, 1988, Oguni et al. 1991).

Although division of the corpus callosum has been reported to help drop attacks related to bilateral polymicrogyria (Kuzniecky et al. 1994), caution is needed because, as mentioned above, attacks tend to cease spontaneously in late childhood (Guerrini et al. 1998[b]).

Third ventricular lesions

In 1951 Kelly described drop attacks in patients with third ventricular colloid cysts. They had brief attacks of paraplegia and dilated lateral ventricles were present in all. Pecker et al. (1974) considered such attacks occurred in over a third of patients with colloid cysts. Following the fall the patient was able to get up without difficulty, but the weakness might persist for 5–15 minutes. He noted that such attacks may occur several times daily.

Similar drop attacks have been reported in a variety of other third ventricular mass lesions including meningioma (Crisculo and Symon 1986) and colloid plexus papilloma (Pollack et al. 1995). The mechanism of the attacks remains obscure and it is uncertain whether they result from direct mechanical effects on the adjacent third ventricular structures or are secondary to the associated hydrocephalus (see later).

Posterior fossa lesions

Space taking lesions in the posterior fossa have infrequently been associated with drop attacks. Kremer (1958) described these in three young adults. He noted a ‘profound diminution of tone’ when the neck was extended in one who had a compressive lesion extending through the foramen magnum. He speculated that brainstem ischaemia may have been the mechanism, particularly by interfering with blood supply ‘to the connections of the cerebellum which deprives the postural-tone mechanism of the control of the gamma-fibre servoloops which go out of action’. There have been many other descriptions of sudden and unexpected falls caused by similar lesions. One of Kremer's (1958) patients had a fourth ventricular ependymoma, but large arachnoid cyst (Shinoda et al. 1998), giant vertebral artery aneurysm (Gautier et al. 1982), Chiari type I malformation (Bardella et al. 1984), and basilar impression (Bewermeyer et al. 1984) have all been recorded. Congenital separation of the bony margin of the foramen magnum, a so-called proatlas (Gil-Nagal et al. 1992), is another abnormality in this area which has been associated with drop attacks.

Hydrocephalus

Drop attacks have also been reported as a manifestation of occult hydrocephalus. Botez et al. (1977) reported five cases in which such falls were attributed to ventricular dilatation. In at least three there was associated cerebral atrophy. They considered the mechanism of the drop attacks to be similar to that occurring in patients with colloid cysts and infratentorial masses, possibly as the result of tentorial herniation following a rise in intracranial pressure. Brain ischaemia caused by hydrocephalus was also considered as a possible cause of the falls. It remains uncertain whether the hydrocephalus associated with mass lesions of the third ventrical or posterior fossa is responsible for the drop attacks or whether they are caused by the mechanical effects of the lesions themselves.

Cervical lesions

Drop attacks may occur on head movement (Sheehan et al. 1960, Gortvai 1964, Kubala and Millikan 1964, Wilkinson 1971). Most commonly this has been attributed to compression of the vertebral artery with resultant brainstem ischaemia. Many such reports are in the older literature and it is uncertain whether some of these patients also had other brainstem symptoms suggestive of vertebrobasilar transient ischaemic episodes, which would take them out of the realm of pure drop attacks. Compression of the spinal cord has also been associated with drop attacks (Maurice-Williams 1974) and such bouts may occur in cases with extreme cervical instability or fracture (Kremer 1958, van Norel and Verhagen 1996). Even in these cases, however, the mechanism may be ischaemic, as suggested by dizziness, confusion, and dysarthria, which have been reported to occur in association with transient tetraparesis (van Norel and Verhagen 1996).

Vestibular dysfunction

In 1936 Tumarkin described sudden attacks of falling, unassociated with episodic vertigo, tinnitus, hearing loss, and a sensation of pressure in the ear which occurred in patients with Meniere's disease. He speculated that the problem resulted from a ‘hydrolithic catastrophie’ caused by mechanical deformation of the otolithic organs. There have been many subsequent descriptions of this phenomenon. It probably occurs in about 5–7% of patients with Meniere's disease (Black et al. 1982, Baloh et al. 1990) and may sometimes afflict patients with other peripheral vestibular disorders (Kuhl 1980). Although drop attacks may start many years after the onset of Meniere's syndrome it can rarely be the initial manifestation. These patient's symptoms differ from those occurring in other forms of drop attacks in that they experience a sensation of being pushed, thrown, or knocked to the ground or a sudden illusion of movement of the environment, which leads to the fall (Table 52.4) (Baloh et al. 1990). Patients may ‘fall like a tree’ and this is often in the same direction with repeated attacks (Kuhl 1980). They are usually able to get up immediately after the episode.

Table 52.4 Description of typical drop attacks in 12 patients with Meniere's syndrome

Patient no.

Description

1.

Sudden fall to ground as though pushed

2.

While sitting at dining table, fell forward into food, as if pushed from behind

3.

Sensation of being slapped on the side of the head, fell to the ground

4.

‘Knocking episodes,’ first occurred while sitting in taxi, thought someone pushed her to the floor

5.

Suddenly ‘thrown’ to the ground from sitting or standing position

6.

While sitting had illusion that the chair was falling backward, fell forward onto the floor

7.

Sudden fall to ground as though pushed

8.

Sudden falls as though pushed, hit head on concrete, dazed but no loss of consciousness

9.

Sitting at lab bench, thought bench suddenly moved away from him, fell backward from stool to floor

10.

Sensation of sudden push to the ground, along with an electric shock-like sensation in centre of head

11.

Sudden fall from a bar stool (before first drink) with illusion of tilting of the environment

12.

Room suddenly tilts, must grab onto something or fall to ground ‘like an earthquake’

Reproduced with permission from Baloh RW, Jacobson BA, Winder T. Drop attacks with Meniere's syndrome. Annals of Neurology 1990; 28:384–387. © John Wiley & Sons.

Drop attacks tend to occur in bouts which eventually resolve spontaneously. Baloh et al. (1990) found that only two out of 12 patients had more than six attacks and in only two cases did they continue for more than 1 year. A similar self-limiting course has been noted by others (Janzen and Russell 1988). Patients show sensorineural hearing loss and in most cases there is an abnormality of caloric responses on the affected side. The pathophysiological mechanism of the bouts is uncertain but it has been postulated that there is a sudden stimulation of the otolithic membrane of the utricle, saccule, or both. Mechanical deformation due to pressure differentials within the inner ear or sudden change in electrolyte content of endolymph due to rupture of the membranous labyrinthine might cause the stimulation. It has been suggested that a burst of neural impulses might pass directly into the vestibulo-spinal reflex pathways or to cortical centres involved in spatial orientation, resulting in a sudden fall.

In patients in whom the bouts do not resolve spontaneously, intratympanic injections of gentamycin (Odkvist and Bergenius 1988, Chung et al. 2007) or vestibular nerve section (Baloh et al. 1990) may be helpful. If there is severe hearing loss, cochleosacculotomy (Kinney et al. 1995) or labyrinthectomy (Black et al. 1982) might be required.

Cataplexy

Cataplexy is characterized by episodes of weakness and loss of muscle tone precipitated by emotion. It is usually part of the narcoleptic syndrome. Although Gelineau (1880) noted attacks of emotionally induced muscular weakness in narcolepsy, it was not until Loewenfeld's (1902) fuller description that the relationship became firmly established. Subsequent reports expanded the syndrome into the narcoleptic tetrad. Thus, narcolepsy or inappropriate daytime sleep was associated not only with cataplexy but also with episodes of paralysis (‘sleep paralysis’) and vivid hallucinations when going off to sleep or waking (‘hypnogogic hallucinations’). Cataplexy is not only the second commonest symptom of narcolepsy but also the most specific one (Billard et al. 2006). However, there is also a form of narcolepsy without cataplexy. The criteria for narcolepsy are listed in Table 52.5.

Table 52.5 The essential diagnostic criteria of narcolepsy with and without cataplexy

Essential diagnostic criteria of narcolepsy with cataplexy

A. Complaints of excessive daytime sleepiness occurring almost every day for at least 3 months

B. A definite history of cataplexy, defined as sudden and transient episodes of loss of muscle tone triggered by emotions, is present

C. Whenever possible confirmation by nocturnal polysomnography followed by a multiple sleep latency test. On the latter, the mean sleep latency is at least 8 min and two or more sleep onset rapid eye movement periods (SOREMPs) are observed following sufficient nocturnal sleep (minimum 6 h) during the night prior to the test. Alternatively, hypocretin-1 levels in the CSF are 110 pg/ml or more, or one-third of mean normal control values

D. The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder

Essential diagnostic criteria of narcolepsy without cataplexy

Criteria A and D have to be fulfilled. For criteria B and C:

B. Typical cataplexy is not present, although doubtful or atypical cataplexy-like episodes may be reported

C. Confirmed by nocturnal polysomnography followed by a multiple sleep latency test. The mean sleep latency on MSLT is at least 8 min and two or more SOREMPs are observed following sufficient nocturnal sleep (minimum 6 h) during the night prior to the test

Reproduced with permission from Billiard M, Bassetti C, Dauvilliers Y, Dolenc-Groselj L, Lammers GJ, Mayer G, Pollmächer T, Reading P, Sonka K; EFNS Task Force. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006; 13:1035–48. © John Wiley & Sons. MSLT = multiple sleep latency test

Although pathophysiological mechanisms underlying cataplexy and narcolepsy are uncertain, they may involve a disturbance of brainstem cholinergic, serotinergic, and/or catecholamine systems, which are thought to control regulation of muscle tone and rapid eye movement and non-rapid eye movement sleep. In narcoleptic and cataplectic dogs the number of cholinergic receptors in the pontine reticular formation is increased and cholinergic drugs induced cataplexy, while atropine reverses this effect (Reid et al. 1994). PET studies in humans have not confirmed an increase in muscarinic cholinergic receptors (Sudo et al. 1998). Another important neurotransmitter for sleep regulation is orexin/hypocretin, a hypothalamic neuropetide involved in various hypothalamic functions such as energy homeostasis and neuroendocrine functions (Sakurai et al. 1998) [see Nishino (2007) for review]. Alterations in orexin levels can clinically be detected as reduced levels in the cerebrospinal fluid (CSF) (Nishino et al. 2001), and this is one of the diagnostic criteria by the International Classification of Sleep Disorders (Table 52.5).

Although most cases of human narcolepsy are sporadic, there is emerging evidence that human narcolepsy is human leukocyte antigen (HLA)-associated, multigenic, and environmentally influenced (see Mignot 2004), and genetic mutations have been identified in animals with narcolepsy. In humans an increased incidence of HLA DRI5 (DR2) and DQB10602 has been found. The latter is particularly associated with cataplexy and is found in 85% of cases compared with 38% of controls (Rogers et al. 1997, Mignot 1998). Mutations in hypocretin/orexin-related genes are, however, rare in humans.

A variety of pathologies involving the ponto-medullary region can cause symptomatic narcolepsy and cataplexy, including encephalitis (Wilson 1928), tumour (Onofrj et al. 1992, D’Cruz et al. 1994), head injury (Lankford et al. 1994, Maeda et al. 1995, Francisco and Ivanhoe 1996), multiple sclerosis (D’Cruz et al. 1994, Sandyk 1996), and inherited metabolic disorders such as type C Niemann-Pick (Boor and Reitter 1997) and Norrie's disease (Vossler et al. 1996).

Hypersomnolence is the most common member of the tetrad, followed by cataplexy, which is present in two thirds of narcoleptics (Yoss and Daly 1960). Approximately a third to a half of cases with narcolepsy are familial (Kamphuisen 1981). Most inherited cases, however, usually have a lower incidence of cataplexy. In a large family described by Daly and Yoss (1959) only 25% of patients had cataplexy which was occasional and mild. Cataplexy may occur in patients unaffected by the rest of the syndrome and this has been striking in occasional families. Gelardi and Brown (1967) reported 11 patients in three generations with isolated hereditary cataplexy. The disorder seemed to be inherited as an autosomal dominant trait with high penetrance, but transmission from father to child did not occur and there was a strong female preponderance.

The prevalence of cataplexy is uncertain, but narcolepsy affects 0.03–0.16% of the general population (Kamphuisen 1981, Shimizu 1998, Nishino 2007). Onset ranges from childhood to adult life. In cases with both features narcolepsy usually predates cataplexy, often by many years. In approximately 10%, however, cataplexy develops before narcolepsy (Daly and Yoss 1977). The severity of cataplexy usually mirrors that of the hypersomnolence (Mitler et al. 1998).

Cataplectic attacks are triggered by emotional events and, generally speaking, the stronger the emotion the more severe the attack. Surprise, anger, anxiety, pleasure, and amusement are all precipitants. Laughter is among the most potent. Even normal subjects can develop a degree of weakness with intense emotions, such as fear or laughter, but loss of positional tone in narcolepsy has been estimated to be almost 10 times greater than in controls (Parkes et al. 1998). Cataplexy may be more likely to occur if the patient is drowsy. Both weakness and loss of muscle tone occur. Attacks can vary from a focal feeling of mild weakness to complete generalized paralysis. There may be diplopia, ptosis, facial weakness, or paralysis of jaw muscles. The mouth can sag open or the head slump forwards. Weakness of limbs and trunk may result in the arms falling to the sides, the knees buckling, or toppling from the sitting position. Generalized paralysis with falling may endanger the patient. Cataplectic attacks usually last less than half a minute and seldom exceed a few minutes. Rarely they persist for a more prolonged period, sometimes for hours, a state that has been called ‘status cataplecticus’. Approximately a quarter of children with narcolepsy, however, are reported to have experienced this (Challamel et al. 1994).

Cataplexy is unaccompanied by loss of consciousness or tongue biting. Incontinence has only rarely been recorded (Vgontzas et al. 1996). Blood pressure may rise and be accompanied by a fall in pulse (Guilleminault 1998). Examination during an attack is reported to show flaccid weakness with areflexia (Roth 1957, 1962). H-reflexes are lost (Daly Yoss 1977, Guilleminault et al. 1998). In spite of this the response of axial and limb muscles to magnetic stimulation of the motor cortex during cataplexy is normal, possibly due to enhanced cortical excitability (Rosler et al. 1994). The EEG, however, shows no significant change (Daly and Yoss 1977).

Diagnosis is based on clinical features, although EEG may show that sleep commences with a period of rapid eye movement instead of the normal initial slow wave sleep. The maintenance of wakefulness test, which involves multiple measurements of the latency to EEG sleep onset in a darkened room, is abnormal with 85% of narcoleptics showing an average latency of 12 minutes or less (Mitler et al. 1998). A number of other EEG sleep abnormalities have been reported (Hishikawa et al. 1976). Assessment of HLA status may assist diagnosis. Initial reports of subtle MRI changes in the pontine tegmentum have not been substantiated (Bassetti et al. 1997). For the diagnostic criteria of narcolepsy see Table 52.5.

In 2006, the European Neurological Society published guidelines on the management of narcolepsy with or without cataplexy. The authors concluded that several classes of drugs are recommended for the treatment, namely stimulants for excessive daytime sleepiness and irresistible episodes of sleep, antidepressants for cataplexy, and hypnosedative drugs for disturbed nocturnal sleep. In addition, behavioural measures can be of notable value (Billard et al. 2006).

However, although methylphenidate and dexamphetamine improve narcolepsy, they are ineffective in the treatment of cataplexy, sleep paralysis, and hypnogogic hallucinations (Daly and Yoss 1977). However, as mentioned above, the tricyclic antidepressants clomipramine and imipramine improve these other features (Hishikawa et al. 1966). The selective serotonin re-uptake inhibitors (Billiard 1998), the non-selective monoamine oxidase inhibitor tranylcypromine (Gernaat et al. 1995), and the monoamine oxidase-B inhibitor selegiline (deprenyl) have all been reported to lessen cataplexy (Hublin et al. 1994, Mayer et al. 1995). Interestingly, Norrie's disease, mentioned above, is accompanied by virtual absence of monoaminine oxidase-A and -B (Vossler et al. 1996). Carbamazepine may be worth trying in resistant cataplexy (Vaughan and D’Cruz 1996). Gammahydroxybuterate (under the name sodium oxybate) has been said to ameliorate all aspects of the narcoleptic tetrad (Scharf et al. 1998), but the effect on cataplexy has been uncertain in some early studies (Lammers et al. 1993). However, since sodium oxybate has now become the first-line treatment of cataplexy, second-line treatments are antidepressants, either tricyclics or newer antidepressants (Billard et al. 2006).

Modafinil, a non-amphetamine awakening drug, reduces somnolence (US Modafinil in Narcolepsy Multicentre Study Group 1998). However, based on several large randomized controlled trials showing the activity of sodium oxybate, not only on cataplexy but also on excessive daytime sleepiness and irresistible episodes of sleep, there is a growing practice in the USA to use it for the later indications. Particularly in view of the overuse of amphetamines and such like agents, this should be considered (Billard et al. 2006).

Idiopathic drop attacks

Drop attacks, during which the subject suddenly collapses to the ground without warning, or apparent loss of consciousness may occur without recognized cause. Stevens and Matthews (1973) estimated these affected at least 3.5% of adult females but were unable to find any cases among males. Although the cause was uncertain, they effectively excluded the narcoleptic syndrome, epilepsy, vestibular disturbance, transient ischaemic attacks, syncope, and cervical spondylosis. They speculated that attacks were due to the female ‘mechanism of walking’ and that central factors were not involved. It has been proposed that a delay in long-loop transcortical reflexes may be responsible so that the subject falls before sufficient tension can be generated in the quadriceps to prevent this (Greenwood and Hopkins 1982).

Almost 30% of patients have a positive family history with other close female relatives having been affected (Stevens and Matthews 1973). The average age of onset is approximately 45 years and in two thirds it commences during the 5th decade. The frequency of attacks can range from a single fall to over one a month. Episodes sometimes occur in bouts with prolonged intervals of freedom (Stevens and Matthews 1973).

The falls virtually always occur when walking and do not seem to relate to the type of footwear being worn. Episodes are more frequent out of doors. In the majority the fall is forwards. Most patients are able to break their fall, but it is common to injure the face or upper limbs. Approximately a third recall starting to fall and half are aware of striking the ground (Stevens and Matthews 1973). The attack is so brief that some patients are uncertain about preservation of consciousness, but in none is it definitely suspended. Unless injured, patients are able to rise immediately and have no sequellae.

It is uncertain to what extent idiopathic falls in the elderly overlap with or are an extension of these drop attacks of middle age. Many such bouts in older people, however, may be due to unrecognized cardiac, cerebrovascular, blood pressure, neuromuscular, balance, or gait disturbances, or carotid sinus hypersensitivity (Sheldon 1960, Overstall et al. 1977, Brocklehurst et al. 1978, Gordon et al. 1982).

Psychogenic drop attacks

Drop attacks, like pseudo seizures, occasionally have a psychological basis (Meissner et al. 1986). They resemble brief pseudo seizures, without associated motor activity.

Hemifacial spasm

Hemifacial spasm is a movement disorder of the face consisting of involuntary irregular twitching of muscles innervated by the seventh cranial nerve. While the movements are generally clonic, fusion of these into a more sustained tonic spasm can occur.

Schultze first described this condition in 1875 and by 1888 Gowers had differentiated it from other forms of facial spasm. As it may result in simultaneous contraction at separate sites, it has long been considered to result from abnormal generation of nerve impulses rather than being an innate muscle spasm. It was not until 1947, however, that Campbell and Keedy recognized that irritation caused by a blood vessel in contact with the facial nerve close to the brainstem might be the aetiology. This was largely ignored until Gardner and Sava (1962) reported that surgical microvascular decompression, performed by separating the blood vessel from the nerve, could result in remission of the movements. It is now accepted that this is by far the commonest cause of hemifacial spasm. The exact proportion of cases that have such a vascular aetiology varies from one series to another, depending on referral bias. In a review of 1,688 cases of hemifacial spasm previously reported in the literature Digre and Corbett (1988) found that in only 30% a vascular mechanism had been defined. In 57%, however, an aetiology was not specified. Reported surgical series tend to skew the picture by emphasizing those with either a vascular loop or some other type of mass lesion. Conversely, in groups referred for medical treatment, some mass lesions may have been selected out. In about 90% of cases no other aetiology can be found and it is probably likely most of these harbour such a vascular abnormality (Wang and Jankovic 1998). There is a suggestion that vascular abnormality may be related to the presence of arterial hypertension (Oliveira et al. 1999). Arterial hypertension was found in 66% of their cases with hemifacial spasm as compared to 38% with blepharospasm. In a case-control study, Defazio et al. (2000) also found that arterial hypertension occurred more frequently among 115 patients with primary hemifacial spasm than among age and sex matched controls. The association was not confounded by education level, smoking history, diabetes, or other diseases. However, hypertension in this sample either preceded or followed the onset of hemifacial spasm (Defazio et al. 2000).

When the cause is irritation from an adjacent blood vessel, this is virtually always arterial, with only a few per cent being venous (Loeser and Chen 1983, Caces et al. 1996, Girard et al. 1997). A vascular loop of the posterior inferior cerebellar artery seems to be the most common offending vessel (Caces et al. 1996 Girard et al. 1997), although the anterior inferior cerebellar artery has been responsible in many cases and, according to some authors (Digre and Corbett 1988), may be the most frequent. The vertebral artery has variously been reported to account for about 20–40% of cases. Yuan et al. (2005) reviewed 1200 cases of hemifacial spasm who had undergone microvascular decompression. The authors had found the offending vessel to be the anteroinferior cerebellar artery (AICA) in 511 patients (42.6%) and the posteroinferior cerebellar artery (PICA) in 255 (21.3%). A combination of both AICA and PICA were found in 154 patients (12.8%), AICA and the vertebral artery in 10%, PICA and the vertebral artery in 7%. Finally, all three vessels had offended the nerve in 6%. Sometimes the basilar artery is in contact with the facial nerve. When the vertebral or basilar are involved they may be dolichoectatic and hence elongated and distended. While it is usually the root entry zone of the facial nerve that is affected, the vascular compression can be closer to the internal auditory canal (Fukuda et al. 1997, Ryu et al. 1998[a]). Vascular lesions causing hemifacial spasm have rarely been described, even more distally, including at the geniculate ganglion (Asaoka et al. 1997) and in the parotid space (Rakover et al. 1996).

A variety of other pathologies can trigger this disorder. While these are usually situated intracranially and commonly near the root entry zone of the facial nerve, they may also occur more distally. Bell's palsy is a well-recognized antecedent and Wang and Jankovic (1998) found this in 5.7% of cases. Direct injury to facial nerve may be the cause (Martinelli et al. 1983, 1992) and 3.2% of Wang and Jankovic's patients had significant trauma to that side of the skull or face in the 6 months to 4 years prior to onset of involuntary movements. Injuries included skull fracture and facial laceration. The literature is also awash with cases of hemifacial spasm secondary to other lesions involving the cerebello-pontine angle, brainstem or other sites in the posterior fossa. Usually these have been ipsilateral but occasionally they have been contralateral and thought to result from irritation caused by displacement of the brainstem and seventh cranial nerve (Nishi et al. 1987, Matsuura and Kondo 1996). The frequency of mass lesions causing facial spasm has varied between 0.3 and 1.3% of cases (Auger et al. 1986, Sprik and Wirtschafter 1988, Nagata et al. 1992, Wang and Jankovic 1998). These have included meningioma (Nagata et al. 1992, Rhee et al. 1995, Bhayani and Goel 1996), epidermoid tumour/cholesteoma (Auger and Piepgras 1989, Nagata et al. 1992, Brodkey et al. 1996, Hotta et al. 1996, Magnan et al. 1997), lipoma (Sprik and Wirtschafter 1988, Inoue et al. 1995), schwannoma/acoustic neurinoma (Sprik and Wirtschafter 1988, Samii and Matthies 1995, Kudo et al. 1996), neurinoma (Nagata et al. 1992), ganglioglioma (Bills 1991, Harvey et al. 1996), arachnoid cyst (Takano et al. 1998), glomus juglare tumour (Hausmann et al. 1997, Kinney et al. 1999), subarachnoid cysticerci (Del Brutto 1997), cavernous haemangioma (Asaoka et al. 1997), and arteriovenous malformation (Kim et al. 1991). Other vascular abnormalities that have been recorded in association with this disorder include venous angioma (Chen et al. 1996[a]) and dissection of the basilar artery (Mizutani 1996). Brainstem infarction (Ambrosetto and Forlani 1988, Wang and Jankovic 1998), haemorrhage (Ellis and Speed 1998), and multiple sclerosis plaques (Telishi et al. 1991, van de Bienzenbos et al. 1992) are other examples of intrinsic brainstem pathologies that may lead to hemifacial spasm.

Non-traumatic bony abnormalities of the skull base, including cranio-occipital malformation (Arnould et al. 1962), basilar impression (Klaus and Bohunek 1958), and Paget's disease (Gardner and Dohn 1966), have occasionally been associated, as have benign intracranial hypertension (Selky and Purvin 1994), superficial haemosiderosis of the central nervous system (River et al. 1994), and tuberculous meningitis (Sandyk 1995).

Although it is clear from the literature that lesions affecting the brainstem or seventh cranial nerve along its course can trigger hemifacial spasm, in the vast majority of patients the abnormality seems to lie in the nerve root exit zone, adjacent to the pons. This is sometimes called the Obersteiner-Redlich zone after the pathologists who first described it in 1894. It is the boundary region where the myelin sheath changes from the thicker central nervous system type to the thinner variety found in the peripheral nervous system. There is often loose connective tissue in this area and it is ensheathed only by arachnoid membrane. Biopsies of this zone in patients suffering from hemifacial spasm show both nerve fibres with hypertrophied myelin sheaths and axons that are devoid of myelin and in contact with connective tissue. Normal fibres may be intermixed. These abnormalities are not dissimilar to those reported in trigeminal neuralgia (Jannetta et al. 1970, Kumagani 1974, Ruby and Jannetta 1975). It has been suggested that this region of the nerve is particularly vulnerable to damage by compression.

There are a variety of abnormal neurophysiological findings in hemifacial spasm, some of which appear contradictory and are difficult to explain on the basis of a single unified hypothesis. None the less, they shed considerable light on the possible pathophysiological mechanisms underlying this disorder. EMG of facial muscles shows the brief visible twitches are accompanied by isolated bursts of repetitive motor unit discharge, usually at very high frequencies. Bursts consist of 2–40 discharges of the same motor unit at frequencies between 100 and 400 Hz. Prolonged spasms may result in superimposed irregular discharges of many motor units, some of which fire at lower frequencies, in the order of 20–40Hz (Hjorth and Willison 1973). Infiltration of dilute procaine around the nerve in the region of the parotid gland can abolish such motor activity without causing weakness, perhaps suggesting gamma motor fibre hyperactivity and involvement of peripheral reflexes (Rushworth 1961).

Although facial synkinesis, which occurs when muscles in one part of the face contract automatically as those in another area are activated, may not be apparent on clinical examination, EMG recordings can usually demonstrate this. Stimulating one peripheral branch of the facial nerve results in ‘lateral spread’ of the nerve impulse so that it may cause muscles elsewhere on the ipsilateral side of the face to respond (Auger 1979, Auger et al. 1981, Nielsen 1985). The electrically elicited blink reflex, in which stimulation of the fifth cranial nerve causes a response in the seventh cranial nerve, results in early R1 and late R2 components. The former is a unilateral response which is thought to pass through a simple pontine reflex arc, while the latter is a bilateral response that is felt to descend in the ipsilateral spinal tract of the trigeminal nerve before ascending to activate both the ipsilateral and contralateral facial nerve nuclei (Kimura and Lyon 1972). In hemifacial spasm the size of R1 is increased, suggesting lateral spread with involvement of more fibres (Kimura et al. 1969, Auger 1979). In addition, there is activation of muscles in the lower face during both the R1 and R2 components (Fig. 52.3), although this is variable from one trial to the next, unlike that seen in the synkinesis which accompanies Bell's palsy (Auger et al. 1979). The facial synkinesis in Bell's palsy is thought to result from regrowth of nerves following axonal degeneration with some fibres being erroneously redirected to muscles at a site distant from those from which they originally innervated. Such aberrant regeneration, however, seems unlikely to be the cause of these synkinetic responses in hemifacial spasm as most patients have had no evidence of axonal loss and, as just mentioned, this response can be variable in a way not seen with aberrant reinnervation. It has thus been proposed that the abnormality in the nerve root entry zone might lead to ‘cross talk’ or ‘ephaptic transmission’ (Auger 1979, Auger et al. 1981). This envisages nerve impulses passing from one nerve fibre to another in the nerve root entry zone due to defects in myelination.

Fig. 52.3 The blink reflex in the orbicularis oculi, orbicularis oris, and platysma in a patient with hemifacial spasm. Four consecutive trials show simultaneous recording from the orbicularis oculi and orbicularis oris (top frame) and orbicularis oculi and platysma (bottom frames). Stimulation of the supraorbital nerve on the affected side (left panel) elicited both R1 and R2 not only in the orbicularis oculi but also synchronously in the orbicularis oris and platysma. In contrast, stimulation on the normal side of the face (right panel) evoked R1 and R2 only in the orbicularis oculi

Fig. 52.3
The blink reflex in the orbicularis oculi, orbicularis oris, and platysma in a patient with hemifacial spasm. Four consecutive trials show simultaneous recording from the orbicularis oculi and orbicularis oris (top frame) and orbicularis oculi and platysma (bottom frames). Stimulation of the supraorbital nerve on the affected side (left panel) elicited both R1 and R2 not only in the orbicularis oculi but also synchronously in the orbicularis oris and platysma. In contrast, stimulation on the normal side of the face (right panel) evoked R1 and R2 only in the orbicularis oculi

Kimura J, Ishida T, Yamada T. Electrically and mechanically elicited blink reflex. Adv Ophthalmol Plast Reconstruct Surg 1985; 4:103–124.

Moller and Jannetta (1984, 1985) found, however, that when one branch of the facial nerve was stimulated and recording made from muscles activated by other branches, the latency of response in some cases was a few milliseconds longer than could be accounted for by ephaptic transmission through the nerve root entry zone. This led to the postulation that such lateral spread might be due to nerve impulses passing through the facial nucleus. The motor nucleus of the fifth cranial nerve has thus been envisaged as being ‘kindled’ by the abnormality in the nerve root entry zone so that not only do neurons respond in a hypersensitive way to antidromic nerve pulses from their peripheral nerve fibres but also their hyperactivity causes the spontaneous facial twitching. Using a paradigm of paired stimuli separated by a small interval, one stimulus being delivered to a branch of the facial nerve and the other by way of exciting the blink reflex on the same side, it has been found that the abnormal muscle response resulting from lateral spread and the R1 component of the blink reflex can each suppress whichever response comes second. It has been argued that this supports an interaction within the facial nucleus and that lateral spread may actually be an exaggerated F-response (Moller 1991). A re-evaluation of this lateral response has led others to support its interpretation as an F-wave (Ishikawa et al. 1996[a] and [c], Ishikawa et al. 1997). It is facilitated by repetitive stimulation, which has also been taken to favour its origin in the motor neurons and their hyperexcitability (Ishikawa 1996[b]). In addition, the R2 component of the electrically elicited blink response can be inhibited by a second such stimulus if the inter-stimulus interval is short. In hemifacial spasm the recovery of R2 on the affected side of the face is enhanced, which has also been interpreted as suggesting hyperexcitability of the facial nucleus. In support of this is the report by Eekhoff et al. (2000) comparing patients with Bell's palsy synkinesis to those with hemifacial spasm. The former had a prolonged R1 latency on the affected side in orbicularis oculi and smaller mental compound muscle action potential amplitude as an indication of facial nerve damage and nerve fibre loss. This was not found in patients with hemifacial spasm, who showed an increased amplitude of the R1 and R2 responses in orbicularis oris. Patients with Bell's palsy showed only an increased R1 amplitude in orbicularis oris. Both groups of patients had signs of synkinesis. Lateral spreading was present in all patients with hemifacial spasm but only in half of those with Bell's palsy. The authors suggested that in addition to alterations in facial nucleus excitability in both conditions, ectopic re-excitation of facial nerve axons in hemifacial spasm was possible (Eekhof et al. 2000). Many of these neurophysiological abnormalities are reversed by successful microvascular decompression of the nerve root entry zone of the facial nerve, including the spontaneous EMG discharge, lateral spread on stimulating a branch of facial nerve, and abnormalities of blink response. In some cases these findings revert to normal when the dura or arachnoid are opened at operation, prior to the actual decompression itself, but in the majority the improvement seems to be simultaneous with the actual separation of the artery from the nerve. The lateral spread phenomenon has been noted to disappear intra-operatively in about 66% of cases (Moller and Jannetta 1987). In other patients surgery decreases such EMG abnormality and in many it will revert to normal over the ensuing months. This correlates with the clinical relief of the spasms. Similar changes have been reported by a number of authors and also involve the blink reflex (Moller and Jannetta 1986, Haines and Torres 1991, Ishikawa et al. 1994, 1996[c]). The fact that such changes can occur intra-operatively supports the notion that in spite of the histological findings, the pathophysiological mechanism underlying the spasms involves direct contact between the artery and the nerve root entry zone. Ephaptic transmission through a demyelinated area would not be expected to show such immediate reversal.

Hemifacial spasm usually commences in adult life and the mean age of onset is usually given between 45 and 50 years (Ehni and Voltman 1945, Wang and Jankovic 1998) with a range between about 15 and 90 years. In occasional patients it may develop during childhood. Most such cases, however, are likely to be due to pathology other than compression by a vascular loop in the nerve root entry zone. Hemifacial spasm in infancy seems particularly likely to occur with ganglioglioma. It is usually associated with other physical signs and may be due to epileptic seizures arising in the cerebellum (Harvey et al. 1996). Congenital hemifacial spasm, without obvious cause and with spontaneous remission, has been reported (Zafeiriou et al. 1997). Wang and Jankovic noted that the mean age of onset in a series of 158 patients was similar to that of patients with cranial dystonia but 7 years younger than the mean age of their series of patients with isolated blepharospasm.

There tends to be a slight preponderance of women in the ratio of about 3:2 (Ehni and Voltman 1945, Wang and Jankovic 1998). No racial predilection has been noted. Although most cases are sporadic, familial hemifacial spasm has occasionally been described (Friedman et al. 1989, Carter et al. 1990, Coad et al. 1991, Micheli et al. 1994).

The disorder usually commences with occasional minor twitching of facial muscles, which gradually becomes more frequent and persistent over the ensuing months and years. This most frequently starts in the periocular muscles, particularly those of the lower eyelid (Ehni and Voltman 1945). In only 10% of cases is the initial involvement noted in other parts of the face. Even if the orbicularis oculi is not affected first, it is eventually involved in spasms in virtually every case (Table 52.6).

Table 52.6 Symptom location and anatomic distribution in 158 patients with hemifacial spasm

Location

Site of onset by history [n (%)]

Affected site by examination [n (%)]

Frontalis

0 (0)

38 (24)

Orbicularis oculi

142 (90)

152 (94)

Eyebrow

4 (3)

8 (5)

Zygomatic

0 (0)

87 (55)

Cheek

18 (11)

8 (5)

Paranasal

2 (1)

34 (22)

Perioral

15 (9)

99 (63)

Chin/mentalis

0 (0)

33 (21)

Platysma

0 (0)

48 (33)

Other

2 (1)

5 (2)

Reproduced with permission from Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve 1998; 21:1740–7. © John Wiley & Sons.

Orbicularis oris is involved in about two thirds and the zygomatic muscles in about half of patients. In about 20–30% of cases frontalis, the paranasal muscles, mentalis, and/or platysma are affected. There may be isolated momentary muscle twitches which can be felt by the patient, seen, or palpated. While annoying, these are not usually functionally disabling. Commonly patients also experience bouts in which a rapid succession of such twitches fuse into a tonic contraction that can be sustained for many seconds (Fig. 52.4). This is usually more troublesome and may temporarily interfere with vision. Rarely, bilateral hemifacial spasm can occur, usually after a typical unilateral onset (Tan and Jankovic 1999). In five such patients, the opposite side was involved on average 8.4 years later (Tan and Jankovic 1999).

Fig. 52.4 The appearance during a bout of left hemifacial spasm with narrowing of the palpebral fissure and pulling of the corner of the mouth to that side. There is slight elevation of the corner of the mouth and deepening of the nasolabial fold.

Fig. 52.4
The appearance during a bout of left hemifacial spasm with narrowing of the palpebral fissure and pulling of the corner of the mouth to that side. There is slight elevation of the corner of the mouth and deepening of the nasolabial fold.

A number of factors may trigger the involuntary movements, most prominently emotional stress, anxiety, fatigue, and facial activity (Table 52.7). Maximal voluntary facial movements are especially likely to trigger them, even if they are not otherwise obvious. Thus, screwing up the eyes, frowning, corrugating the forehead, grimacing, parting the lips, tensing platysma, or flaring the nostrils may make twitches or spasms appear or turn the former into the latter. Occasional patients have fluctuation in severity of hemifacial spasm with change in head position, which seems likely to be due to postural alteration in the amount of pressure being applied to the nerve (Moore 1984). Relaxation, alcohol, and touching the affected area will help relieve the symptoms in some patients. Movements commonly persist during sleep and about 80% of patients will be aware of this (Wang and Jankovic 1998). The movements tend to progressively decrease during the deeper stages of sleep and are at a minimum during rapid eye movement sleep (Montagna et al. 1986).

Table 52.7 Factors modifying symptoms in 158 patients with hemifacial spasm (number of patients affected)

Modifying factor

Worsens

Improves

Unknown or no effect

Stress/anxiety

103

0

55

Fatigue

72

0

86

Exercise

12

10

136

Relaxation

5

47

106

Facial movements

62

6

90

Light

43

2

113

Reading

47

1

110

Talking

53

1

104

Chewing

34

4

120

Driving

26

5

127

Alcohol

6

11

141

Touching the area

7

29

122

Eye movement

32

2

124

Reproduced with permission from Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve 1998; 21:1740–7. © John Wiley & Sons.

Patients with hemifacial spasm experience a variety of symptoms in addition to the sensation of facial twitching or spasm (Table 52.8). The most common of these is embarrassment when meeting and socializing with other people. The movements around the eye cause a number of ocular symptoms, most commonly intermittent impairment of vision. Watering and irritation of the eye can also be bothersome and occasional patients feel that light worsens their symptoms.

Table 52.8 Symptoms in 158 patients with hemifacial spasm

Symptom

Percentage of patient group

Social embarrassment

41

Interference with vision

39

Tearing

6

Eye irritation

4

Photophobia

3

Discomfort or pain

11

Dysarthria

8

Facial paresthesia

6

Dribbling

4

Bruxism

4

Trismus

3

Clicking noise

4

Reproduced with permission from Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve 1998; 21:1740–7. © John Wiley & Sons.

Pain is not normally a feature, unless there is associated trigeminal neuralgia (see later). A number of patients, however, complain of diffuse discomfort including aching and tightness. Facial parasthesiae are occasionally reported. In a small number the spasms may interfere with articulation and result in intermittent dysarthria. Dribbling from the affected corner of the mouth, bruxism, and occasionally trismus are reported. Intermittent contractions of the tensor tympani or stapedius muscles (Auger 1986, Illingworth et al. 1996, Wang and Jankovic 1998) infrequently produce clicking or ticking noises in the ear ipsilateral to the facial movements and sometimes the patient notes that these occur synchronously with the facial movements. Rarely patients complain of transient hearing loss on the affected side during bouts of muscle spasm (Wang and Jankovic 1998).

Apart from the involuntary facial movements, neurological examination is usually unremarkable. A small number of patients have mild facial weakness and this was noted in 15% of cases reported by Ehni and Voltman (1945). They had excluded cases in which there was an identifiable cause. The repetitive movements may result in muscle hypertrophy and this has been noted in about 5% (Wang and Jankovic 1998). A degree of deafness has been reported in about 13% (Ehni and Voltman 1945, Wang and Jankovic 1998) but the side does not necessarily correlate with that of the hemifacial spasm. Nonetheless, some patients do experience related hearing loss and audiograms may be abnormal in up to a quarter of patients, with an unusual ‘notch’ in the pure tone audiogram or a low-frequency up-slooping pure tone threshold (Moller and Moller 1985). In addition, a small number of patients suffer from pulsatile or continuous tinnitus ipsilateral to their hemifacial spasm and it has been reported that neurovascular compression of the eighth cranial nerve is common in this group and that decompression relieves the tinnitus. Such a vascular loop contacting the eighth cranial nerve has been noted in only 6% of patients at the time of surgery when tinnitus has not been present (Ryu et al. 1998[b]).

Very occasionally neurovascular compression of the facial nerve extends to other adjacent nerves causing symptoms, the best known being so-called tic convulsif, a term coined by Cushing in 1920 to describe the concurrence of hemifacial spasm and trigeminal neuralgia. This association is found in about 5% of cases of hemifacial spasm (Harsh et al. 1991, Wang and Jankovic 1998). Either hemifacial spasm or trigeminal neuralgia can develop first and the disorder occurs more frequently in women (Digre and Corbett 1988). A patient with familial trigeminal neuralgia and contralateral hemifacial spasm has been reported. The mother of the patient, five siblings, and one nephew also had trigeminal neuralgia (but not hemifacial spasm) inherited in an autosomal dominant fashion. It is possible that the occurrence of hemifacial spasm in this one family member could be by chance. However, sporadic examples occurring in combination with hemifacial spasm has also been reported. Glossopharyngeal neuralgia (Platania et al. 1997). Kobata et al. (1998) used the term hyperactive dysfunction syndrome to describe patients with a combination of trigeminal neuralgia, hemifacial spasm, and/or glossopharyngeal neuralgia. Reviewing 1472 patients presenting with one of these conditions they found 41 (2.8%) with this syndrome who had a combination of such conditions. In this study, all but three of the cases, which were due to tumours or arteriovenous malformations, were idiopathic (Kobata et al. 1998). Overall, aetiologies other than irritation by a simple loop of the anterior inferior or posterior inferior cerebral arteries seem more common in tic convulsif, and dolichoectasia of the vertebrobasilar system, aneurysm, arteriovenous malformation, tumours, and cysts appear to predominate (Digre and Corbett 1988). So-called geniculate or Hunt's neuralgia (Kempe and Smith 1969, Yeh and Tew 1984) has also been reported in association with hemifacial spasm.

Hemifacial spasm is usually a very characteristic disorder and is not difficult to diagnose. They include most disorders causing involuntary facial movement, including facial synkinesis with or without hemifacial contracture following facial nerve palsy, hemifacial contracture associated with brainstem lesions, facial myokymia, facial fasciculations, cranial dystonia, facial tics, focal seizures, facial myoclonus, and hemimasticatory spasm (Digre and Corbett 1988, Auger et al. 1992, Wang and Jankovic 1998).

The neurophysiological and audiological investigations mentioned above are usually only performed in selected cases. Radiology, however, should ideally be performed in all patients, unless the aetiology of the hemifacial spasm is already known. The most useful investigation is CT or MR scan of the posterior fossa. This is important to exclude structural lesions other than a vascular loop, which might require treatment in their own right. If surgery is being considered, MRI can be especially useful in screening for abnormal vessels causing compression. While some studies have suggested vascular compression can be seen in about 65% of cases compared with 6% of controls (Adler et al. 1992), the rate of identification of aetiological vessels can be increased by adopting a variety of specialized techniques. This, however, may increase the rate of false positive identifications. In not all reports has surgery been performed to confirm that the vessel seen on the MRI is responsible for the complaint. Positive identification rates of between 85 and 100% of cases and false positive rates of between 7 (Jespersen et al. 1996) and 13.8% (Hosoya et al. 1995) respectively have been quoted. False negative rates as low as 1% have been reported (Girard et al. 1997). In many patients it is possible to make a reasonably accurate anatomical prediction as to the offending vessel. A thick and/or long high-intensity line along the root entry zone has been reported to be caused by the vertebral artery in 80% of cases, whereas a thin and/or short high-intensity line in the same area was related to compression by the posterior inferior cerebellar artery or anterior inferior cerebellar artery in 100% of patients using pre-operative oblique sagittal gradient-echo MR imaging followed by neurosurgical confirmation (Nagaseki et al. 1998).

A variety of treatments has been used to treat hemifacial spasm. Earlier unsuccessful treatments included ‘nerve tonics’, electric shocks, counter irritation resulting from a blister behind the ear (Gowers 1888), and bathing the face with hot water (Russell 1910). Membrane stabilizing anticonvulsants, such as carbamazepine and phenytoin, which have proved so successful in treatment of trigeminal neuralgia, are disappointing. In a few reports, however, they have been helpful (Shaywitz 1974, Alexander and Moses 1982). Other anticonvulsants which have also been said to help individual patients include clonazepam (Herzberg 1985) and felbamate (Mellick 1995, Patel and Naritoku 1996). Baclofen has also been reported to be useful in a small number of cases (Sandyk and Gillman 1987) as has orphenadrine (Hughes et al. 1980) and levodopa (Milan-Guerrero et al. 2000). While there has been a lack of controlled studies, the overall impression is one of an occasional idiosyncratic improvement rather than any reliable long-lasting benefit. Wang and Jankovic (1998) reported 83% of their patients were tried on a variety of medications but that only 3.8% remained on these. This testifies to their disappointing efficacy.

The medical treatment of hemifacial spasm has been revolutionized by botulinum toxin injections. Significant relief of spasms has been reported in between about 85 and 97% of patients (van den Bergh et al. 1995, Chen et al. 1996[b], Mauriello et al. 1996, Jitpimolmard et al. 1998, Wang and Jankovic 1998, Kenney and Jankovic 2008). Injections are usually made into the obicularis oculi muscle near the inner and outer canthi. While injections can be made into the zygomatic or perioral muscles, these are usually avoided because weakness may result in significant disability. In addition, a ‘trickle down’ effect from injections into the obicularis oculi often results in some reduction in involuntary movements in these lower facial muscles. As mentioned below, however, this may not be due to direct diffusion of toxin.

The mean latency from injection to onset of benefit was found to be 9.4 days and the average duration of benefit was 18.4 weeks in 84 patients treated by Wang and Jankovic (1998). They reported side effects in 37.3% but these were mild and not disabling. They included lower facial weakness, lid weakness, ptosis, a disturbance of lacrimation, diplopia, and haematoma.

The exact mechanism of the action of botulinum toxin in hemifacial spasm is uncertain. While it reduces compound muscle action potential in the obicularis oculi, the lateral spread response or F-wave in this muscle when stimulating branches of the seventh nerve elsewhere in the face is abolished (Glocker et al. 1995). This suggests that the effect is not restricted to the peripheral parts of the nerve. In addition, neurophysiological studies confirm this effect can be noted in muscles too distant to be affected by direct diffusion of toxin (Eleopra et al. 1996). In an interesting experiment to investigate interactions between face and hand representations in the human motor cortex, Liepert et al. (1999) studied patients with hemifacial spasm before and after treatment with botulinum toxin. Focal transcranial magnetic stimulation was used to assess the cortical motor output map of the abductor pollicis brevis muscle (APB) on both sides. Prior to botulinum toxin treatment the representation of the APB ipsilateral to the facial muscle contractions (iAPB) was significantly smaller than on the contralateral side. Two weeks after successful therapy, the iAPB output area was significantly enlarged and expanded into the direction of the face representation. The results showed brain plasticity changes so that the facial cortical area diminished once the spasms were improved, indicating activity-dependent interactions between hand and face representations in the motor cortex.

A variety of other procedures involving needling of the face have been used, most directed against branches of the facial nerve. Usually these have been carried out using EMG guidance. They include injections of alcohol or phenol, which usually result in relief of spasm, but recurrence within 1 year is common (Wakasugi 1972, Toremalm et al. 1977[a], Seidman and Vacharat 1980, Elmquist et al. 1982, Takahashi and Dohi et al. 1983). While the terminal branches of the nerve have usually been favoured for injections, as this allows greater control over the degree of weakness, some have targeted the main branch (Russell 1910, Toremalm 1977[b]). Thermolysis, which involves heating the tip of the needle in contact with the nerve to between 55 and 65°C, may also be helpful (Battista 1977, Hori et al. 1981). Even the small amount of physical damage caused by putting a needle into the nerve may be enough to improve the spasms (Wakasugi 1972, Ludman 1976). While this has generally been done in its distal segments, needling through the tympanic membrane has been reported to be effective (Ogale et al. 1995). Another approach has been to inject the muscles with doxorubicin and it has been proposed that the use of a priming injection of local anaesthetic 2 days before the doxorubicin may make the procedure more effective (Nguyen et al. 1998, Wirtschafter and McLoon 1998).

Direct surgical attack on the muscles and peripheral nerve branches has also been employed. While orbital myectomy has been more commonly employed for treatment of blepharospasm, it has also been helpful in hemifacial spasm (Garland et al. 1987, Friedman et al. 1989). Selective or complete facial neurotomy, involving avulsion of sections of nerve, has also been advocated (Scoville 1969, Miehlke 1981, Iwakuma et al. 1982). In some cases neurectomy has been associated with anastomosis of the distal stump to the spinal accessory or hypoglossal nerve (Harris 1932, Harrison 1976). By and large, such direct surgical attacks on facial muscles and nerves may result in unacceptable facial weakness, a variety of complications including epiphora, ectropion, and punctate keratitis, and a high recurrence rate due to regrowth of nerves (Samii et al. 1981).

In addition to the above destructive procedures, complete decompression of the facial nerve in the petrous block has been attempted, with about half of patients experiencing relief. Facial paralysis is, however, frequent (Pulec 1972, Wizmann and Dieckmann 1982).

Microvascular compression of the facial nerve root exit zone was introduced by Gardner and Sava in 1962 and subsequently popularized by Jannetta (Jannetta et al. 1977). It involves separating the facial nerve from the compressing vessel using a piece of suitable material. Excellent or satisfactory relief of facial spasms has been reported in about 70% (Rushworth and Smith 1982) to 90% (Illingworth et al. 1996) of cases and results tend to be better in large more recently reported series (Barker et al. 1995, Caces et al. 1996, Acevedo et al. 1997, Kondo 1997). Although, as mentioned above, neurophysiological improvement may occur intra-operatively and spasms cease from the time of surgery, there are a number of patients in whom improvement occurs more gradually and some authors have advised that re-operation for unsuccessful surgery is delayed, possibly for 1–2 years (Sindou et al. 1996, Ishikawa et al. 1997, Shin et al. 1997). On the other hand, however, others have reported that re-operation is more successful if performed within 1 month (Barker et al. 1995) In the series by Yuan et al. (2005) of 1200 hemifacial spasm patients who had undergone microvascular decompression symptoms had disappeared immediately after operation in 66%.

There is an incidence of recurrence of hemifacial spasm, even after apparently successful microvascular decompression, and the rate of such failures has varied widely from 1 or 2% to 55.5% (Rushworth and Smith 1982, Illingworth 1996, Kondo 1997, Yuan et al. (2005)). Jankovic and Wang (1998) reported recurrence in 21% of patients. In addition, significant long-term complications have been reported in most series and vary from about 3% to almost 30% (Barker et al. 1995, Caces et al. 1996, Acevedo et al. 1997, Kondo 1997, Wang and Jankovic 1998). Ipsilateral hearing loss is the commonest, followed by facial weakness. Tinnitus, ataxia, meningitis, leakage of cerebrospinal fluid, diplopia, hydrocephalus, intracranial haematoma, stroke, and death have all been reported.

Because of the ease of administration, excellent results, and lack of serious side effects, botulinum A injections into the obicularis oculi muscle are the preferred initial mode of treatment for this disorder. Surgery should be considered only for patients in whom the results are unsatisfactory and microvascular decompression of the facial nerve root entry zone is the procedure of choice. Other forms of therapy seem best reserved for the occasional case in whom these other forms of therapy are unsatisfactory (Wirtschafter and McLoon 1998).

Involuntary movements in amputation stumps

In 1852 Hancock described a case of a 29-year-old woman who had an above elbow amputation because of septic arthritis. Three months later she developed pain in the stump followed by ‘spasmodic twitchings’ of the shoulder and neck. This may have been the first description of involuntary movements in amputation stumps, although the question of simple partial seizures has been raised because the platysma and leg subsequently became involved. In 1872 Mitchell published a monograph on the ‘Injuries of nerves and their consequences’, relating experiences from the American Civil War. He described severe phantom pain in amputated limbs along with tremor, jerks, and spasms in the stump. A number of further reports were produced in the early part of the 20th century (Tinel 1927, Vinard 1927, Thomas and Amyot 1928). In 1929 Amyot wrote a thesis on stump spasms entitled ‘Les Convulsions des Moignons’. There has subsequently been a smattering of other reports but most have included only a small number of patients (Ritchie 1970, Russell 1970, Steiner et al. 1974, Baruah 1984, Iacono et al. 1987[a], Marion et al. 1989, Kulisevsky et al. 1992). A case of psychogenic ‘jumpy stump’ has also been described (Zadikoff et al. 2007).

Jerking or jactitation of an amputation stump, often coinciding with momentary severe local pain, may occur in the post-operative period and then settle over the ensuing weeks or months (Henderson et al. 1948, Russell 1970). In most of the published papers, however, the movements have been chronic. They have generally commenced within days to months of surgery (Marion et al. 1989, Kulisevsky et al. 1992). Pain has been a feature of many cases and this can be a persistent aching, gnawing, burning sensation or lancinating neuralgic discomfort. The pain tends to be at its worst when the stump is moving. This has led to the suggestion that the movements may be similar to those seen with causalgia and reflex sympathetic dystrophy (Kulisevsky et al. 1992) (see Chapter 43). In some patients, however, pain has been absent or inconspicuous (Marion et al. 1989, Kulisevsky et al. 1992). Both upper and lower limb amputation stumps have been affected.

Most studies have described the movements as being ‘jerks’ or ‘jumps’ and sometimes they have been considered to be myoclonic (Baruah 1984). While they are generally present at rest, they may be precipitated or accentuated by involuntary movement. Touching the stump has in some cases triggered the jerking, but in most cases this feature has been absent. Not infrequently stump movements have prevented rehabilitation with a prosthesis.

The cause of these movements is uncertain. It has been suggested that it may relate to hypersensitivity of the neuroma, which is formed by axonal sprouting at the end of the nerve (Steiner et al. 1974, Marion et al. 1989). The onset within days of surgery, however, would make this unlikely. Functional changes in spinal or cortical circuitry have also been proposed (Marion et al. 1989), but the exact pathophysiological mechanisms underlying the movements remain uncertain. Parallels have been drawn with the movements associated with causalgia and reflex sympathetic dystrophy, dystonia occurring after peripheral nerve trauma (see Chapter 43), and the syndrome of ‘painful legs and moving toes’ (see Chapter 48).

Marion et al. (1989) suggested that ‘traumatic amputation, infection of the limb and/or amputation stump and central nervous system trauma’ have been common to many of the reported cases and point out that such involuntary movements seemed to be more frequent in the latter part of the 19th and early part of the 20th century than they are today. They suggest improvements in surgical technique with less extensive soft tissue injury may be responsible for the apparent decrease in the incidence.

EMG of the stump muscles merely shows bursts of motor unit firing occurring coincident with the movements. Brain scan, EEG, and backaveraged EEG have been unremarkable (Marion et al. 1989, Kulisevsky et al. 1992).

While these involuntary movements usually persist and have been reported to continue for up to 40 years (Marion et al. 1989), spontaneous remission may occur. As mentioned above, resolution is particularly likely in the first few months following surgery (Kulisevsky et al. 1992).

By and large, attempts at suppressing the movements using a variety of medications have been ineffective. These include phenytoin, carbamazepine, chlorpromazine, propranolol, and benzodiazepines (Jankovic and Glass 1985). Clonazepam (Marion et al. 1989), doxepin (Iacono et al. 1987[a]), and baclofen (Iacono et al. 1987[b]) have been reported to give some relief in individual cases.

Dorsal rhizotomy and sympathectomy do not prevent the movements (Jankovic and Glass 1985, Kulisevsky et al. 1992). Mazars and Merienne (1980) claimed that these involuntary movements can be suppressed by deep brain stimulation using chronically implanted electrodes in the parvocellular portion of the ventral posterolateral nucleus of the thalamus. They reported this also suppresses associated stump pain but that the dyskinesias are controlled whether or not pain is a feature. They considered that sensory deafferentation was the important feature and could not obtain the same results with stimulation in this region in patients with other dyskinetic disorders unassociated with sensory impairment (Merienne and Mazars 1982).

The relationship of these movements to deafferentation and the sensory illusion of phantom limb remains uncertain. The phantom sensation can be reproduced by stimulating the post-central gyrus following amputation of the contralateral limb and abolished by lesions of the parietal cortex (Hecaen et al. 1956). While it is known that widespread peripheral and central changes occur to the nervous system following amputation of a limb, including atrophy of the contralateral sensory motor cerebral cortex (Campbell 1905, Sunderland 1978), it is uncertain what alterations occur in the thalamus, neostriatum, or globus pallidus. They may, however, be affected and it has been reported that dopamine receptor blocking drugs may trigger the development of a dyskinetic phantom sensation in an amputated limb and this can be persistent, even when dyskinetic movements elsewhere in the body have settled (Jankovic and Glass 1985).

Involuntary movements of the abdominal wall

Involuntary movements of the abdominal wall can take a number of different forms. Brief jerks can result from myoclonus. As part of a generalized myoclonic jerk, the abdominal contraction is unlikely to be seen as a distinctive entity. The brief contraction, however, may be localized to the abdominal and adjacent truncal muscles in spinal myoclonus (Jankovic and Pardo 1986). Propriospinal myoclonus (Brown et al. 1991) and spinal reflex myoclonus (Kono et al. 1994) are variants that can also produce localized abdominal jerks. Palatal myoclonus may also cause rhythmic twitches of the abdominal muscles.

Occasionally isolated jerking of the abdominal muscles may have a cerebral origin. Partial epileptic seizures are an example (Matsuo 1984). Tardive dyskinesia can also produce focal involvement of abdominal muscles (Furukawa 1979) and l-dopa or dopamine agonists can result in abdominal dyskinesia in Parkinson's disease or other parkinsonian syndromes (Shan et al. 1996). These movements have been covered in the chapters dealing with these various disorders.

In addition to these there are other involuntary movements of the abdomen which are of less certain aetiology. Diaphragmatic flutter results in repetitive jerks of the upper abdominal and lower intercostal muscles and diaphragm, which are unrelated to respiration. They may be irregular in both rhythm and amplitude. Sometimes they occur in clusters followed by pauses. There can be associated slower movements of the muscles of the abdominal wall causing umbilical movement. It has been suggested that this disorder can represent a restricted form or variant of palatal myoclonus and thus be due to a lesion of the dentatorubro-olivary connections (Iliceto et al. 1990).

Another type of involuntary abdominal movement has been described which is more gradual, sinuous, sustained, and flowing. Frequency of these movements tends to have been between 15 and 30 per minute, but EMG bursts are relatively prolonged lasting 200–1000 msec and may follow a complex pattern of organization. Thus, contraction in muscles of the central abdominal wall (rectus abdominis) may alternate with that in the muscles of the lateral abdominal wall (external oblique) (Fig. 52.5). This can produce a writhing contorting movement of the umbilicus, which has led to the term ‘belly dancer's dyskinesia’ (Iliceto et al. 1990). Four such cases were reported by Iliceto et al. (1990). In three patients abdominal surgery preceded the onset, and in the other the abdominal movements followed childbirth. Pain was a predominant symptom in two cases and occurred in the region affected by the abdominal movements. Four similar cases were reported by Caviness et al. (1994), all of whom experienced pain. Three of them had previous abdominal surgery. Onset of belly dancer's dyskinesia following central pontine and extrapontine myelinolysis associated with severe hyponatriemia (Roggendrof et al. 2007) and a case related to an intramedullary spinal tumor (Shamim and Hallett 2007) have also been described.

Fig. 52.5 Concentric needle electromyographic (EMG) recordings from the abdominal muscles in a 25-year-old woman. Upper pair of traces show slow regular bursts of EMG activity (frequency 30–40 per minute) recorded bilaterally and synchronously in both upper and lower rectus abdominis muscles. In the lower pair of traces, activity is shown in muscles of the lateral abdominal wall (external oblique), with a similar slow frequency but alternating with the recti bursts. This combined effect produced a writhing and contorting movement of the umbilicus, reminiscent of the umbilical movement of a belly dancer.

Fig. 52.5
Concentric needle electromyographic (EMG) recordings from the abdominal muscles in a 25-year-old woman. Upper pair of traces show slow regular bursts of EMG activity (frequency 30–40 per minute) recorded bilaterally and synchronously in both upper and lower rectus abdominis muscles. In the lower pair of traces, activity is shown in muscles of the lateral abdominal wall (external oblique), with a similar slow frequency but alternating with the recti bursts. This combined effect produced a writhing and contorting movement of the umbilicus, reminiscent of the umbilical movement of a belly dancer.

Reproduced with permission from Iliceto G, Thompson PD, Day BL, et al. Diaphragmatic flutter, the moving umbilicus syndrome, and “belly dancer's” dyskinesia. Movement Disorders 1990; 5:15–22. © John Wiley & Sons.

These movements have been present when lying, sitting, standing, and walking. In some cases they have been able to be suppressed involuntarily for short periods and have been reduced by deep breathing and breath holding. Stress appears to have exacerbated them and they have been reported to both continue (Iliceto et al. 1990) and disappear (Caviness et al. 1994) during sleep. Pregnancy, menstruation, and hyperthyroidism may exacerbate them (Iliceto et al. 1990).

Brain scan, EEG, visual evoked responses, somatosensory evoked potentials, myelography, and CSF examination have been reported to be normal or may show a space occupying lesion as in the case of the intramedullary spinal tumor. Alcohol, halloperidol, chlorpromazine, tetrabenazine, l-dopa, benzhexol, carbamazepine, balcofen, cyproheptadine, and benzodiazepines do not seem to provide significant relief.

The nature of these movements is uncertain. Their flowing appearance has been somewhat suggestive of chorea, but against this is their stereotyped nature and restriction to a body segment. It has been suggested that these might be examples of focal dystonia, possibly triggered by local trauma, and thus be similar to that which occurs after injury to the limbs (see Chapter 43).

Stereotypy

The characteristics of stereotypy have been defined in Chapter 3 on ‘Clinical Assessment’. This type of movement disorder, however, is not easily defined. We regard it as a repetitive, coordinated movement, posture, or noise which has no purpose, although superficially it may seem to have a function. Thus, phenomenologically there is overlap between tics and stereotypies in that in both the motor act is repeated in a similar form time after time. Stereotypies are often ritualistic. Stereotypies are the type of involuntary movement most commonly seen in mentally disturbed patients and they are particularly common in the borderland between neurology and psychiatry. Stereotypies are sometimes accompanied by somatic discomfort or an unpleasant psychological feeling, such as tension or compulsion, and the movement may temporarily relieve this. They can normally be suppressed by an act of will.

These activities may be simple, such as rocking the body, tapping with the hand, or touching the face. Other stereotypic movements are complex and these can involve quite complicated rituals, such as crouching and standing up, sitting and getting out of a chair, wringing the hands together, and crossing or uncrossing the legs. Stereotypies thus overlap with and may be difficult to distinguish from tics and obsessive compulsive behaviour. Other movement disorders including orofacial dyskinetic movements are sometimes regarded as stereotypies. Stereotypies can also closely resemble mannerisms which are little fragments of behaviour peculiar to an individual. These latter movements help give a person his or her manner. While most are part of normal behaviour, some border on the pathological and overlap with stereotyped movements.

The pathophysiological mechanisms underlying stereotypy are uncertain. Similar activities have been observed in animals and it has been suggested they are more common with caging or restraint. This has been considered to perhaps result from reduced stimulation, and the stereotypy has been seen as a self-stimulating device, possibly associated with reduction in stress (Dantzer 1986). It has been noted that such movements are accompanied by a reduction in the range of behaviour that would normally be seen in unrestricted animals.

Stimulation of dopamine receptors by agonists or by drugs which release dopamine stores produces a range of repetitive activities in rodents, which have been regarded as stereotypies. These include licking, washing, sniffing, rearing, and head shaking (Costall et al. 1977, Koller and Herbster 1988). Dopamine receptor blocking drugs will abolish these movements (Tschanz and Rebeck 1988). It has also been suggested that activation of D2 dopamine receptors and not D1 receptors causes stereotypy, although D1 receptor stimulation seems to potentiate the D2-mediated effect (Chipkin et al. 1987, Koller and Herbster 1988). Both striatal (Kuczenski and Segal 1989, Jicka and Salamone 1991, Maraganore et al. 1991) and the nucleus accumbens–amygdala neural curcuit have been felt to be involved (Costall et al. 1977, Hiroi and White 1989). Other neurotransmitters such as serotonin (Kuczenski and Segal 1989), cholecystokinin, and neurotensin (Blumstein et al. 1987) might also be involved.

Stereotypies can involve any area of the body. As mentioned above, they overlap with tics and these can be seen in many otherwise normal individuals, particularly in children. Thus, what has been regarded as simple childhood tic and discussed in Chapter 26 could equally well be regarded as physiological stereotypy. Most such movements spontaneously subside in later childhood or early adult life. In addition, stereotypies can be associated with a variety of pathological disorders and these are listed in Table 52.9.

Table 52.9 Causes of stereotypy

Physiological (primary)

Same as simple childhood tic. See Chapter 26

Symptomatic (secondary)

  • Mental retardation

  • Autism

  • Rett's syndrome

  • Schizophrenia

  • Catatonia

  • Obsessive compulsive disorders

  • Gilles de la Tourette's syndrome

  • Tardive and drug induced

  • Akathisia

  • Neuroacanthocytosis

  • Basal ganglia lesion

  • Post-infectious, e.g. associated antibasal ganglia antibodies (ABGA)

See Chapter 52

See Chapter 52

See Chapter 52

See Chapter 52

See Chapter 52

See Chapters 27 and 52

See Chapters 27 and 52

See Chapters 13, 23 and 52

See Chapters 46 and 52

See Chapter 21

Edwards et al. 2004

Mental retardation and autism

A wide range of disorders causing mental retardation are associated with stereotypic movements. Dura et al. (1987) found 34% of mentally retarded institutionalized adult patients had stereotypy, including rhythmic movement (26%), bizarre posturing (13%), and manipulation of objects (7%).

As many as six per every 1000 children may have a form of autistic spectrum disorder. Autism commences in infancy or early childhood and is characterized by impoverished interaction with others and reduced verbal and non-verbal expression. There is marked loss of interest and reduction in general activities. Repetitive noises, facial movements, waving the hand or objects in front of the face, body rocking, handling or touching objects, toe walking, and adoption of strange postures are some of the stereotypies seen. Others may include inflicting self injury by biting, head banging, and scratching.

Infantile autism has some common features and overlaps with Asperger's syndrome (Gillberg and Gillberg 1989, Szatmari et al. 1989). Asperger's syndrome is usually later in onset and does not become fully evident until 2–3 years of age. Speech is usually better developed than in infantile autism. Other disorders causing autism include the fragile X syndrome and the eponymously named Kanner's and Heller's diseases (Wing and Attwood 1987, Burd et al. 1989).

Self-injurious stereotypic movements are not infrequent in autistic patients and have been said to be improved after opiate blockers, such as naloxone and naltrexone. Along with a possible increase in plasma and CSF beta-endorphin levels, it has been suggested to be evidence of abnormality of the endogenous opiate system (Sandman 1988).

Rett's syndrome

In 1966 Rett described a disorder in 22 girls who developed mental retardation, autism, and a movement disturbance, which included stereotypy. He also noticed increased blood ammonium levels. Hagberg et al. in 1983 reported 35 more girls who had similar findings, apart from the hyperammonaemia, and labelled it ‘Rett's syndrome’. This is an X-linked recessive disorder which occurs almost exclusively in females and it has been proposed that this is caused by an X-linked dominant mutation with lethality in hemizygous males. Exclusion mapping studies using Rett's syndrome families mapped the locus to Xq28. Using a systematic gene screening approach, Amir et al. (1999) showed that Rett's syndrome is caused by mutations in the X-linked gene called MECP2, encoding methyl-CpG-binding protein 2. This has been confirmed by other groups (Bienvenu et al. 1999, Wan et al. 1999, Huppke et al. 2000), and many different mutations (mostly truncating or missense) seem to cause the disorder. With the discovery of the gene a much broader phenotypic variability seems to be emerging including the fact that rarely males with MECP2 mutations may survive (Wan et al. 1999, Clayton-Smith et al. 2000) and female heterozygotes with favourably skewed X-inactivation patterns may have little or no clinical signs (Wan et al. 1999).

Normal psychomotor development proceeds until 6–18 months of age when there is failure to progress, followed by gradual loss of motor skills, speech, and social responsiveness. As learned manual abilities disappear they are replaced by stereotypic movements. These also involve other body parts. The disorder is gradually progressive and associated with mental retardation and withdrawal.

In an analysis of the motor and behavioural findings in 32 patients aged 21 months to 30 years, FitzGerald et al. (1990[a], [b]) found that they all had stereotypic movements and gait abnormalities. The most frequent stereotypic movements were clapping, wringing, and clenching, followed by washing, patting, and rubbing (Figs 52.6 and 52.7). These are often asymmetrical and in about 20% may be virtually unilateral. Even in the absence of involuntary movements, upper limbs are seldom engaged in purposeful activity and are generally useless (Elian and Rudolf 1996). Body rocking and shifting weight from one leg to another is also common. FitzGerald et al. (1990[a],[b]) also reported dystonic movements, including bruxism in 97%, ocular deviations, usually upwards, in 63%, and focal or generalized dystonia in 59%. Myoclonus particularly of the head and trunk was present in 34% and choreoathetosis usually affecting the hands was seen in 13%. They noted that these hyperkinetic movement disorders were especially prominent in the younger patients and that with age an akinetic–rigid syndrome became more prominent with dribbling (75%), reduced facial expression (63%), rigidity (44%), and bradykinesia (41%).

Fig. 52.6 Stereotypic hand washing or hand wringing movements in a girl with Rett's syndrome.

Fig. 52.6
Stereotypic hand washing or hand wringing movements in a girl with Rett's syndrome.

Reproduced with permission from FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement disorders. Movement Disorders 1990; 5:195–203. © John Wiley & Sons.

Fig. 52.7 Several different movement disorders in Rett's Syndrome patients: (A, B) bruxism and prognatism in a adult patient; (C) severe scoliosis in a 14-year-old patient; (D) segmental dystonia; (E, F) the same peculiar dystonic feet posture in two different patients aged 2 and 16 years, respectively; (G) dystonia of the left inferior limb that interferes with gait; (H, I) two different patients with feet dystonia; (J) severe fixed feet in an adult patient; (K) dystonia of the hands in a 12-year-old patient (L); hand athetosis in a 14-year-old patient.

Fig. 52.7
Several different movement disorders in Rett's Syndrome patients: (A, B) bruxism and prognatism in a adult patient; (C) severe scoliosis in a 14-year-old patient; (D) segmental dystonia; (E, F) the same peculiar dystonic feet posture in two different patients aged 2 and 16 years, respectively; (G) dystonia of the left inferior limb that interferes with gait; (H, I) two different patients with feet dystonia; (J) severe fixed feet in an adult patient; (K) dystonia of the hands in a 12-year-old patient (L); hand athetosis in a 14-year-old patient.

Reproduced with permission from Temudo T, Ramos E, Dias K, et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Movement Disorders 2008; 23:1384–90. © John Wiley & Sons.

For a genotype–phenotype analysis Temudo et al. (2008) studied 88 patients who fulfilled the current revised clinical criteria for Rett's syndrome (Hagberg et al. 2002). Of these, 60 patients were found positive for MECP2 mutations. All but one patient exhibited hand stereotypies. Other stereotypies were also frequent (95%), particularly bruxism (80%). Generalized dystonia was more common in those with truncating mutations (present in 46.2%) compared to those with missense mutations (17%). The latter group more commonly had focal dystonia (42% compared to 20% among those with truncating mutations). Both tremor and rigidity were present each in half of the patients. Myoclonus was rare and only present in one patient (Temudo et al. 2008).

Gait disturbance is common. A jerky gait ataxia was seen in 31% and 28% were unable to walk (FitzGerald et al. 1990). A broad base, toe-walking, and mixed gait disturbances were present in the remainder. The disturbance in walking is gradually progressive and in a report of 30 patients aged 22–44 years (Witt-Engerstrom and Hagberg 1990) only 20% were still ambulant, although 60% had previously been able to walk. Dystonia was particularly common in those who had lost walking skills, while the group who had never walked had lower motor neuron findings, including peroneal weakness and pes cavus. In addition, spasticity, hyperreflexia, and extensor plantar responses are common (Rett 1977). Scoliosis is seen in about half of the cases and may result from truncal dystonia (FitzGerald et al. 1990[a]). In the study by Temudo et al. a similar number acquired independent gait (63%). In some 40% of those, gait was both ataxic and rigid. Dystonia was present in more than 60% and scoliosis (probably a consequence of truncal dystonia) was seen in 72%.

Growth failure is frequent and it has been attributed to the additional energy requirements caused by the involuntary movements (Motil et al. 1994).

Epileptic seizures are common and a peculiar respiratory abnormality is seen in the majority of patients with bouts of breath holding followed by hyperventilation. Stereotypic movements may increase during the bouts of over-breathing (Kerr et al. 1990, Elian and Rudolf 1996). The involuntary movements and abnormal respiratory pattern disappear during sleep (Marcus et al. 1994). There is, however, disturbance of sleep phases on polysomnography (Segawa and Nomura 1992). In the study by Temudo et al. (2008) epilepsy was present in 57% of the patients and all were under treatment with one or more of the subsequent antiepileptics: valproate, carbamazepine, and lamotrigine.

MRI scans have shown generalized brain and bilateral caudate atrophy (Casanova et al. 1991, Reiss et al. 1993). Neuropathological findings include microcephally, diffuse cortical atrophy, mild gliosis, increased neuronal lipofuscin, underpigmentation of the zona compacta of the substantia nigra with reduced immunoreactivity for tyrosine hydroxylase, decreased numbers of basal forebrain cholinergic neurons, and cerebellar atrophy. Abnormal neurites and reactive or degenerative axonal swellings have been noted in the frontal cortex and caudate nucleus, and it has been suggested that abnormality of the dopaminergic nigrostriatal pathways may be responsible for this. There are also minor changes in the hypothalamus and pituitary (Jellinger 1988, Armstrong 1992, Wenk 1997).

Much work has concentrated on the state of the catecholaminergic systems, but even with the histological changes mentioned above, showing decreased numbers of neurons and evidence of cell death in the substantia nigra (Kitt and Wilcox 1995), no clear picture has emerged. In spite of earlier reports of decreased striatal levels of dopamine, these have subsequently been found to be within the normal range (Lekman et al. 1989, Wenk 1996), as have the concentrations of homovanillic acid, dopamine re-uptake sites, and D1 and D2 receptors (Wenk 1995, 1996). However, this may have to do with what sort of MECP2 mutation the patient is carrying (Amir et al. 2000). Comparing, CSF neurochemistry in patients with missense mutations and those carrying truncating mutations, Amir et al. (2000) reported that patients with truncating mutations had a higher incidence of awake respiratory dysfunction and lower levels of CSF homovanillic acid. One persistent finding, however, has been an increase in beta-endorphin levels in the CSF (Myer et al. 1988, Zoghbi et al. 1989, Nagamitsu et al. 1997).

Although the mechanisms underlying the stereotypies in Rett's syndrome remain uncertain, enlarged somatosensory evoked potentials, a hyperexcitable and markedly prolonged C-reflex, and normal motor evoked potentials following cortical stimulation have led to the speculation that the jerks may be a form of cortical reflex myoclonus with prolonged intracortical delay of the long-loop reflex (Guerrini et al. 1998[a]).

Catatonia and schizophrenia

Catatonia is discussed in more detail below. It should be noted here, however, that in the original description of catatonia by Kahlbaum in 1873, half of the patients had involuntary movements, including jaw clenching, grimacing, and lip protrusion, which were similar to orofacial dyskinesia and could be regarded as stereotypies. Catatonia can be associated with a variety of stereotypic movements, particularly when it has a psychiatric cause or is due to neuroleptic medication. Characteristic stereotypies include saying the same phrases (verbigeration) or repeating someone else's speech (echolalia), bucco-lingual movements, touching, maintenance of abnormal posture, repetitively moving, and ritualistic behaviour. There are also many descriptions of such stereotypies in non-catatonic schizophrenic patients prior to the introduction of neuroleptic medication into the medical armamentarium.

Obsessive-compulsive disorders and Gilles de la Tourette's syndrome

As mentioned above, obsessive compulsive disorders and the complex tics of Gilles de la Tourette's syndrome may produce repetitive behaviour similar to, or identical with, stereotypy. The distinction is frequently impossible and may be artificial. Patients may repetitively perform the same activity, such as touching, hitting, putting objects in order, washing, and performing rituals. These have been dealt with in Chapter 27.

Akathisia and tardive stereotypies

The tardive dyskinesias caused by neuroleptics may resemble stereotypies. In a study of patients with drug-induced movement disorders Miller and Jankovic (1990, Jankovic 1994) felt 63% had tardive stereotypy. The problem was four times more common in women and the majority of patients were in their 6th or 7th decades. Bucco-lingual dyskinesia and truncal movements were the commonest. Stacey et al. (1993) reported stereotypy to be present in 78% of patients with tardive dyskinesia. Many of the restless actions seen in drug-induced akathisia might also be regarded as complex stereotypies (Burke et al. 1989, Miller and Jankovic 1990). To a large extent it is a matter of nomenclature, definition, and interpretation. Tardive movement disorders are covered in Chapter 23 and akathisia in Chapter 46.

Anti-N-methyl-D-aspartate (NMDA)-receptor encephalitis

Limbic encephalitis is a group of disorders characterized by subacute onset of seizures, cognitive decline and personality changes. In a subset specific autoantibodies directed against surface-expressed neuronal proteins can be detected. Distinct movement disorders may be assoicated, like faciobrachial dystonic seizures in LGI1-associated limbic encephalitis or complex hyperkinetic movements in the anti-NMDA-receptor variant (Irani et al. 2011).

Of these, anti-N-methyl-D-aspartate (NMDA)- receptor encephalitis is a recently described paraneoplastic syndrome often associated with ovarian teratoma. Among others patients develop a hyperkinetic movement disorder with stereotypic and choreic movements with orofacial grimacing. However, the movement disorder may be complex and difficult to classify and the disorder is thus discussed here in this section.

The disorder most commonly affects young females accouting for 91% in a series of 100 cases reported by Dalmau et al. (2008). In another series, among 44 patients, 31 were females (70%) and ages ranged from 2 to 49 years (median 22 years) (Irani et al. 2010).

The most common presenting features include behavioral abnormalities, confusion, amnesia, psychosis and seizures which are thought to due to cortical temporal lobe dysfunction, as frequently seen in classical limbic encephalitis. (Irani et al. 2010). Rare symptoms at onset may include hyperacusis, deafness, ataxia and dystonia. Preceding infections may occur which may reflect an inflammatory event. (Irani et al. 2010) The most distinctive clinical features, however, occur later and include stereotypies and choreoathetoid movements with prominent orofacial involvement with grimacing. There may be complex movements of the extremities, abdomen or pelvis with abnormal postures, as well as muscle rigidity, or increased tone. (Dalmau et al. 2008) Oculogyric deviation may be present. Overall, movement disorders of any kind were observed in 86% of patients in one large series. (Dalmau et al. 2008). Furthermore, episodic dysautonomia is characteristic with hypoventilation and tachy- or bradycardia and a spontaneous fall in conscious level so patients are often stuporous and mute. (Irani et al. 2010) Overall, the typical clinical evolution of anti-NMDA-receptor encephalitis can be divided into five phases:

  • phase I (prodromal phase) – a ‘viral-like’ illness;

  • phase II – characterized by acute psychosis and behavioral symptoms;

  • phase III – intractable seizures, central hypoventilation and dysautonomia;

  • phase IV – a hyperkinetic phase with prominent orofacial grimacing;

  • phase V – the gradual recovery from the illness.

Notably, most patients progress to a severe clinical syndrome and require admission to intensive care, but mild forms may occur. An average hospital stay of 160 days has been reported with long periods of ventilation and multiple infectious complications.

Investigations reveal lymphocytosis in the CSF analysis in early disease stages, followed by absence of CSF lymphocytosis in later stages. In contrast there is early absence of CSF-specific oligoclonal bands compared to their later presence. Brain imaging is often normal (in 89% at initial MRI) and remains normal (in 77%). (Irani et al. 2010) Some patients may show mild alterations in the hippocampi or within white matter regions on T2/fluid attenuated inversion recovery scans. Electroencephalography demonstrated epileptiform discharges in half of the patients in the Irani series, which were present usually early during the course of the disease. Later during the disorder there was generalized slowing in the slow theta or delta range, present in 80% of patients. Thus, switches in the CSF, MRI and EEG findings have been found, suggesting that the neurological disease occurs in two distinct clinical and neuropathological stages.

Anti-NMDA receptor antibody encephalitis has been associated with tumours, especially teratomas. Other malignancies such as Hodgkin's lymphoma or testicular teratomas have also rarely been associated. In the 100 cases described by Dalmau et al. (2008) 59% had ovarian tumours. However, the data vary and in the study of 44 patients by Irani et al. 2010 only eight female patients were detected to have ovarian teratomas (26%), with no other tumours in females. Among the 13 males there was only one tumour, namely the recurrence of a previously-treated Hodgkin's lymphoma at the age of 49 years. In the remaining 23 females and 12 males there was no detectable tumours, despite intensive whole body/pelvic imaging in all. Thus, besides, as a paraneoplastic syndrome, this disorder may be idiopathic in 30% to 40% of patients.

NMDA-receptor encephalitis is related to antibodies against NR2B or NR2A subunits of NMDA receptors in serum and cerebrospinal fluid. NR2B binds glutamate and are thought to inhibit NMDA receptors in presynaptic GABAergic interneurons, resulting in reduced GABA release and disinhibition of postsynaptic glutamatergic transmission with excessive release of glutamate in the prefrontal/subcortical structures. (see Irani et al. 2010) The pathogenic role of these antibodies is further supported by their disappearance in parallel to the clinical improvement. In view of the relatively high proportion of non-Caucasians patients it has been suggested that there may be human leucocyte antigen or other genetic factors involved in disease susceptibility. (Irani et al. 2010).

The treatment is removal of the underlying neoplasm, combined with immunotherapy, plasma exchange, intravenous immunoglobulin, and corticosteroids. Paraneoplastic patients may remain severely affected until tumour removal. Patients who received early tumour treatment (usually with immunotherapy) had better outcome and fewer neurological relapses and a trend has been noted towards better outcomes when corticosteroids were combined with at least one other immunotherapy rather than given alone. While in patients with teratoma its removal plus immunotherapy have resulted in substantial recovery, in the minority of patients without a tumour, recovery appeared to be less impressive (Dalmau et al. 2007, 2008).

Overall, in the series by Dalmau et al. (2008) 75% of patients recovered or had mild deficits and 25% had severe deficits or died. Relapses occurred in about 15–25% patients with a median time between initial presentation and last relapse of about 18 months (1 month – 6 years) (Dalmau et al. 2008, Irani et al. 2010). As stated above outcomes have been better when corticosteroids had been combined with at least one other immunotherapy and analysis revealed that among the relapsers a proportion had received no immunotherapy or were administered only 3–5 days of intravenous glucocorticosteroids. Relapses immediately after glucocorticosteroid withdrawal have also been observed.

Thus, anti-N-methyl-D-aspartate (NMDA)- receptor encephalitis should be considered predominantly in young women who develop a subacute-onset encephalopathy and commonly a prominent movement disorder. Frequently an underlying ovarian teratoma is associated.

Catatonia

In 1873 Ludwig Kahlbaum described 25 psychotic patients with depression or mania who had a motor disturbance which he entitled ‘catatonia’. They showed a variety of features, including generalized immobility or akinesia, withdrawal, staring, refusal to eat, mutism, verbigeration, echolalia, negativism, rigidity, and waxy flexibility, so that they would tend to maintain the position following displacement of a limb. They also exhibited a variety of repetitive movements, particularly of the face and mouth, which have been mentioned above under ‘Stereotypy’. In some patients the immobility was broken by periods of hyperactivity. Since that time the term ‘catatonia’ has been used to describe a number of other conditions and states, including the similar features that may be caused by a variety of general medical and intracranial disease states. Its use has thus become somewhat loose and it has often been applied to withdrawn patients with impaired responsiveness who do not demonstrate features such as negativism or waxy flexibility. Some authors have even regarded stupor occurring in isolation as evidence of catatonia (Benegal et al. 1992). We think this interpretation is too liberal. Increased motor activity has often been absent from cases with general medical disorders that have been labelled as ‘catatonic’ in the literature. This can, however, occur. Patients with psychogenically determined catatonia may be more likely to exhibit excitement, hyperactivity, and restlessness, particularly as the catatonic phase commences.

Thus, while the concept of catatonia has broadened since Kahlbaum's description, diagnosis should be based on the basic features he outlined. There have been a number of attempts to establish diagnostic criteria (Rosebush et al. 1990, Lund et al. 1991, Bush et al. 1996[b], Northoff et al. 1999). Bush et al. (1990) proposed that the diagnosis of retarded catatonia should be based on the coexistence of three cardinal features (immobility, mutism, and withdrawal/refusal to eat or drink) or two cardinal signs plus at least two secondary features (staring, rigidity, posturing, grimacing, negativism, waxy flexibility, echolalia/echopraxia, stereotypy). Northoff et al. (1999) used a rating scale with three different categories, i.e. motor, behavioural, and affective, containing 40 items, each of which was scored on a three-point scale. They claimed that psychogenic catatonia can be diagnosed by having a score of > 7 and with at least one item being positive in each of the three categories. While such instruments are useful for reporting studies of catatonic patients, they are of limited use in day to day practice.

We regard catatonia as a non-specific syndrome, which can result from organic or psychogenic conditions or follow withdrawal of neuroleptics. Organic catatonia in turn can result from specific brain disease or be secondary to a variety of systemic disorders, such as metabolic disturbance, toxic substances, or an acute febrile illness. Focal intracranial lesions causing such a state are particularly likely to involve structures in the cortico-striato-thalamo-cortical circuit and hence affect the frontal lobe (Gelenberg 1976, Wolanczyk et al. 1997), or basal ganglia (Mettler 1955, Kleist 1960, Neuman et al. 1996). Other specific intracranial disorders that can produce a catatonic state include acute viral encephalitis (Primavera et al. 1994) and encephalopathies due to HIV, progressive multifocal leukoencephalopathy, and the like (Carroll 1994).

Catatonia can be caused by a variety of acute or chronic metabolic disturbances. For example, it can occur due to decreased levels of thiamine and nicotinic acid (Teare et al. 1993) or be associated with such conditions as Wilson's disease (Akil et al. 1991, Davis and Bordet 1993) and late-onset Tay-Sach's disease (Rosebush et al. 1995). It has also been reported in renal failure (Carroll et al. 1994). Pharmacological agents with effects on brain neurotransmitter systems can induce catatonia. Thus, dopamine receptor blockers, including those used as antiemetics or vestibulo-sedatives (Rodgers 1992), and drugs resulting in dopamine receptor stimulation, such as amphetamine (Ebadi et al. 1990, Chern and Tsai 1993), can have this effect, as can those acting on glutamatergic (phencyclidine), serotonergic (mescaline), and GABAergic (ethanol) systems (Klimke and Klieser 1994[a]). As mentioned below, catatonia can also follow rapid tapering or abrupt withdrawal of dopamine receptor blocking neuroleptic medication and has occasionally been reported on abrupt cessation of benzodiazepines. In fact, it has been proposed that many reported cases of catatonia attributed to general medical conditions might actually have resulted from benzodiazepine withdrawal (Rosebush and Mazurek 1996). It is also a rare idiosynchratic reacion to a number of other medications, including valproate (Lauterbach 1998), fluoroquinolone antibiotics, such as ciprofloxacin (Akhtar and Ahmad 1993), maprotiline, and adrenocorticotrophic hormone (Klimke and Klieser 1994[a]). An overwhelming systemic infection, usually in association with high fever, can produce a catatonic-like state and non-convulsive status epilepticus may result in a similar appearance (Louis and Pflaster 1995).

Although psychogenically determined catatonia has been traditionally classified as a subtype of schizophrenia, it is more commonly seen in affective disorders. The exact proportion of psychogenic catatonia which is due to schizophrenia depends on the diagnostic criteria used. Diagnostic systems, such as the DSM-III-R, tended to have enlarged the spectrum of affective disorders at the expense of schizophrenia. Thus, patients diagnosed as having schizophrenia on the DSM-I and -II systems would now be regarded as having an affective disorder (Ries 1985). While about 10% of psychiatric inpatients have catatonia (Rosebush et al. 1990, Blumer 1997), in more than two thirds of psychogenic catatonia the diagnosis is that of an affective disorder, especially mania or a bipolar illness, and only between 5 and 20% have schizophrenia (Morrison 1973, Abrams and Taylor 1976, Fein and McGrath 1990, Peralta et al. 1997). Catatonia, however, may be especially likely to occur in elderly patients who develop severe depression (Starkstein et al. 1996). In those fulfilling the criteria of DSM-III-R catatonic schizophrenia, two patterns of catatonia have been distinguished, ‘systematic’ and ‘periodic’. The latter is a largely familial condition which is probably genetically based and shows anticipation from one generation to the next (Stober et al. 1995, Beckmann et al. 1996). Other psychiatric disorders displaying features of catatonia include dissociative states, hysteria, and post-traumatic stress disorder (Gelenberg 1976, Shiloh et al. 1995). When catatonia is present in patients with chronic psychiatric disorders it may be associated with involuntary movements, particularly involving the orofacial musculature, and these may be regarded as stereotypies or tardive dyskinesia, depending on whether neuroleptic medication has been administered (Kahlbaum 1873, Bush et al. 1997). If antipsychotic medication has been exhibited there may be coexisting parkinsonism (Bush et al. 1997). The question of antipsychotic related catatonia, however, is discussed below.

A febrile life-threatening catatonic state was first described by Calmeil in 1832 and in 1934 Stauder termed it ‘lethal catatonia’. It is also referred to as ‘malignant catatonia’ and defined as a life-threatening febrile neuropsychiatric disorder characterized by psychosis with autonomic instability, hyperactivity, mutism, and stuperous exhaustion (Baker et al. 2008). Typically there is a prodromal period lasting about 2 weeks in which there is difficulty with sleeping, variability of mood, and possibly anorexia. Marked motor excitability and the appearance of catatonia follow this. Delusions, hallucinations, and confusion may be present. Fever, tachycardia, hypertension, sweating, and dehydration are frequent during this hyperactive stage, which can go on for hours or weeks but usually lasts approximately a week. Eventually the patient becomes exhausted, stuperose, and lapses into a coma. Marked hyperthermia, cardiovascular collapse, and death may supervene (Fricchione 1985, Mann et al. 1986, Bridler and Hell 1997). Although historically nearly always fatal, in younger years mortality declined, secondary to earlier diagnoses and appropriate treatment implementation, such as administration of standing benzodiazepines and electroconvulsive therapy (ECT) (Baker et al. 2008) (also see later).

Dopamine D2 receptor blocking neuroleptic drugs can produce catatonia with withdrawal, mutism, akinesia, posturing, and waxy flexibility. In some patients there may be additional parkinsonian features and/or tardive dyskinesia (May 1959, Behrman 1972, Rifkin et al. 1975, Gelenberg and Mandel 1977). It can be difficult to differentiate this from aggravation of the underlying psychiatric state. In addition, such drugs may trigger the neuroleptic malignant syndrome, which was first reported by Delay et al. in 1960 (see Chapter 13). A similar disorder can result from sudden withdrawal of l-dopa or other antiparkinsonian medication (Toru et al. 1981, Friedman et al. 1985) and has occasionally been noted following cessation of atypical neuroleptics (Lee and Robertson 1997). It has also been suggested that the toxic serotonin syndrome, in addition to the neuroleptic malignant syndrome, is a variety of catatonic disorder (Fink 1996). Withdrawal, mutism, akinesia, rigidity, fever, tachycardia, and fluctuating blood pressure are present. Many authors have regarded neuroleptic malignant syndrome and malignant catatonia as being the same or closely related disorders (Hynes and Vickar 1996, Topka and Buchkrener 1996). While the prodromal phase of motor excitement is usually absent in neuroleptic malignant syndrome, it has occasionally been reported (Lee and Robertson 1997).

As mentioned above, non-convulsive epileptic status may present with a clinical picture resembling catatonia. In addition, however, patients with acute catatonia may develop epileptic seizures secondary to intracranial pathology (Primavera et al. 1994). Another complication of catatonia is pulmonary embolus and it has been suggested that this may partly explain excess early mortality in this disorder (McCall et al. 1995). Dehydration, infection, and malnutrition also add to the morbidity. Because of the risk of serious complications and death, it is important a diagnosis of the underlying cause of the catatonia is made at an early stage and this requires a full range of ancillary investigations including plasma biochemistry, screening for toxins and infections, as well as EEG, brain scan, and CSF examination in selected cases.

Treatment may be non-specific and supportive, designed to correct and maintain fluid balance, electrolyte status, and temperature, or it may be specifically aimed at abolition of the catatonia. The latter involves measures to decrease associated akinesia and rigidity, as well as treating the underlying cause of the syndrome. Institution of early therapy is important because of the potentially life-threatening nature of the problem. A flow diagram outlining possible courses of management is shown in Fig. 52.8. Benzodiazepines seem to be beneficial in most cases, although clearly should be avoided in the rare instances in which the cause is benzodiazepine overdose (Ebadi et al. 1990). Care must be taken to avoid respiratory or cardiovascular depression (Sassin and Grohmann 1988, Klimke and Kliesler 1994[b]). The most commonly used agent has been lorazepam (with the initial dose being in the order of 1–2 mg) (Menza and Harris 1989, Hawkins et al. 1995, Bush et al. 1996[a], Fink 1996). In a prospective series of over 100 episodes, approximately 85% of patients with retarded catatonia showed complete resolution of catatonic features within 3 hours of administration of 1–3 mg sublingual or intramuscular lorazepam. Patients with schizophrenia are less likely to improve and response rates may be in the order of 40–50% (Rosebush and Mazurek 1999). Other benzodiazepines may be effective, including diazepam (10–20 mg) (McEvoy and Lohr 1984), clonazepam (1–2 mg) (Martenyi et al. 1989), and midazolam (5 mg) (Delisle 1991). While benzodiazepines are the drugs of choice in treatment of acute catatonia, they are not satisfactory for its long-term control, so that it is important to start other therapy aimed at the underlying cause.

Fig. 52.8 Flow diagram of the differential therapy of catatonic subtypes. Treatments in parentheses are second-line therapies.

Fig. 52.8
Flow diagram of the differential therapy of catatonic subtypes. Treatments in parentheses are second-line therapies.

Abbreviations: ECT = electric convulsive therapy; NMS = neuroleptic malignant syndrome.

(Redrawn from Klime and Klieser 1994[a])

In patients with psychogenic catatonia, ECT has often been recommended if benzodiazepines fail. It should be considered if there is no response to 1–3 doses of benzodiazepine (Rosebush and Mazurek 1999). In some series up to 80% of drug-resistant, non-febrile (Klimke and Klieser 1994[a]), and young patients (Rey and Walter 1997) have been said to be improved by ECT. It may be particularly indicated in malignant catatonia and some have suggested it is the therapy of first choice (Mann 1986, Heils and Lesch 1997). Some authors have claimed that ECT may be better if combined with a benzodiazepine (Petrides et al. 1997).

Other aspects of treatment of psychogenic catatonia will depend on the underlying psychiatric diagnosis and in an affective disorder may include antidepressants, lithium carbonate, and carbamazepine, while in schizophrenia antipsychotics may be appropriate (Klimke and Kiesler 1994[a]). In antipsychotic-induced catatonia, reduction or discontinuation of neuroleptic or change to an atypical neuroleptic, such as clozapine, will probably be appropriate. In occasional non-febrile patients anticholinergics may be considered, but scientific evidence of efficacy is lacking (Klimke and Kiesler 1994[a]).

In neuroleptic malignant syndrome, withdrawal of antipsychotics and administration of benzodiazepines is appropriate. In addition, the administration of dopamine agonists such as bromocriptine has been advocated (Levenson 1985, Adityanjee and Chawla 1989), although some studies have not found these to be useful (Rosebush and Stewart 1989). Similarly dantrolene (no 4) has been used (Ward et al. 1986), although it was no better than supportive care in one trial (Rosebush and Stewart 1989). The N-methyl-D-aspartate (NMDA) receptor antagonists amantadine and memantine have also been advocated, not only in neuroleptic malignant syndrome (Weller and Kornhuber 1992) but also in non-neuroleptic-related catatonia (Northof et al. 1997).

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