37 Idiopathic (primary) cranial dystonias

Pictorial representation of cranial dystonias may have preceded their description in the medical literature. Close inspection of some 16th century Flemish paintings reveals examples of bizarre facial contortions. The most convincing is that of Pieter Brueghel, The Elder, who has depicted the screwed up eyes and wide open mouth which are so typical of this disorder (Fig. 37.1). The first written description, however, was not until 1910 when Meige, a Parisian neurologist, published a paper entitled ‘Les Convulsion de la Face, une Forme Clinique de Convulsion Faciale Bilateral et Mediane’. He clearly and concisely outlined the important clinical features and distinguished them from other involuntary movement disorders affecting the face, such as tic, hemispasm, and post-paralytic spasm. Although described as ‘a facial convulsion’, he did not imply the disorder was epileptic.

He emphasized that the spasms were bilateral, tended to affect the upper face more than the lower, but could also involve the jaw and floor of the mouth, including the tongue. They were precipitated by a variety of stimuli, could be temporarily restrained by voluntary effort or certain manoeuvres, and disappeared during sleep. He noted improvement following surgical division of the supraorbital nerves. In spite of this excellent description, the disorder was largely ignored and reappeared in the literature over half a century later (Liversedge 1969, Altrocchi 1972, Marsden 1976[a]). Since then there have been a large number of publications on the disorder.

Cranial or cephalic dystonia has a number of other synonyms, including ‘blepharospasm’, ‘blepharospam-oromandibular dystonia’, ‘orofacial dystonia’, orolingual dystonia’, Brueghel's syndrome’, and ‘Meige's syndrome’. The disorder is characterized by repetitive, irregular, involuntary, symmetrical, dystonic contractions of the muscles of the head. It involves the upper or lower face, jaw, floor of the mouth, pharynx, or larynx. The extraocular muscles are spared. There are several features that distinguish the disorder from orofacial chorea (Table 37.1), which is described in Chapter 23 under ‘Spontaneous Orofacial Chorea and Tardive Dyskinesia’. The essential difference in these two conditions is that the movements of cranial dystonia are prolonged (usually greater than 1 second), whereas in orofacial chorea they are brief. This difference in duration underlies the distress and disability suffered by patients with this dystonia, in contrast to those with chorea. In addition, the upper face is frequently involved in cranial dystonia, whereas this is uncommon in orofacial chorea. While the latter is frequently drug induced, this is unusual in the former.

Cranial dystonia may occur as part of generalized idiopathic (primary) dystonia, such as dystonia musculorum deformans, or be due to symptomatic (secondary dystonia). These are not discussed further here but are dealt with under these other diseases. The term ‘idiopathic cranial dystonia’ is reserved for an idiopathic dystonia which commences in the musculature of the head and is largely restricted there, although it may spread to the neck or upper limbs. There may be other neurological abnormalities, such as postural tremor, but these are usually minor.

Several varieties of cranial dystonia may be distinguished, but this should not be taken to imply that they are different disorders. Current evidence suggests that they are different patterns of involvement due to the same underlying disease process. Thus, involvement may be 1) restricted to the upper face (blepharospasm – Fig. 37.2), 2) restricted to the lower face (oromandibular dystonia – Fig. 37.3), 3) restricted to the larynx or pharynx (laryngo-pharyngeal dystonia – see later under ‘Spasmodic dysphonia and stridor’), or 4) involve multiple sites (Fig. 37.4). The terms ‘Meige's’ and ‘Bruehgel's’ syndrome have been used to described various patterns of cephalic involvement but are restricted here to cases with involvement at multiple sites. Clinical features of the various patterns of cranial dystonia show differences and are thus dealt with separately. Other aspects of these disorders are discussed together.

The relationship of cranial dystonias to generalized primary dystonia or dystonia musculorum deformans has been debated. It has been suggested that the former and other adult-onset focal dystonias may be varieties of idiopathic torsion dystonia (Marsden 1976[b]), but others (Tolosa 1981) have taken the view that they are unrelated conditions (see later under ‘Pathophysiological mechanisms’). Recent advances regarding the genes involved have begun to provide some answers to these questions (see later under ‘Clinical features’ and Table 35.8 of DYT loci).

There are very few autopsy studies of patients with cranial dystonia. Those that exist are contradictory. Garcia-Albea et al. (1981) reported no anatomical abnormality in a carefully studied case. Holton et al. (2008) studied patients with adult-onset focal dystonia with excluded DYT1 gene mutations and found no consistent changes (see Table 37.2).

In a single patient Altrocchi and Forno (1983) showed patchy neostriatal changes which had a mosaic appearance. It now seems likely that this Philippino male had X-linked dystonia parkinsonism (see Chapter 36). Decreased neuronal population, however, was noted in the substantia nigra, dorsal raphe nucleus, and midbrain tegmentum in another case (Zweig et al. 1986). Nigral cell loss was also found in the zona compacta of a further patient and was associated, with similar changes in the locus coeruleus, midbrain tectum, and dentate nucleus. Lewy bodies were also present in the pigmented brainstem nuclei (Kulisevsky et al. 1988). Lewy bodies were found in the substantia nigra, locus coeruleus, nucleus basalis of Meynert, and nucleus ambiguus in another patient, along with neuronal loss in the substantia nigra and to a lesser extent in the locus coeruleus (Mark et al. 1994).

While these studies suggest that pathology in the forebrain and brainstem may be associated with blepharospasm in some patients, their significance to most cases of Meige's syndrome is uncertain. Most of these subjects have been elderly and the studies lack adequate control data. Gibb et al. (1988) reported three cases who showed no significant abnormality when compared with age-matched controls, although a fourth patient had an 0.5 mm angioma in the dorsal pons at the site of the central tegmental tract. The latter is probably an example of secondary cranial dystonia, as are others with a variety of pathological lesions in the basal ganglia (Kean and Young 1985, Pauranik et al. 1987, Herraiz et al. 1988), thalamus and brainstem (Jankovic and Patel 1983, Powers 1985, Day et al. 1986), or hydrocephalus (Jankovic 1984, Sandyk and Gillman 1984). (See Chapter 41 under ‘Acquired Secondary (Symptomatic) Dystonias’.)

The pathophysiological mechanisms underlying cranial dystonias are uncertain. Although patients are frequently subjected to psychiatric therapy, there is no evidence that the disorder has a psychological basis (Marsden 1976[a]). Depression has been recorded before and after the onset of the dystonia (Marsden 1976[a], Tolosa 1981), but certainly not all patients show features of psychiatric illness (Gundel et al. 2007) and psychiatric therapy has been unsuccessful in treating the movements.

The disorder is thus thought to be organic. Apart from the pathological findings mentioned above, analogy with symptomatic dystonias suggests the abnormality may lie in the basal ganglia or its output. This is, for example, also supported by electrophysiological and imaging studies (Etgen et al. 2006). There is similarity to the blepharospasm of Parkinson's disease, the blepharospasm and oromandibular dystonia of encephalitis lethargica, the tardive dyskinetic and dystonic movements seen after dopamine receptor blocking drugs (Glazer et al. 1983), and the facial dystonia that occasionally occurs with l-dopa therapy (Weiner and Nausieda 1982).

Biochemical abnormalities underlying this disorder are largely unknown as there are almost no studies of brain biochemistry, and definite cerebrospinal fluid (CSF) abnormalities have not been demonstrated. In an autopsy study of a single case in which Meige's syndrome was associated with Lewy body formation in several brainstem nuclei including the substantia nigra, there was a decrease in homovanillic acid levels in the substantia nigra pars compacta, striatum, globus pallidus, nucleus accumbens, and subthalamic nuclei. Serotonin, 5-hydroxyindolacetic acid, and noradrenaline were also decreased in the accumbens nucleus. Dopamine levels were essentially normal although there was a minor increase in the medial globus pallidus (Mark et al. 1994). These changes are similar to those in Parkinson's disease, raising the possibility that the patient could have been developing this disorder. The significance of these observations is thus uncertain.

Inconsistent and contradictory results have made it difficult to explain the mechanism on the basis of pharmacological data. Relative dopaminergic preponderance has been suggested as drugs that stimulate dopamine receptors may worsen movements, while those that block dopamine receptors or deplete dopamine stores improve them. Improvement with anticholinergic drugs and deterioration with agents that increase cholinergic activity have been taken to support this hypothesis (Tolosa and Lai 1979, Casey 1980, Tanner et al. 1982) and it has been suggested this may distinguish cranial dystonia from tardive dyskinesia (Tolosa and Lai 1979, Jankovic 1981). These studies, however, have been based on small numbers of patients who have often been tested without double-blind techniques. Lack of effect with both dopamine receptor stimulating and anticholinergic drugs has been reported (Tolosa and Lai 1979, Nutt et al. 1983) and the former may even improve patients (Tolosa and Lai 1979), while the latter may cause deterioration (Casey 1980). In a group of 56 patients reported by Marsden et al. (1983), no consistent pharmacological response was obtained using a variety of drugs to manipulate dopamine and acetylcholine systems of the brain. Similarly, the effects of drugs that modify GABA receptors have been unpredictable (Snoek et al. 1987).

Although lack of teeth has been associated with oral dyskinesia, these movements usually have the characterisitics of chorea (Koller 1983). A few such patients, however, have been reported to have oromandibular dystonic-like movements (Sutcher et al. 1971) and it has been postulated that loss of proprioceptive input from the peridontal membrane may be an aetiological factor. It seems unlikely, however, that such cases make up more than a small fraction of those with cranial dystonia and such a mechanism could hardly account for involvement of structures beyond the mouth. Loss of teeth is not uncommon in the age group affected and fortuitous coexistence remains a possibility. It has also been suggested that ill-defined sensory symptoms, such as burning, tingling, numbness, feeling of swelling, aching, and general irritation, may commonly precede the development of motor activity by weeks or months, and that patients may consider that the movements are initially an attempt to relieve the discomfort (Ghika et al. 1993). Soonawala et al. (1999) also reported excessive eye itchiness, discomfort, or eyelid trauma in over half of their 99 patients prior to the onset of blepharospasm.

The disordered neurophysiology can be studied by means of electromyography (EMG). The commonest abnormality is tonic spasm, which may start in the upper or lower facial muscles and within seconds extends to involve other areas. Sometimes muscles of the upper face, lower face, and mouth may be involved synchronously. Tonic discharges persist for a second or more. In addition, brief clonic discharges of less than about 300 ms may occur and sometimes precede, or follow, tonic spasms. In between such spasms, the muscles are electrically silent (Juvarra et al. 1981,  Tolosa 1981). Similar prolonged discharge has been reported in pharyngeal muscles in cases with dysphagia (Kakigi et al. 1983).

As mentioned below in the section on ‘Laboratory tests’, neurophysiological studies show relatively minor changes in the oligosynaptic R1 component of the blink reflex but major alterations in the polysynaptic R2 component. The latter depends on pathways in the lateral brainstem reticular formation, and its reduced suppressability following a stimulus suggests that the neurons involved are in a facilitated or disinhibited state. It is known that the sensorimotor cortex can facilitate these neurons via the corticospinal pathways (Berardelli et al. 1983, Ongerboer de Visser 1983), but the absence of the normal Bereitschaftspotential during involuntary spasms suggests they do not originate from the cortex.

The basal ganglia also influence the blink reflex as shown by the decreased habituation in Parkinson's disease (Kimura 1973) and the converse in Huntington's disease (Esteban and Gimenez-Roldan 1975). Studies in the rat also show that the basal ganglia can influence reflex blinking (Evinger et al, 1993). In fact, an animal model of blepharospasm was simulated in the rat by inducing a partial (< 30%) 6-hydroxydopamine lesion of the dopaminergic neurons of the substantia nigra pars compacta (which reduces tonic inhibition of the trigeminal blink reflex) combined with triggering eye irritaion by weakening the contralateral orbicularis oculi muscle (Schicatano et al. 1997). Thus, abnormal input from the basal ganglia causing hyperexcitability of interneurons involved in the blink and other brainstem reflexes may underlie cranial dystonias. It has been postulated that interference to such descending normally inhibitory influences may be the mechanism by which diencephalic brainstem lesions trigger secondary cranial dystonia (Berordelli et al. 1988) (see Chapter 43).

Studies using transcranial magnetic stimulation suggest overexcitability and a reduction in motor inhibitory circuit activity/function, evident at many levels of the nervous system, but most likely with its origins in the basal ganglia. Also there is evidence of abnormal plasticity in dystonia compatible with theories of lack of ‘surround inhibition’ in dystonia or disordered sensory ‘gating’ of movement (Mink et al. 2003). For comparative results see Table 38.4.

Positron emission tomography (PET) also supports the role of the basal ganglia in the pathopysiology of this disorder. In one study of 10 patients with essential blepharospasm, significantly elevated [18F]fluorodeoxyglucose metabolism was reported in the striata and thalami, suggesting overactivity of these structures (Esmaeli-Gutsein et al. 1999, Suzuki et al. 2007). Mazziotta et al. (1998) found glucose hypometabolism of the thalami and cerebellum during sleep in patients with craniocervical dystonia compared with normal controls, in whom the sleep–wake subtraction studies did not show any area of focal change. This suggested a relative increase in metabolism when awake and the dystonia was evident.

A study using PET in combination with the radioligand [18F]spiperone to measure the in vivo binding of the dopaminergic function in the putamen suggested a decrease of dopamine D2-like binding in the putamen (Perlmutter et al. 1997).

Under normal circumstances voluntary eye closure occurs as the result of contraction of orbicularis oculi and inhibition of the tonic contraction of the levator palpebrae superioris. The latter can be effective alone because elastic forces of the upper lid tend to pull it down. Eye opening is usually associated with a brief period of post-inhibition potentiation of activity in the levator palpebrae superioris before contraction settles down to its baseline level. The disturbance of movements in blepharospasm can involve all of these functions (Aramideh et al. 1994[a]). At the one extreme there may be isolated spasm of orbicularis oculi, and at the other, pure inhibition of levator action, so-called apraxia of eyelid opening (Goldstein and Cogan 1965). In between, various combinations of disturbance of function can be distinguished, including cocontraction of both muscles (Aramideh et al. 1994[a]). Sometimes spasm of the pretarsal portion of orbicularis oculi may cause the problem in the absence of overt contraction (Elston 1992). This pretarsal type of eyelid opening problem can be demonstrated by simultaneous EMG recordings from the levator palpabrae and the orbicularis oculi (Armideh et al. 1995[a]). In addition, many patients can be shown to have disturbance of eye movements with prolonged latency, reduction in gain of horizontal saccades, and decreased peak velocity of downward saccades (Lueck et al. 1990, Hotson and Boman 1991). A few patients may also have difficulty with fixation of gaze, involuntary brief saccadic jerks, and prolonged forced deviation of the eyes (extraocular muscle dystonia or oculogyric crises) (Aramideh et al. 1994[b]). Such disturbances in extraocular muscle function have been suggested to reflect dysfunction of the basal ganglia, especially the substantia nigra pars reticularis, and brainstem structures such as the paramedian pontine reticular formation (Aramideh et al. 1994[b]).

The prevalence of cranial dystonias is uncertain, although a survey from the Mayo Clinic suggests it is about 140 per million. Blepharospasm was found to be 17.2, oromandibular dystonia 68.9, and spasmodic dysphonia 51.7 per million persons (Nutt et al. 1988). Cranial dystonia including blepharospasm, spasmodic dysphonia, and cranial-segmental dystonia was the second most common type of primary dystonia after cervical dystonia, accounting for 34.4% of all primary dystonias in an epidemiological study from North England (Duffey et al. 1998). A female preponderance of all forms of focal dystonia affecting the cranial and cervical regions has been noted (Soland et al. 1996). In this study the female to male ratio for cranial dystonia was nearly 2:1 (Soland et al. 1996) while others have reported it to be in the order of 1.5:1 (Marsden 1976[a], Tolosa 1981, Grandas et al. 1988). A female predominance of 3:1 has been reported in one large study on blepharospasm (Jankovic and Orman 1984). The average age of onset is in the sixth decade (Marsden 1976[a], Tolosa 1981, Tanner 1982). The range is generally between 35 and 75 years, but occasional patients commence outside of this and onset as early as 10 years of age has been reported (Tolosa 1981).

Although the disorder may progress rapidly, deterioration is usually gradual and, on average, maximum severity is reached approximately 10 years after onset. Severe visual disability from blepharospasm, however, is reached in a mean of about 2 years from onset (Grandas et al. 1988). About a third of patients have a history of depression prior to the commencement of the dystonia and a few more subsequently develop this. Most, however, have no psychiatric disturbance (Marsden 1976[a], Tolosa 1981). When cases with possible tardive dystonia due to previous neuroleptic exposure were excluded, Grandas et al. (1988) found only 13.2% of patients with blepharospasm had a prior history of psychiatric disorder. A small number of cases have been reported to occur in association with myasthenia gravis (Kurland et al. 1987).

The majority of patients have no family history of cranial dystonia (Cramer and Otto 1986), although it has occasionally been reported (Nutt and Hammerstad 1981, Tolosa 1981). It is more common to obtain a family history of other dystonic disorders, but this is only present in some 15% of patients or so (Elia et al. 2006).

Thus, Meige (1910) noted the mother of a patient had torticollis, and blepharospasm has been reported in a family with minor limb and trunk dystonia (Zeman et al. 1960). This latter family probably had generalized primary dystonia or dystonia musculorum deformans. In addition, a family history of essential tremor, Parkinson's disease, tics, Huntington's disease, Sydenham's chorea, and orofacial dyskinesia has been noted in a few cases (Tolosa 1981, Cramer and Otto 1986, Grandas et al. 1988). This has not, however, been shown to be greater than expected by chance. In a series of 264 cases of blepharospasm Grandas et al.(1988) found a family history of blepharospasm in 2.3% and other dystonias in 3.8%. There was increased blinking in family members in an additional 3.4%. There is evidence to suggest such history taking is unreliable and in a study in which first degree relatives of 40 patients with idiopathic focal dystonias were examined 25% of index cases had relatives with dystonia (Waddy et al. 1991). Although this study included 16 cases of blepharospasm or oromandibular dystonia, patients in whom these were combined were excluded as they were considered to have segmental dystonia. The authors felt the results suggested the presence of an autosomal gene or genes with reduced penetrance and considered this could be the same gene responsible for the majority of cases of inherited dystonia in Britain, irrespective of distribution or severity.

However, more recently there is evidence mounting that different genes may be responsible for the early-onset primary torsion dystonia and the late-onset dystonias affecting the craniocervical region. First, the DYT1 locus which is responsible for most cases of early-onset limb generalized dystonia (Kramer et al. 1994, Valente et al. 1998) (see Chapter 35) has been excluded in some large (non-Jewish) families with autosomal dominant late-onset or cervical-cranial predominant dystonia (Holmgren et al. 1995, Bressman et al. 1996). Second, further loci including DYT6, DYT7 and DYT13 have been identified in these ‘non-DYT1’ families (also see Chapter 35; including Table 35.8]) The DYT6 dystonia due to mutations in the THAP1 gene located on chromosome 8 was originnaly mapped in two North American families with a mixed phenotype of both childhood-onset and adult-onset dystonia beginning in both limb and cervical-cranial areas (Almasy et al. 1997). The dystonia mainly affected the cervical and cranial regions and dysphonia, dysarthria, blepharospasm, and torticollis produced the greatest disabilty in these cases (Almasy et al. 1997) (see also Chapter 35). The DYT7 locus on chromosome 18 was mapped in a German family mainly presenting with adult-onset torticollis (Leube et al. 1996) (see Chapter 35 and 38). DYT13 refers to a single Italian family with craniocervical dystonia (see Chapter 35). The role of these latter loci in the general population of late-onset primary dystonia affecting the craniocervical region still needs to be assessed but must await identification of the genes.

Some of the features that distinguish cranial dystonia from orofacial chorea are shown in Table 37.3 and the usual distribution of dystonia is outlined in Table 37.4.

In Marsden's (1976[a]) patients 33% had involvement of the upper face alone and in 23% it was restricted to the oromandibular area. The remaining patients had involuntary movements in both these areas. In contrast, only 12% of Tolosa's (1981) patients had involvement of the upper face alone, 88% had both upper face and oromandibular movements, and there were no examples of isolated oromandibular dystonia. In Cramer and Otto's (1986) series 18% had upper facial movements only and 2% had dystonia restricted to the mouth and jaw. The reason for these differences is not clear but may be explained by case selection and the average duration of disease, which was 5 years in Marsden's, 6 years in Cramer and Otto's, and 10 years in Tolosa's patients. In Grandas et al.'s (1988) study of blepharospasm, only 22% had isolated involvement of the upper face and in 71% the oromandibular structures were involved, while in the patients of Defazio et al. (1989) with Meige's syndrome the respective figures were 48% and 52%. It can thus be seen that there is considerable variation in the precise patterns of facial involvement in different series.

The involuntary movements typically persist for a few seconds to several minutes. Occasionally they may last 15 or 20 minutes (Marsden 1976[a]). As mentioned above, minor clonic movements may precede or follow spasms. In general, the only physical signs are those caused by the movements themselves. There is no intellectual deterioration, seizures, wasting, weakness, or pyramidal, cerebellar, or sensory signs. In between spasms, facial movements are normal. Blepharospasm, oromandibular dystonia, or Meige's syndrome are with dystonia of the neck or upper limbs in approximately half of the cases (Marsden 1976[a], Tolosa 1981). By contrast, involvement of the upper face or oromandibular area alone is infrequently associated with dystonia beyond the head; this was present in only two out of 22 of Marsden's patients, both of whom had oromandibular dystonia (Fig. 37.5). Only very rarely do adult-onset cases of cranial dystonia become generalized or involve the lower limbs (Schneider et al. 2006) and this should make the clinician suspicious of a rare cause. Similarly, isolated oromandibular dystonia in children is rare, but has rarely been reported (see Chapter 35 under ‘Generalized Primary Dystonia’). In Meige's syndrome extracranial involvement affects the neck, respiratory muscles, trunk, or upper limbs in decreasing order of frequency. There may be torticollis, retrocollis, or antecollis. Forced and held inspiration is the commonest form of respiratory involvement. Lateral flexion, rotation, kyphosis, lordosis, or tortipelvis may affect the trunk. Action dystonias, including writer's cramp, or spontaneous dystonic posturing may affect the upper limbs (Marsden 1976[a], Tolosa 1981, Marsden and Sheehy 1982). Tremor may also occur and usually affects the upper limbs, being similar to benign essential tremor. It has been reported in 12.5% of cases with blepharospasm (Grandas et al. 1988). It may occasionally involve the head or face and rest tremor has been recorded (Marsden 1976[a], Tolosa 1981). Other neurological abnormalities have not been noted in most studies. Although gradual progression occurs over years, the disorder usually becomes static. Complete remissions have only infrequently been recorded, but some patients show improvement, even after years of disability (Tolosa 1981). Grandas et al.(1988) noted 11.4% had a remission of blepharospasm lasting more than 1 month and in 5.5% it was complete. Recurrence, however, occurred in virtually all cases after periods varying from 1 month to 40 years.

When blepharospasm is present there is a somato-topic distribution of other dystonias with rapid fall-off in frequency of affected regions below the neck (see Table 37.4).

Seventy seven percent of Marsden's (1976[a]) and all of Tolosa's (1981) patients had involvement of the upper face. Excessive blinking before onset of typical spasms has been noted in 37% of cases and has been present for a mean of 7.9 years prior to frank blepharospasm (Grandas et al. 1988). The dystonic movements are identical whether they occur alone or as part of Meige's syndrome. Blepharospasm is present in all cases, but there may also be involvement of other muscles with eyebrow elevation or frowning. Although blepharospasm may initially involve only one eye, it soon becomes bilateral. Approximately 20% of the cases of Grandas et al.(1988) commenced unilaterally but virtually all spread to affect the other eye after a mean latency of 2 years. The infrequent and brief blinking spasms gradually become replaced by frequent sustained paroxysms. Light lid closures give way to severe ‘screwing up’ of the eyes. Sometimes sustained eye closure may occur in the absence of obvious orbicularis oculi spasm and can result from activation of the pretarsal part of this muscle (Elston 1992) or inhibition of the levator palpebrae superioris (Aramideh et al. 1994[a]), so-called apraxia of eye opening (Golstein and Cogan 1965). Such cases can be idiopathic but have also been associated with degenerative diseases involving the extrapyramidal system, such as Parkinson's disease (Elston 1992), Steele–Richardson syndrome (Elston 1992), multiple system atrophy (Lepore and Duvoisin 1985), amyotropic lateral sclerosis-parkinsonism-dementia of Guam (Lepore et al. 1988), and neuroacanthocytosis (Bonaventura et al. 1986).

The movements blepharospasm are aggravated by bright lights, television, reading, looking upwards, driving, fatigue, and emotional stress. Conversely they are improved by concentration, looking downwards, movements of the lower face, sleep, and relaxation. Manoeuvres to open the eye include prising the lids apart with fingers, pressing over the eyebrow, neck extention, and opening the mouth as wide as possible, and 17% of cases have been recorded as using such special tricks (Grandas et al. 1988). These are the equivalent of the geste antagoniste, which is seen in spasmodic torticollis. The majority of patients have local ocular disease or ocular symptoms prior to onset of blepharospasm, but only a few subsequently develop new eye problems (see Table 37.5).

Significant disability is common and about two thirds of patients are rendered functionally blind being unable to read, watch television, drive, or even cross the road safely (Grandas et al. 1988). Involuntary extraocular muscle activity, especially oculogyric crises and diplopia, may lead to further visual disability in a few patients (Aramideh et al. 1994[b]).

Involvement of the oromandibular musculature occurred in 67% of patients with cranial dystonia reported by Marsden (1976[a]) and 88% of those reported by Tolosa (1981). These muscles were also affected in 71% of patients with blepharospasm studied by Grandas et al.(1988). The movements seem identical whether they occur alone or as part of Meige's syndrome. The most commonly reported abnormality is forced jaw opening and this may be accompanied by jaw protraction and lip retraction (Figs 37.3 and 37.6a). Jaw clenching and pursing of lips are also frequent (Fig. 37.4). Platysma may go into spasm. Muscles of the floor of the mouth may be affected and the tongue may be involuntarily protruded. Initially, movements usually occur when talking, chewing, or less frequently when singing. As the disorder progresses they occur spontaneously and become more frequent, forcible, and sustained. Even at this stage, however, they may be aggravated by the above acts, yawning, blowing with the lips, fatigue, or stress. Touching the lower face or placing something in the lips or mouth may improve the spasms, similar to the response in the upper face (Fig. 37.6). Occasionally patients will have the equivalent of ‘paradoxical kinesia’ (see Chapter 35) and may be able to sing but not speak, or vice versa (Marsden 1976[a]). In most patients these movements produce dysarthria and difficulty in chewing. Between a third to a half may also have difficulty in swallowing (Marsden 1976[a]). The tongue may involuntarily push food out of the mouth. Severe tongue protrusion dystonia is suspicious of a secondary cause (Schneider et al. 2006). For causes of severe tongue protrusion dystonia see Table 37.6. Persistent bruxism may wear down teeth and the lips or tongue can become lacerated. In a few cases, dislocation of the jaw occurs and vigorous movements have snapped inappropriate dental wiring (Marsden 1976[a]). As with involvement with the upper face, oromandibular dystonia may produce severe disability.

In the vast majority of cases involvement is bilateral, but in a few cases dystonic spasms may be restricted to one side. Thus, unilateral activity in pterygoid, masseter, facial, lingual, and other muscles can cause marked lower facial asymmetry with deviation of the jaw, face, or tongue to one side (Thompson et al. 1986, Lagueny et al. 1989). Jaw tremor may be present.

Laryngo-pharyngeal dystonia presenting in the absence of other features of Meige's syndrome presents a difficult diagnostic problem (see later under ‘Spasmodic dysphonia and stridor’). When it occurs with Meige's syndrome, it may be overlooked because of the visually more dramatic oromandibular dystonia. Indeed, under these circumstances, it may be difficult to separate these two elements and it is thus uncertain how many cases of cranial dystonia are accompanied by spasm of the larynx, pharynx, or soft palate. Dysarthria or dysphagia may be expected if these are oral, mandibular, or lingual movements and may be attributed to these when spasms of the larynx and pharynx are really responsible. Laryngeal spasm, however, produces a marked reduction in volume with whispering or forced strangled speech, unlike the slurring that results from involvement of the orofacial musculature. Laryngeal and pharyngeal dystonia have been noted in 17 and 7% respectively of patients with blepharospasm (Grandas et al. 1988). Three out of 17 of Tolosa's patients with cranial dystonia were said to have pharyngeal spasm.

Difficulty in initiating swallowing from the pharynx, once food or fluid has been pushed to the back of the mouth, commonly accompanies the speech difficulty. Pharyngeal EMG shows breakdown in the normal swallowing pattern with prolonged spasms and inability to relax (Kakigi et al. 1983). Barium studies may reveal failure of relaxation at the laryngo-oesophageal junction with aspiration into the trachea (Marsden 1976[b]).

Combined dystonia of the upper face, lower face, and mouth (Meige's or Brueghel's syndrome) is the commonest eventual pattern of involvement (Figs 37.4 and 37.6). The upper and lower face were affected simultaneously in 13 out of 17 patients reported by Marsden (1976[a]) and the upper face was involved first in the remainder. In a large study of blepharospasm, 78% had dystonia elsewhere and in almost all the disorder commenced in the upper face (see Table 37.7). In a few cases, however, Meige's syndrome may evolve from oromandibular dystonia (Nutt and Hammerstad 1981). In the fully developed case the patient presents a grotesque sight with frequent repetitive irregular spasms involving the whole face and mouth. Vision, talking, and feeding may all be severely impaired.

In 1871 Traube reported spasms affecting the larynx which were restricted to speech. Schnitzler (1885) suggested the disorder was due to ‘cramping of the vocal cords’ and termed it ‘spastic dysphonia’. These and the ‘spastic dysphonia’ reported by Critchley (1939) may well have been due to laryngo-pharyngeal dystonia. The latter described a ‘peculiarly forced character in the speech, which appears difficult of accomplishment, almost as though the patients were trying to talk whilst being choked’. Some of his cases had other dystonic and extrapyramidal features. He concluded that the site of the pathology was likely to be in the basal ganglia or cerebellum. There have now been quite a large number of cases described under several other names, including ‘spastic aphonic’, ‘phonic laryngeal spasm’, and ‘spasmodic dysphonia’.

The disorder may occur in isolation or as an initial presentation of a more extensive cranial dystonia (Marsden 1976[b]). Onset is usually in adult life and commonly in middle age. Respiratory infection, laryngeal injury, and excessive use of the voice are said to have preceded some cases. It can commence with a tight or pulling sensation in the throat and the majority of cases give a history of ‘sore throat’ before onset of other symptoms (Rosenfield 1988). Although speech may intially be normal, as the disorder progresses the volume decreases. The patient may end up talking in a whisper and having to force air in and out through a larynx in spasm. This produces a monotonous, strained, slurred speech. Initially the problem may only occur when singing certain notes or making certain sounds. It progressively affects a greater range of speech and may make talking virtually unintelligible.

The adductor muscles of the larynx are stronger than the abductors and the condition is usually one of adductor spasm with the vocal cords opposed. This produces a strained, hoarse, almost strangled voice which may vary in amplitude and be interrupted by frequent pauses (‘spastic dysphonia’) (Aronson et al. 1968, Aminoff et al. 1978). Abductor muscle over-action results in low-volumed, soft speech or sudden loss of voice during on-going articulation (‘whispering’ or ‘breathy dysphonia’). Rosenfield (1988) found that only three of 41 patients with this disorder had abductor overaction. Sometimes this may only affect the usual voice, and singing or shouting may be normal. Occasionally speech in sleep has been reported to be unaffected. The problem tends to be made worse by emotional stress and a psychological cause is often initially suspected. Psychiatric investigation, however, has not shown relevant abnormality (Aronson et al. 1968, Rosenfield 1988).

In some patients the dystonia remains isolated, but in others it gradually spreads to involve the tongue, jaw, and lips (Marsden 1976[b]) and Meige's syndrome may eventually result. Other cases may have associated tremor. In a series of 41 patients who were referred with spasmodic dysphonia but without recognized evidence of other neurological disease, Rosenfield (1988) found 18 had associated tremor and 10 had Meige's syndrome, with three of these patients having both disorders. In addition, six patients were hypothyroid. In seven of the 18 patients with tremor, direct laryngoscopy showed this movement involved the larynx. This was also common in the Meige group, and in eight of the nine to undergo this procedure it was found to be abnormal. Overall, 73% of the whole group were thought to have definite neurological disease. In the remaining 11 no underlying reason for the dysphonia was established. Pool et al. (1991) reported 71% of 32 patients with spasmodic dysphonia had other neurological abnormalities on examination, especially difficulty with rapid alternating movement, weakness, and tremor.

Investigation may show dysfunction in other branches of the vagus nerve (see later). In some cases spasmodic dysphonia appears to be secondary to other degenerative disorders (see ‘Secondary dystonias’, Chapter 43).

Laryngeal stridor, or so-called Gerhardt's syndrome, has been reported to be due to spasm of the adductor muscles of the vocal cords rather than paralysis of the abductors. Some patients show other manifestations of dystonia. The vocal cords are held in the paramedian position and cause noisy dyspnoea (Marion et al. 1992).

Haematological and biochemical investigations have revealed no abnormality. It has been reported that some patients have serological evidence of disordered immunity with high titres of antinuclear antibody and rheumatoid factor (Jankovic 1981), thyroid disease, and Sjogren's syndrome (Jankovic 1981, Jankovic and Ford 1983, Lang 1985, Herraiz et al. 1988). Antinuclear antibody titres of greater than 1 in 80 were present in 15 of 58 patients with Meige's syndrome reported by Jankovic and Ford (1983), and evidence of thyroid abnormality was found in 13 of 25 women with this disorder in studies by Nutt et al. (1984). The significance of these findings is uncertain. Pneumoencephalography has been reported to show frontal cortical atrophy without ventricular dilatation in three out of five patients (Chopra et al. 1981), but it seems unlikely that this finding is relevant as other series have shown no abnormality on CT and MRI brain scanning (Tolosa 1981). More advanced imaging techniques may reveal subtle changes in some patient groups (Colosimo et al. 2005, Bonilha et al. 2007, Fabbrini et al. 2008), but these are not available on a routine basis. Electroencephalograpy (EEG) and routine examination of CSF have been unremarkable (Marsden 1976[a]).

EMG of facial muscles has been mentioned under ‘Pathophysiological mechanisms’. It may show irregular bouts of continuous muscle firing, lasting seconds and corresponding to sustained muscle contractions. In the orbicularis oculi, there may be repetitive short bursts of 100–200 ms caused by blinks which seem to end in the prolonged spasms (Fig. 37.7) (Berardelli et al. 1988).

If two sequential electrical stimuli are delivered to the supraorbital nerve and the EMG of orbicularis oculi is measured, the blink reflex and its state of excitability can be assessed. In normal subjects a single stimulus produces an oligosynaptic response (R1), which is followed by a longer bilateral polysynaptic response (R2). If a second stimulus is given soon after the first, the second R2 is suppressed in normals when the interstimulus interval is less than 250 ms, and its amplitude gradually recovers to 30% of the first R2 if the interstimulus interval is increased to 1 sec (Tolosa et al. 1988). In patients with cranial dystonia, latencies of R1 and R2 are normal, but the amplitudes of R1 and R2 are increased, as is the duration of R2. Some patients also show a contralateral R1 (Fig. 37.8). In addition, recovery of R2 after a second stimulus is increased so that it can be obtained when the intertest interval is as short as 100 ms and is 100% of its amplitude when the interval is 1 sec (Fig. 37.9) (Berardelli et al. 1988). Although successful botulinum toxin treatment (see under ‘Management’) diminishes the amplitude of R1, it has no effect on the enhance recovery of R2 (Valls-Sole et al. 1991). Although this facilitation of R2 is most prominent in blepharospasm, it is also found in other varieties of cranial dystonia, including laryngeal dystonia (Tolosa et al. 1988, Cohen et al. 1989). Interestingly, patients with blepharospasm in combination with levator inhibition, however, have been reported often to have normal blink reflex recovery cycles (Armideh et al. 1995[b]).

Stimulation of supraorbital nerves during light voluntary contraction of orbicularis oculi or masseter muscles results in a brief silent period in the EMG in normal subjects. Such exteroceptive suppression was absent in orbicularis oculi in seven out of 15 and in masseter in five out of 15 patients with blepharospasm studied by Berardelli et al.(1988). The latency of the jaw jerk, however, was normal.

As mentioned previously under ‘Pathophysiological mechanisms’, the changes in blink response and the failure of exteroceptive suppression of facial muscles has suggested that the brainstem interneurons underlying these mechanisms are in a facilitated or disinhibited state, and this could arise from decreased descending inhibitory input. Averaged EEG in patients with blepharospasm shows the normal slow negative wave or Bereitschaftspotential before voluntary eye closure, but not before involuntary spasms (Fig. 37.10), suggesting that the latter arise at a subcortical level (Berardelli et al. 1988).

Patients with spasmodic dysphonia have also been found to have other abnormalities of brainstem reflexes. It has been reported that brainstem auditory evoked responses show an increase in latency if click frequency is increased from 20 to 90 Hz when the stimulus is 60 decibels above threshold (Sharbrough et al. 1978, Finitzo-Hieber et al. 1982), although others have found a decrease in latency (Feldman et al. 1984). Reduced gastric secretion to stimulation and abnormal cardiac response to Valsalva manoeuvre and respiration have been cited as evidence of defective parasympathetic innervation of the stomach and heart (Feldman et al. 1984). Investigations for laryngeal dystonia should include laryngoscopy.

An extensive range of drugs have been used to treat cranial dystonias and the more frequently used ones are listed in Table 37.8. In summary, medical therapy is unsatisfactory in most cases and botulinum toxin injections have become the first choice where feasible (see later). Anticholinergics have been helpful in treating many dystonias. Benzhexol (trihexyphenidyl) has been used most commonly but there is no evidence to suggest that it is more effective than other anticholinergics. Children and generalized dystonias respond better than adults and focal dystonias (Fahn 1983, Marsden et al. 1984). Thus cranial dystonias may be expected to respond less satisfactorily to anticholinergic drugs than other types of dystonia. Nevertheless, encouraging results have been reported, with up to 90% of patients in some studies showing improvement (Tanner 1982). Unfortunately the numbers of patients have been small and double-blind assessment has not always been used. Marsden et al. (1983) found that only three of 25 patients improved on anticholinergics and Nutt et al. (1983) in a double-blind study found no definite benefit. Doses used in these studies, however, were modest. High dose therapy (benzhexol 20–130 mg/day) has been more promising and approximately 20% of patients may be improved (Fahn 1983, Marsden et al. 1984, Grandas et al. 1988).

Although some studies have suggested cholinergic agents can aggravate cranial dystonias (Tolosa and Lai 1979), a few patients seem to have improved on the purported cholinergic agonist deanol (Casey 1980).

Benzodiazepines, which increase the effect of GABA at its receptors, may produce improvement (Marsden 1976[a], Merikangas and Reynolds 1979, Cramer and Otto 1986). Benefit from these agents, however, is usually modest and Grandas found only 8% of patients with blepharospasm received any benefit. Baclofen has been reported to improve a small number of patients (Gollomp et al. 1983) and it has been used in conjunction with sodium valproate (Brennan et al. 1982). A small double-blind crossover study, however, found the latter to be ineffective (Snoek et al. 1987).

Dopamine receptor blocking and dopamine store depleting drugs may also reduce cranial dystonia (Marsden 1976[a], Tolosa and Lai 1979, Gollomp et al. 1983, Defazio et al. 1989). It has been suggested that oromandibular dystonia may be more responsive than blepharospasm (Marsden 1976[a]), but controlled trials are lacking. Jankovic and Beach (1997) reported a very favourable response with tetrabenazine in 62% of 108 patients with primary dystonia of which 44% had cranial dystonia. Chlorpromazine and haloperidol each improved about 14% of cases of blepharospasm in one large uncontrolled study (Grandas et al. 1988). Improvement may be limited by unacceptable drug-induced parkinsonism and tardive dyskinesia. On the whole, these agents are less effective than when used in the treatment of chorea.

l-dopa seemed initially ineffective in the treatment of cranial dystonia (Tolosa and Lai 1979, Marsden et al. 1983), but subsequent reports suggest 20% of patients may get some benefit (Grandas et al. 1988). The dopamine receptor agonist lisuride has been reported to improve a similar or even slightly greater number of patients (Micheli et al. 1982, Marsden et al. 1983, Quinn et al. 1985, Grandas et al. 1988) and has even been given by continuous subcutaneous infusion (Micheli et al. 1988). l-dopa has been found to help some cases of so-called eyelid-opening apraxia (Dewey and Maraganore 1994).

Other agents that have been purported to help a small number of subjects include antidepressants, propranolol, and lithium (Grandas et al. 1988). Cyproheptadine has also been found to be useful in a few patients (Fasanalla and Aghajanian 1990). Tizanidine, a centrally active benzothiadazol which is thought to decrease the activity of excitatory interneurons, has been reported to be ineffective (Lang and Riley 1992).

Overall, the results of drug therapy in cranial dystonia are disappointing. In a review of the literature Gollomp et al. (1983) reported 44% of patients had sustained improvement on anticholinergic, deanol, baclofen, or antidopaminergic therapy and this was similar to 49% of their own patients who benefitted from one or other of a large range of drugs. Marsden et al. (1983) had less success in a larger group of patients with not more than 15% showing improvement to a similar range of drugs. Only 7% of their 136 drug trials carried out in 56 patients produced improvement. Thus, drug treatment of cranial dystonias is empirical, with a small number of patients seeming to respond unpredictably to one or more of a variety of agents. In general the more stringent the evaluation of the results the less impressive they are.

Surgery was used to treat cranial dystonias before their description by Meige in 1910. In 1907 Rochon-Divgneaud and Weill reported the treatment of blepharospasm by avulsion of the supraorbital nerves. Recently this form of treatment has been revived and modified. Using a percutaneous needle, branches of the facial nerve to various portions of obicularis oculi are located by electrical stimulation and then lesioned thermolytically. This results in weakness of the muscle and a reduction in involuntary contractions. Improvement was obtained in 27 out of 28 patients operated on by Battista (1983) and in 19 the result was assessed as being good or excellent. As reinnervation of the muscle occurs the results are temporary, providing relief for between 1 and 5 years and repeat treatment is necessary. Recurrence is lessened by open operation with avulsion of nerves (Talbot et al. 1982). Reoperation, however, is difficult because of scarring. Not only are branches to the upper face injured, but those to levator anguli oris may be lesioned to prevent reinnervation of the upper face and to help lessen lower facial movements. If surgery is complete total paralysis of the upper face results with loss of expression. Preservation of some fibres increases the chance of recurrence. This surgery is not without its complications but these are usually relatively mild. Corneal irritation may result from exposure. Ectropion may require surgical correction. Transient problems with eating, dribbling, and accumulation of parotid secretions may occur. An irritating, spontaneous Bell's phenomenon may develop, but usually this is transient. In spite of these complications and the disadvantage of loss of expression most patients prefer the result to the preoperative disability, for vision is restored.

Partial resection of the orbicularis oculi muscle has been used to treat blepharospasm. It also weakens the face but has the advantage of preventing recurrence (Gillum and Anderson 1981). In some cases limited myectomy can be useful, but in those with severe symptoms who are unresponsive to botulinum toxin treatment (see later) a full myectomy may be a considered option (Patel and Anderson 1993).

Cricopharyngeal myotomy may produce improvement in dysphagia in patients with dystonia of the pharynx (Marsden 1976[a], Tolosa 1981). Unilateral recurrent laryngeal nerve section has been used for spasmodic dysphonia (Dedo 1976, Aminoff et al. 1978). The treated vocal cord is paralysed in partial adduction. This is not always successful and symptom recurrence is frequent due to compensatory overaction of the contralateral vocal cord (Rosenfield et al. 1984). It is best to have a trial of temporary laryngeal paralysis, using local anaesthetic on the recurrent laryngeal nerve and botulinum A toxin in the vocalis muscle, before considering surgery. Unfortunately there is no satisfactory surgical procedure to relieve oromandibular dystonia.

Local intramuscular injections of botulinum A toxin have largely replaced surgical procedures in cranial dystonias and have become the treatment of choice (Fig. 37.11). Botulinum toxin is also available as type B (and other serotypes). Most data are available for type A botulinum toxin, but some studies have compared the different types (Pappert et al. 2008).

Botulinum toxin attaches to the motor nerve terminals, preventing release of acetylcholine and thus weakening the muscle. Decrease in dystonic spasms and side effects related to weakness take from 2 to 7 days to develop (Dutton and Buckly 1986). The beneficial effects usually last between 2 and 3 months and the procedure thus needs to be repeated 4–5 times a year. Muscles chosen for injection are those maximally affected by the dystonia. In a small number of cases antibodies have developed to the toxin, causing subsequent courses to lose their effect (Brin et al. 1988). Use of other botulinum serotypes like F or type B may be helpful in this situation, but some studies have suggested that the duration of action may be less, with a mean of 4.7 weeks for type F compared with 3 months for type A (Green and Fahn 1993, Mezaki et al. 1995).

In open studies of blepharospasm treated by periocular injection of toxin there was significant improvement in 77% of 101 cases (Elston 1978), 78% of 151 cases (Grandas et al. 1988), and 69% of 42 cases (Brin et al. 1988). In 36% of Grandas et al.'s (1988) patients, relatively normal vision was restored. In a smaller double-blind placebo-controlled study, Jankovic and Orman (1987) found all of 12 blepharospasm patients benefitted, with improvement averaging 72% on a clinical rating score. Results may be able to be improved by use of EMG to identify cases in which the major problem is due to contraction of the pretarsal or septal parts of orblicularis oculi or failure of levator palpebrae superioris contraction (Elston 1992, Aramideh et al. 1994[a]). Side effects of this treatment are common and are listed in Table 37.9. They include transient ptosis, diplopia, and lower facial weakness. These lasted from 1 to 45 days. In addition, Grandas et al.(1988) had persisting problems in 15.2% of cases, consisting of spontaneous Bell's phenomenon (9.9%), levator inhibition (3.9%), and levator disinsertion (1.3%). Dutton and Buckley (1988) had an incidence of 22.6% of side effects in 172 patients given 898 treatments over 4 years, with symptomatic dry eye in 7.5%, ptosis in 7.3%, photophobia in 2.5%, and diplopia in 0.5%.

Grandas et al. (1988) found that 32% of patients undergoing injections of the orbicularis oculi muscles for blepharospasm also had relief of lower facial or oromandibular dystonia. However, muscles affected in these latter conditions, such as masseter and temporalis, may be directly injected. Results are not as good as with blepharospasm and Jankovic and Orman (1987) found only 37.5% of patients with oromandibular dystonia benefitted. Blitzer et al. (1989) injected masseter, temporalis, and/or pterygoid muscles in 20 such patients and found 47% improvement overall.

In view of these and similar studies, a subcommittee of the American Academy of Neurology in 2008 performed a literature search for an evidence-based recommendation regarding botulinum toxin (Simpson et al. 2008). The authors concluded that the highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies), compared to hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study). This topic has also been covered by a Cochrane Review (Albanese et al. 2006).

Doxorubicin injection which causes a localized chemical myemectomy has been said to produce relief of spasm lasting over a number of years (Wirtschafter and McLoon 1998). However, further clinical trials are required before it can be considered as an alternative to botulinum toxin.

Patients with spasmodic dysphonia may also be treated (Jankovic and Orman 1987). Such treatment has the risk of aggravating swallowing and speech difficulties with spillage of food and fluid into the trachea, but Brin et al. (1988) found this was relatively mild and transient. All three patients they treated had benefit. Subsequently large numbers of patients have been treated, with both unilateral (Ludlow et al. 1988) and bilateral (Blitzer and Brin 1991) injection being used. The thyroarytenoid muscle has been targeted for adductor spasm and the posterior cricoarytenoid for abductor spasm. About 95–100% of patients with the more common adductor type of spasm receive benefit (Blitzer and Brin 1991, Whuur et al. 1993) and this can be marked. The response is less satisfactory in abductor spasm but it may still be useful. Most series contain a mixture of aetiologies, making assessment of treatment in primary focal dystonia of the larynx difficult to assess.

Studies of biofeedback are too meagre to allow assessment of their efficacy in cranial dystonias. They have been reported useful in treating facial and jaw movements associated with more widespread dystonia, but long-term follow-up is lacking (Bird and Cataldo 1978) and experience suggests such therapy has little to offer. Although psychiatric therapy may be required for associated depression it is ineffective in lessening the dystonia.

A suggested plan of management for cranial dystonias involves starting with botulinum A toxin injections for those with disabling blepharospasm, and only if this is unsuccessful progressing to trials of drug therapy. If these are unhelpful surgery should be considered. Because of the risk of serious complications and less satisfactory response to injections, drug therapy should be tried initially in oromandibular, pharyngeal, and spasmodic dysphonias, with botulinum A injections and surgery held in reserve.