Adult-onset dystonia

Handbook of Clinical Neurology, Vol. 100 (3rd series) Hyperkinetic Movement Disorders W.J. Weiner and E. Tolosa, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 37

Adult-onset dystonia MARIAN L. EVATT, 1, 2 ALAN FREEMAN, 1 AND STEWART FACTOR 1 * Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

1 2

Atlanta VA Parkinson’s Disease Consortium Center, Department of Veterans Affairs Medical Center, Decatur, GA, USA

INTRODUCTION Dystonia is defined as involuntary sustained muscle contractions producing twisting or squeezing movements and abnormal postures. The movements can be stereotyped and repetitive and they may vary in speed from rapid to slow; sustained contractions can result in fixed postures. Dystonic disorders are classified into primary and secondary forms. Several types of adult-onset primary dystonia have been identified but all share the characteristic that dystonia (including tremor) is the sole neurologic feature. The forms most commonly seen in neurological practice include cranial dystonia (blepharospasm, oromandibular and lingual dystonia, and spasmodic dysphonia (SD)), cervical dystonia (CD: also known as spasmodic torticollis), and writer’s cramp. These are the disorders that benefit most from botulinum toxin injections. A general characteristic of dystonia is that the movements or postures may occur in relation to specific voluntary actions by the involved muscle groups (such as in writer’s cramp). Dystonic contractions may occur in one body segment with movement of another (overflow dystonia). With progression, dystonia often becomes present at rest. Dystonic movements typically worsen with anxiety, heightened emotions, and fatigue, decrease with relaxation, and disappear during sleep. There may be diurnal fluctuations in the dystonia, which manifest as little or no involuntary movement in the morning followed by severe disabling dystonia in the afternoon and evening. Morning improvement (or honeymoon) is seen with several types of dystonia. Patients often discover maneuvers that reduce the dystonia and which involve sensory stimuli, such as touching the chin lightly in CD. These maneuvers are known as sensory tricks, or gestes antagonistes.

This chapter will focus on adult-onset focal dystonias, including cranial dystonia, CD, and writer’s cramp. The chapter will begin with a review of the epidemiology of focal dystonias, followed by discussions of each major type of focal dystonia, covering clinical phenomenology, differential genetics, and diagnosis. The chapter will conclude with discussions of the pathophysiology, the few pathological cases published of adult-onset focal dystonia, and management options, and a brief look at the future.

EPIDEMIOLOGY OF FOCAL DYSTONIA Early-onset (before age 20) primary dystonia tends to present with focal symptoms and become segmental or generalized; dystonia with onset after age 20 tends to remain focal or segmental, with symptoms in the eyelids (blepharospasm), jaw (oromandibular), neck (CD or torticollis), larynx (SD), or upper limb (limb dystonia or writer’s cramp). However, there are remarkably few epidemiologic studies of focal dystonia and case ascertainment for epidemiology studies of focal dystonia is logistically difficult for several reasons. Firstly, patients with milder forms may not be diagnosed with dystonia, or may be misdiagnosed and undercounted (e.g., patients with CD and head tremor or writing tremor not present with other fine motor activities may be diagnosed with essential tremor). With widespread access to the internet, this misclassification may be less common because patients may easily find descriptions of dystonia online and self-refer for medical care. Secondly, patients with the same type of focal dystonia may be seen in a variety of clinics: patients with blepharospasm may be seen by either ophthalmologists or movement disorders

*Correspondence to: Stewart Factor, MD, Emory University, Department of Neurology, Wesley Woods Health Center, 1841 Clifton Road, Suite 32, Atlanta, GA 30322, USA. Tel: (404) 728-6415, Fax: (404) 728-6685, E-mail: [email protected]

482 M.L. EVATT ET AL. neurologists and patients with SD may be seen by otofeatures are manifestations of one form of adult-onset laryngologists or movement disorders neurologists. focal dystonia. Cranial dystonia has been referred to in Such variety may impact case ascertainment if the the literature by several names, including “Meige’s study is based on record review from a single type of syndrome” (after the French neurologist Henry Meige clinical setting. Thirdly, clinical presentations are not who wrote his seminal article in 1910 and brought uniform and multiple classifications exist based on attention to the use of tricks). Meige called the age of onset, body distribution, and etiology (primary syndrome “spasm facial median,” and differentiated versus secondary). Information from studies using it from hemifacial spasm and tics (Meige, 1910; Tolosa one classification system is not easily comparable to and Klawans, 1979). “Brueghel’s syndrome” is another studies using another system. Furthermore, the age name, after Pieter Brueghel, the 16th-century Flemish ranges in denominator populations have not been conartist who painted De Gaper in 1558 (which presumably sistent, nor are age-adjusted estimates consistently depicted a man with blepharospasm and jaw-opening reported, making comparisons between studies diffidystonia) (Fig. 37.1) (Marsden, 1976). Gilbert (1996) cult. With these limitations in mind, the data on the episuggested that the term be reserved for cases with pure demiology of primary focal dystonia are summarized. jaw-opening dystonia, while others have questioned the To identify epidemiology studies of primary dystonia, use of the term since it appears that Brueghel was we used the search terms “prevalence” or “epidemiolapparently painting the face of someone yawning ogy” and “dystonia” in PubMed, Google Scholar, and (Parkes and Schachter, 1981). Other less frequent labels OVID to identify articles written since 1950. In addition, include “Blake syndrome” (for the artist William Blake articles cited were reviewed for inclusion. After who presumably painted focal and generalized dystoexcluding review articles, only 18 were identified in which nias in the 17th century) or “Wood syndrome” (after primary dystonia prevalence or incidence is reported, Horatio Wood, an American neurologist, who, in some only in abstract (Table 37.1). 1874, may have been the first to describe blepharoIncidence data are extremely rare, and most studies spasm with facial grimacing in his book Treatise on report prevalence estimates (Marras et al., 2007; Stacy, Therapeutics) (Parkes and Schachter, 1981; Gilbert, 2008). The incidence of CD is thought to be approxi1996; Satija and Ondo, 2007). Descriptively, the mately 1.0–1.2 per 100 000 person-years (Erjanti et al., syndrome is most commonly referred to as blepharo1996; Marras et al., 2007). Cranial and other focal spasm-OMD syndrome (Marsden, 1976) or cranial dystonias occur in adult life, usually in the sixth decade dystonia. or beyond, so prevalence estimates tend to increase Blepharospasm and OMD are the most common with increasing age. Women are more commonly manifestations of cranial dystonia and may occur indeaffected than men (Marsden, 1976; Jankovic and Ford, pendently or in combination. In fact, any of the muscle 1983; Grandas et al., 1988; Tan and Jankovic, 2000). groups may develop dystonia in isolation, such as linSpontaneous remissions are uncommon (
11%), and gual dystonia, jaw dystonia, or laryngeal dystonia tend to occur within the first 5 years (Tolosa et al., (Tolosa and Marti, 1988) or in any combination. Onset 1988; Castelbuono and Miller, 1998). Prevalence esticould be simultaneous or in any order of appearance, mates vary widely depending on the type of focal dystowith spread occurring in days to months (Tolosa nia – from 0.3 per 100 000 for oromandibular dystonia et al., 1988). The combination of blepharospasm and (OMD) to 18.3 per 100 000 for CD (Nutt et al., 1988b; OMD occurs in 43–76%, blepharospasm alone in Butler et al., 2004). Blepharospasm in isolation is more 11–33%, and oromandibular alone in 2–23% (Tolosa common than OMD (Jankovic and Ford, 1983; Tolosa and Marti, 1988). Extracranial involvement has been et al., 1988), and CD is the most focal dystonia (Nutt reported in up to 60% of cases, including neck and et al., 1988a). Prevalence estimates for limb dystonia upper limbs (Tolosa and Marti, 1988). Unknown are lower than for blepharospasm and CD (Defazio factors govern whether dystonia spreads to other et al., 2004). regions. One study examined factors determining spread by retrospectively comparing several demoCRANIAL DYSTONIA graphic and historic features in 104 patients with pure (BLEPHAROSPASM-OROMANDIBULAR blepharospasm and 55 with blepharospasm-plus, where DYSTONIA SYNDROME) the blepharospasm component occurred first (Defazio et al., 1999). There was an inverse relationship between Clinical features and natural history age of onset of blepharospasm and time to initial Cranial dystonia involves the eyelids, lower facial and spread – the older the age of onset, the more likely jaw muscles, and/or larynx and, at times, the cervical the dystonia was to spread. Female sex and history of muscles. In 1976, Marsden concluded that these head or face trauma with loss of consciousness also

Table 37.1 Original epidemiology studies Reference

Type of study

Type of dystonia

Prevalence per 100 000 (95% CI) or incidence per 100 000 person-years*

Comments

Li et al. (1985)

Door to door

Focal

Nutt et al. (1988a)

Records linkage (Rochester Epidemiology Project) 1950–1982

Focal and generalized

Age-adjusted to 1960 US census population Patients with segmental or multifocal dystonia were not included One of the few studies reporting incidence data

Kandil et al. (1994)

Door to door Assuit, Egypt 1988–1990

Focal

Prevalence 30 (4–110) Crude prevalence Bleph 1.72 (0.05–9.58) OMD 6.89 (1.87–17.6) Laryngeal 5.17 (1.07–15.1) Cervical 8.86 (2.87–20.7) Writer’s cramp 6.89 (1.87–17.6) Generalized 3.4 (0.41–12.4) Crude incidence (per 105 person-years) Bleph 0.46 (0.8–0.95) OMD 0.33 (0.11–0.77) Laryngeal 0.27 (0.07–0.69) Cervical 1.09 (0.54–1.95) Writer’s cramp 0.27 (0.07–0.69) Generalized 0.20 (0.04–0.58) 4

Cervical

Incidence (per 105 person-years) 1.2 (0.5–1.9)

One of the few studies reporting incidence data Age- and sex-adjusted incidence rate reported Crude and age-specific prevalence rates reported

Claypool et al. (1995)

Nakashima et al. (1995)

Service-based Tottori Prefecture, Japan 1988–1993

Focal

Prevalence Facial (bleph or OMD) 1.63 (0.11–3.15) Cervical 2.85 (0.79–4.91) Writer’s cramp 1.63 (0.11–3.15) Overall 6.12 (3.08–9.16)

Erjanti et al. (1996)

Community-based South-western Finland 1996

Cervical

Prevalence Cervical 20.9 for women 13 for men Incidence 1.4 for women 0.7 for men

Duffey et al. (1998), Butler et al. (2004)

Record linkage Northern UK 1994–2002

Focal and segmental

Prevalence Cervical 18.31 Bleph 8.14 Laryngeal 4.26 Writer’s cramp 2.46 Overall 38.08

Crude prevalence rates

Abstract form only Crude prevalence rates only Higher prevalence than previous US and Asian prevalence estimates

Continued

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Table 37.1 Continued Reference

Type of study

Type of dystonia

Prevalence per 100 000 (95% CI) or incidence per 100 000 person-years*

ESDE (2000)

Service-based

Focal

Prevalence Bleph 3.6 (3.1–4.1) Cervical 5.7 (5.1–6.4) Writer’s cramp 1.4 (1.1–1.7) Laryngeal 0.7 (0.5–0.9) Overall 1.17 (1.08–1.26)

Castelon Konkiewitz et al. (2002)

Service-based Munich, Germany 1996

Focal and generalized

Muller et al. (2002b)

Random population sample Bruneck, South Tyrol 2000 Records linkage (Rochester Epidemiology Project) 1976–1995

Primary dystonia

Point prevalence Bleph 3.1 (2.4–4.1) Cervical 5.4 (4.2–6.7) Laryngeal 1.0 (0.4–1.5) All focal 10.1 (8.4–11.9) 732 (95% CI 319–1564) (population standardized)

Blepharospasm

Incidence Bleph 1.2

Le et al. (2003)

Service-based Oslo, Norway 2001

Focal and segmental

Matsumoto et al. (2003)

Service-based Japan

Focal and segmental

Point prevalence Bleph 4.7 Cervical 13.0 Laryngeal 2.8 Limb 2.4 OMD 0.8 Meige’s 1.0 Face and cervical 0.8 Overall focal/segmental 25.4 Prevalence Focal dystonia overall 8.2

Pekmezovic et al. (2009)

Service-based Belgrade (Serbia), Yugoslavia 2001

Focal, and segmental and multifocal

Bradley et al. (2003)

Focal 11 (29.4–13.3) Cervical 5.9 (4.6–7.5) Bleph 1.9 (1.2–2.8) Writer’s cramp 1.9 (1.2–2.8) Laryngeal 1.1 (0.6–1.9) Other focal forms 0.4 (0.1–0.9) Segmental 2.2 (1.5–3.2) Multifocal 0.2 (0.1–0.7) All types 13.6 (11.6–15.9)

Comments

General population, 50 years and older

Note: This population appears to overlap with that reported by Nutt et al. (1988b) Half the cases had Meige’s syndrome Crude prevalence and age-specific prevalence estimates reported (no age-adjusted overall rate)

Prevalence rates were not calculated for the different types of focal dystonia, but facial dystonia was more prevalent than cervical Age 20 years and older

ADULT-ONSET DYSTONIA

485

Table 37.1 Continued Reference

Type of study

Type of dystonia

Prevalence per 100 000 (95% CI) or incidence per 100 000 person-years*

Comments

Wenning et al. (2005)

Population-based cohort longitudinal study Bruneck Study

Primary dystonia 0.76 (0.21–1.3)

Study not designed to capture dystonia

Asgeirsson et al. (2006)

Entire population Iceland, 2003

Movement disorders, including primary and secondary dystonia Focal, segmental, generalized

First study of an entire population

Marras et al. (2007)

Record linkage Northern California 1997–1999

Cervical

Focal 31.2 (25.1–38.4) Cervical 11.5 (7.9–16.1 Limb 8.0 (5.1–12.0) Laryngeal 5.9 (3.4–9.4) Blepharospasm 3.1 (1.4–5.9) Oromandibular 2.8 (1.2–5.5) Segmental 3.1 (1.4–5.9) Multifocal 2.4 (1.0–5.0) Generalized 0.3 (0.0–1.9) All types 37.1 (30.4–44.9) Incidence Minimum estimate 0.80 Corrected estimate 1.07 (0.86–1.32)

Das et al. (2007)

Stratified population sample Kolkata, Eastern India

Primary

Health maintenance organization, Northern California, USA
25–30% of the region’s population ↑ with ↑ age ↑ in those of European versus Asian or African descent

Crude prevalence 43.91 (28.41–64.81) Standardized estimated prevalence Bleph 7.22 (1.49–21.10)

*Where indicated, incidence estimate noted. CI, confidence interval; Bleph, blepharospasm; OMD, oromandibular dystonia.

were independently associated with spread in the multivariate analysis. Among features not associated with spread were positive family history of focal dystonia and prior ocular disease. Spread generally occurred within 5 years and was in a somatotopic manner: blepharospasm followed by lower face and jaw, then larynx, followed in turn by neck and finally upper limb. However, in some patients the spread skipped regions, resulting in blepharospasm and CD. Another study demonstrated that patients beginning with blepharospasm were more likely to spread to multifocal or segmental dystonia than those beginning with cervical, laryngeal, and upper-limb dystonia (Weiss et al., 2006). In nearly 60% of patients

with onset of blepharospasm spread, older age of onset was a risk for spread (Weiss et al., 2006). Dystonia spread to the lower face in 45%, neck 31%, larynx 1%, and beyond the craniocervical region in 3%. Although the number of those patients with onset in lower face or jaw was small, 64% experienced spread either to neck or eyelids. On the other hand, only 9% of patients with SD experienced spread, mainly to neck and upper extremities (Weiss et al., 2006).

BLEPHAROSPASM Blepharospasm (referred to as benign essential blepharospasm (BEB)) involves the orbicularis oculi and surrounding muscles and causes involuntary blinking,

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Fig. 37.1. De Gaper, painted by Peter Brueghel in 1558.

compared blepharospasm to hemifacial spasm. Those with blepharospasm experience a greater reduction in vision-targeted health-related quality of life and are more prone to symptoms of depression and anxiety (Hall et al., 2006). Earlier studies found Short Form 36 (SF36) and Health-Related Quality of Life measures were significantly worse in blepharospasm subjects compared to healthy controls (Reimer et al., 2005). Features that aggravate blepharospasm include attempting to open eyelids (reflex blepharospasm), sunlight (many patients wear the wrap-around dark sunglasses, even indoors), looking upward, stress, fatigue, watching television, walking, driving, talking, and even yawning (Tolosa and Marti, 1988). Patients use sensory tricks to open their eyes, including forced opening of the eyelids, pressure on the superior orbital ridges or canthus with a finger, and rubbing the eyelids. Some patients find that wearing dark glasses or other movements such as forced mouth opening, specific neck motions, whistling, and singing are helpful. Patients may also use eyeglasses with eyelid crutches (also known as ptosis crutches) (Fig. 37.2) or wire loops (Lundie loops) to hold the lids open (Hallett et al., 2008).

OROMANDIBULAR repetitive contractions (blepharoclonus), and squinting or sustained closing of the eyes (Tolosa and Marti, 1988). Some patients have bursts of spasm with periods of normalcy. BEB is often preceded by eye irritation feeling like dry eyes (not infrequently leading to a diagnosis of blepharitis, which may co-occur), photophobia, and increased blinking (Grandas et al., 1988). These early symptoms commonly occur within a year of onset of blepharospasm, mostly between ages 40 and 59 (Martino et al., 2005). Symptoms are infrequent at first and may occur in specific situations, but over time they increase in frequency and duration. Symptoms also progress from clonic to tonic eye closure. The dystonia may spread to neighboring muscles, including frontalis, procerus, and corrugator supercilii, and some lower facial muscles such as zygomaticus and mentalis (Tolosa et al., 1988). BEB may occasionally begin in one eye and spread to the other but more commonly starts in both. Approximately two-thirds of patients are significantly disabled and 12–36% of these patients are considered functionally blind and homebound because of their inability to open their eyes voluntarily (Jankovic and Ford, 1983; Grandas et al., 1988; Tolosa and Marti, 1988). These patients can no longer drive, read, watch television, or ambulate independently. Several studies examined the impact of blepharospasm on quality of life. One used the 25-item National Eye Institute Visual Function questionnaire and

DYSTONIA

OMD involves the dystonic contraction of jaw muscles in various combinations, leading to sustained or repetitive jaw opening or closing, protrusion or retraction, bruxism, or deviation. This is sometimes associated with facial grimacing, lip pursing, and other facial contortions, seen in approximately 32% (Tan and Jankovic, 2000). Jaw closing has been considered to be the most common form (Tan and Jankovic, 2000; Satija and Ondo, 2007) and is less likely to be associated with dystonia in other craniocervical regions compared to the

Fig. 37.2. Ptosis crutches, from the Benign Essential Blepharospasm website (http://www.blepharospasm.org/gallery/nonsurgical-aids/IMG_1588Peterc). (Courtesy of Peter Bakalor.)

ADULT-ONSET DYSTONIA opening variety (Singer and Papapetropoulos, 2006). The muscular anatomy of the jaw includes: (1) closers: medial pterygoids, masseters and temporalis and symmetric contraction lead to pure closing dystonia or bruxism; and (2) openers: lateral pterygoids and digastric muscles and symmetric contraction lead to jaw opening and/or protrusion. Asymmetric contraction of openers or closers leads to deviation (ipsilateral if medial pterygoid is involved, contralateral if lateral pterygoid is involved) in combination with opening or closing (Thompson et al., 1986) (Table 37.2). Simultaneous or alternating movements of openers and closers may result in jaw tremor (Schneider and Bhatia, 2007). OMD frequently causes disability related to difficulty in speaking, chewing, swallowing, or pain. One study suggested that 16% develop eating dysfunction significant enough to cause substantial weight loss (Papapetropoulos and Singer, 2006a) by emotional stress, fatigue, driving a car and talking, chewing, or swallowing. Some patients demonstrate improvement of jaw movements with chewing, indicating that central generators can override spontaneously occurring dystonia (Moller et al., 2007). There are forms of OMD that are purely action-induced. Some of these patients are misdiagnosed as temporomandibular joint syndrome (Nishioka and Montgomery, 1988; Raudino, Table 37.2

487

1994). In such cases, opening of the jaw results in overactivity of the lateral pterygoids and subluxation of the mandible from the temporomandibular joint. The main complaint in these patients may be pain. Stuttering may be a manifestation of action-induced dystonia of the jaw, face, or tongue muscles (Sveinbjornsdottir et al., 1993; Kiziltan and Akalin, 1996; Alm, 2004); interestingly, stuttering was more common in family members of dystonia patients (Fletcher et al., 1991). Dystonia has also been reported with other specific actions such as speaking in a certain manner or playing a musical instrument (embouchure dystonia) (Scolding et al., 1995; Frucht et al., 2001). Sensory tricks (gestes antagonistes) utilized in OMD include pressing on the lips or teeth with fingers, pressing on the hard palate with the tongue, putting a finger in the mouth, placing other items like cigarettes in the mouth, chewing gum or placing items between molars or in the cheek (a toothpick for instance), singing, and humming. These are recognized in about one-third of patients, although many others may benefit if these tricks are sought out (Sankhla et al., 1998; Frucht et al., 1999; Lo et al., 2007; Schramm et al., 2007). Some patients reportedly utilized removable oral prosthetics that mimic their tricks to improve function, with great success (Lo et al., 2007). Others suggested tricks work better for jaw-opening than jaw-closing dystonia (Singer and Papapetropoulos, 2006), but this requires confirmation.

Dystonic movements Dystonic motion Jaw motion Jaw closure Symmetric activation Jaw opening Symmetric activation Ipsilateral deviation Asymmetric activation Contralateral deviation Asymmetric activation Head/neck motion Rotation

Lateral tilting

Retrocollis

Shoulder elevation

Muscles involved

Medial pterygoids Masseters Temporalis Lateral pterygoids Digastric muscles Medial pterygoid Lateral pterygoid

Splenius capitis Semispinalis capitis Suboccipital m. Sternocleidomastoid Semispinalis capitis Suboccipital m. Scalenes Suboccipital m. Splenius capitis Semispinalis capitis Levator scapulae

LINGUAL

PROTRUSION DYSTONIA

Lingual protrusion dystonia is rare but has been recognized as a manifestation of OMD since early descriptions (Meige, 1910; Marsden, 1976). In one study of OMD, lingual protrusion dystonia was present in only 7.6% of patients (Tan and Jankovic, 2000). Nevertheless, in 2006, 8 cases were presented and the authors suggested that the severe form should indicate the presence of a heredodegenerative disease (Schneider et al., 2006). A table of causes of this phenomenon was published, but did not include Meige’s syndrome. Ten patients with severe tongue protrusion dystonia, five of whom were part of adult-onset idiopathic cranial dystonia, were reported (Esper et al., 2010). Lingual dystonia in association with jaw dystonia or in isolation can be the initial symptom of Meige’s syndrome (Tolosa and Marti, 1988; Charles et al., 1997; Esper et al., 2010). Tongue movements may be repetitive or tongue protrusion may be sustained. Movements can be action-induced, most commonly with speaking (Ishii et al., 2001; Baik et al., 2004; Tan and Chan, 2005) and occasionally the tongue may curl instead of protruding (Papapetropoulos and Singer, 2006b).

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Tongue dystonia can be quite disabling by preventing speaking, chewing and swallowing. Some patients push food or dentures out of the mouth (Charles et al., 1997). OMD with jaw closing may cause self-mutilation with tongue biting or airway obstruction. Acute worsening requiring intubation and respiratory support has been described with secondary forms (Schneider et al., 2006), but this has not been reported in idiopathic cases. These patients invariably suffer from pronounced drooling and the disorder is quite embarrassing for patients. Tricks utilized by patients are similar to those listed for OMD.

SPASMODIC

DYSPHONIA

Laryngeal dystonia (vocal cords) causes uncoordinated contraction of the vocal cords during speech, and is also called SD (Meyer and Blitzer, 2007). The smooth flow of speech is lost and certain sounds are held longer and overemphasized. SD is somewhat different from the other forms of cranial dystonia. Although there were several descriptions in the late 19th and early 20th centuries, in 1939 it was first referred to as “spastic dysphonia.” Not until the late 1960s was it thought to be an organic neurological illness; its relationship to other forms of cranial dystonia was realized in the 1980s when it was reported in conjunction with other cranial dystonias (Critchley, 1939; Aronson et al., 1968a, b; Blitzer et al., 1985; Meyer and Blitzer, 2007). This observation came 70 years after Meige described the phenomenology (Meige, 1910; Tolosa and Klawans, 1979). What is unusual is that only a minority occur in conjunction with other cranial dystonias (Weiss et al., 2006). In a study of 1300 patients, 82% had isolated SD; 12% progressed to another cranial site and 5% to extracranial sites (Blitzer et al., 1998; Hallett et al., 2009). Several types of SD have been described, including adductor dysphonia, where there is excessive glottal closure in a rigid fashion so that the larynx is completely shut off, preventing air flow. The muscles involved are the thyroarytenoids. The resulting speech is tight, constricted, strained, strangled, and forced or effortful with guttural stops. This is the most common form. In 1939 Critchley described the speech in these patients “as though the patient were trying to talk whilst being choked.” Abductor dysphonia, characterized by open glottal configuration and a paucity of vocal cord vibration, produces speech which is effortful but soft and whispery sounding. This form is much less common. The primary muscle involved in this form is the posterior cricoarytenoid. Some patients have a mixed form, although the frequency of this is a matter of debate (Hallett et al., 2009). Blitzer and colleagues (1998)

found that, of 900 patients, 82% were of the adductor type and 17% were of the abductor type. SD is typically action-induced by speech. Rarely (approximately 1%), adduction of the vocal cords occurs with inspiration, resulting in stridor (Gerhardt’s syndrome) (Marion et al., 1992; Blitzer et al., 1998; Hallett et al., 2009). In these cases, patients can have SD or a normal voice, have normal cough and swallow and breathe normally during sleep. The inspiratory stridor can be quite uncomfortable but rarely causes hypoxia. SD occurs more in women – approximately 80% in one study (Blitzer et al., 1998). The age of onset is lower than other cranial dystonias (35 years) (Blitzer et al., 1988). SD is a chronic disorder that is insidious in onset. Symptoms increase with stress, long periods of vocalization, or speaking on the telephone. SD, like other forms of dystonia, is better in the morning and some patients are still able to sing, yell, and laugh without problems. There is a rare form of occupational dysphonia in singers, so-called singer’s laryngeal dystonia (Hallett et al., 2009). Diagnostic evaluation should include flexible fiberoptic laryngeal exam (Meyer and Blitzer, 2007). In 14 patients, electromyogram (EMG) of the larynx was examined for changes that might be specific to SD; seven patients had normal EMG, three had actioninduced activation and abnormally increased amplitude, and two had asynchronous activity typical of tremor (Blitzer et al., 1985). Another study reported that perceptual assessment by experienced voice clinicians could be used for measuring severity of SD (Chhetri et al., 2008).

NONMOTOR

FEATURES OF CRANIAL DYSTONIA

Nonmotor features of blepharospasm and other forms of cranial dystonia have not been studied (Green and Factor, 2007). Two early studies of blepharospasm indicated that 13% and 18% of patients were depressed at initial evaluation (Marsden, 1976; Grandas et al., 1988). More recent studies found depression in 37% of cases, and women were more severely affected than men (Muller et al., 2002a; Reimer et al., 2005). One study in SD found a high prevalence of psychiatric comorbidity in patients (41%), including depression, anxiety, and adjustment disorders. Psychiatric comorbidity significantly correlated with the extent of voice pathology (Gundel et al., 2007). Sleep studies in 10 patients with blepharospasmOMD demonstrated impaired sleep efficiency and reduced slow-wave and rapid-eye-movement sleep correlated with symptom severity (Sforza et al., 1991). Pain is another nonmotor feature seen in cranial dystonia. Periorbital pain in blepharospasm has been described (Jankovic and Ford, 1983). In 11 patients with

ADULT-ONSET DYSTONIA 489 blepharospasm pain, discomfort, and other sensations inherited and acquired, can have cranial dystonia as a were experienced before facial dystonia emerged and manifestation of the disease, including progressive disappeared when the movement disorder developed, supranuclear palsy, Huntington’s disease, Wilson’s dissuggesting that sensory phenomena may be the earliest ease, and PANK2 (Tolosa and Marti, 1988; Tolosa manifestation of cranial dystonia (Ghika et al., 1993). et al., 1988; Thomas and Jankovic, 2004). Finally, strucPain is also common with OMD. The pain is primarily tural lesions in the basal ganglia and brainstem have been located in the temporomandibular joint and is often reported to cause cranial dystonia, including stroke and misdiagnosed if dystonia is not obvious (Jankovic and multiple sclerosis (Jankovic and Patel, 1983; Jankovic, Ford, 1983). 1986; Tolosa et al., 1988; Tolosa and Marti, 1988).

Etiology and differential diagnosis

CERVICAL DYSTONIA

Blepharospasm, which is the active involuntary closing of the eyes due to contraction of the orbicularis oris, should be distinguished from apraxia of eyelid opening. The latter is due to failure of activation or inhibition of the levator palpebrae muscle. This phenomenon may be associated with isolated contraction (dystonia) of the pretarsal orbicularis oculi. Apraxia of eyelid opening may not respond to botulinum toxin in the manner that blepharospasm does unless the pretarsal area is specifically targeted (Satija and Ondo, 2007; Hallett et al., 2008). No causative gene has been discovered for cranial dystonia. However, several studies have indicated that approximately one-third of patients have a first- or second-degree relative with a movement disorder or focal dystonia (Jankovic and Nutt, 1988; Tan and Jankovic, 2000; Defazio et al., 2006) and twins with blepharospasm have been reported (Sieberer et al., 1999). The pattern of inheritance suggests an autosomal-dominant pattern with reduced penetrance of
20% (Defazio et al., 2006). A positive family history of dystonia is found in approximately 12% of SD patients (Hallett et al., 2009). Studies have examined the dopamine receptor D5 (DRD5) gene on chromosome 4 and its association to cranial dystonia, with mixed results (Misbahuddin et al., 2002; Clarimon et al., 2007). Cranial dystonia has been seen in other hereditary dystonia syndromes, including DYT7, DYT13, and DYT1, and a single study showed an association with DYT1 (Clarimon et al., 2007), but classical cases have generally not been associated with these or other known genetic abnormalities (Defazio et al., 2003; Dhaenens et al., 2005; Satija and Ondo, 2007).

Clinical features and natural history

Evaluation and treatment Most important in the differential diagnosis of cranial dystonia is drug-induced or tardive cranial dystonia. The features can be identical to primary cranial dystonia, with blepharospasm, OMD and even lingual dystonia and SD (Tolosa et al., 1988; Tan and Jankovic, 2000). Levodopa in parkinsonian patients can also cause cranial dystonia, particularly in multiple-system atrophy (Esper et al., 2010). Other neurodegenerative diseases, both

CD, also called “torticollis,” is the term applied to focal dystonia involving the neck muscles. Agonistantagonist spasms in neck muscles cause pain and abnormal postures and movements of the head. In the strictest semantic meaning, “torticollis” specifically refers to turning/rotation of the head to the right or left. However, CD is usually a combination of torticollis, anterocollis (forward tilting of the head), laterocollis (head tilting to one side), and/or retrocollis (backward tilting of the head) (see Table 37.2 regarding which neck muscles cause which posture). In addition, a minority (17%) of patients experience involuntary jerking movements, for which the term “spasmodic torticollis” is frequently applied (Chan et al., 1991). Many patients report transient alleviation of muscle pulling and pain from a geste antagoniste (sensory trick) — a light sensory stimulus is applied to the head or neck (e.g., touching chin, head, or face with a finger). Over time, sensory tricks frequently become less effective (Muller et al., 2001; Filipovic et al., 2004). Head tremor and/or limb tremor frequently accompany CD, with about 30–60% of patients exhibiting head tremor and one-quarter of patients experiencing an upper-extremity tremor that resembles essential tremor (Chan et al., 1991; Jankovic et al., 1991; Molho et al., 1998). Electrographically, CD is characterized by sustained EMG activity (producing sustained postures) as well as two types of phasic activity (repetitive/rhythmic activity with 200–500 ms bursts and much shorter (< 100 ms) bursts similar to what may be seen in myoclonus); loss of reciprocal inhibition can be demonstrated (Berardelli et al., 1998). Although CD is a focal dystonia, approximately 20% of patients with CD have other body segments involved (i.e., segmental dystonia) (Dauer et al., 1998) and threequarters of patients have associated pain (Chan et al., 1991). The typical onset age for CD is early 40s, though patients with accompanying hand tremor may present later in life (Chan et al., 1991). Spread of dystonic symptoms beyond the neck region occurs in approximately 10% (Weiss et al., 2006) of patients. Spontaneous

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remissions have been reported to occur in 12–21% of patients, typically in the first 1–5 years, and are not sustained (Friedman and Fahn, 1986; Jahanshahi et al., 1990). CD occurs more commonly in females, but CD phenotype and characteristics do not differ between males and females (Chan et al., 1991).

Etiology and differential diagnosis The differential diagnosis for CD includes sporadic idiopathic CD, CD associated with genetic mutations, pseudodystonia, dystonic tics, medication-induced, and psychogenic CD. Rare mutations in chromosomes 8 (DYT6) and 18 (DYT7) have been reported with CD (Almasy et al., 1997b; Leube et al., 1997a). Although these are autosomal-dominant mutations, penetrance is incomplete – 15% (DYT6) and 42–82% (DYT 7) – and patients may not report a family history (see Table 37.3 for clues of a genetic etiology). Pseudodystonia may appear similar to CD but the abnormal cervical postures are due to structural abnormalities (atlantoaxial and C2–3 rotary dislocation), cranial nerve IV palsy (head tilt), or muscle weakness. For example, the “dropped-head” syndrome may mimic anterocollis. Brainstem, third ventricle, and spinal cord lesions have been reported to manifest with dystonia, but one would expect accompanying clinical findings (Kiwak et al., 1983; Suchowersky and Calne, 1988). Dystonic tics may sometimes appear phenotypically similar to CD, and botulinum toxin has been used to manage symptoms (Adler et al., 1996). Medication-induced dystonia may be due to medications, particularly dopamine-blocking drugs (Molho et al., 1998). Clues that support a diagnosis of psychogenic CD are the same as for any psychogenic movement disorder – abrupt onset, distractibility, and selective disability (Factor et al., 1995). Because of the gestes phenomenology, CD patients were frequently incorrectly labeled as psychogenic, and many now consider psychogenic CD a diagnosis of exclusion. Posttraumatic torticollis has also been considered to be psychogenic. Table 37.3 Features suggestive of genetic contribution of cervical dystonia symptoms Early age of onset (late 20s or earlier) Specific exacerbating or triggering factors such as caffeine, diurnal variation Belonging to specific ethnic groups in which known familial forms of dystonia are more common (Ashkenazi Jews, Mennonites) Accompanying signs of parkinsonism

Evaluation A careful history and physical examination, along with indicated radiological and laboratory work-up, should be completed in all CD patients to rule out secondary causes in patients with suspected CD. For example, Wilson’s disease screening in patients with a history of liver or psychiatric disease, particularly if their age of onset was in their teens or 20s, should be considered. Screening for Wilson‘s disease in patients presenting up to age 50 has become common, though some cases of Wilson’s have presented as late as the mid-60s. The vast majority present earlier (Sohtaoglu et al., 2007). Patients with focal neurologic abnormalities referable to the spinal cord or brain should be examined with magnetic resonance imaging (MRI). Medication reconciliation should exclude current or previous history of neuroleptic exposure or other related compounds (e.g., metoclopramide and phenergan). A targeted family history is essential, and one should inquire about specific symptoms suggestive of dystonia in other family members. A family history suggestive of dystonia, along with other historical or clinical features suggestive of a genetic form of dystonia, should lead the clinician to consider genetic counseling and testing (see Chapters 39–41 for further details). The examination should explore other neurological signs suggestive of secondary causes of dystonia, e.g., the presence of other unexplained neurological findings. The presence of ataxia with CD may suggest spinocerebellar ataxia 3, 7, or 17 (Lang et al., 1994; Modi et al., 2000; Hagenah et al., 2004). Specific maneuvers are extremely helpful, particularly if considering botulinum toxin therapy. Greater deviation of head posture once visual fixation is removed by asking the patient to close the eyes can be observed. The patient’s neck and shoulder should be palpated to determine degree and distribution of muscle spasm. Management of CD should include consideration of comorbidities frequently associated with CD and other dystonias, including anxiety and depression (Pekmezovic et al., 2009).

WRITER’S CRAMP DYSTONIA Focal dystonia that affects muscles controlling hand movements during writing or performing other skilled tasks is referred to as “writer’s cramp.” This may be considered a minor disability for some people; however, it can be a serious problem if one’s employment depends on writing. Writer’s cramp can be divided into two groups: simple writer’s cramp and dystonic writer’s cramp (Sheehy and Marsden, 1982). In the former, difficulty occurs only when writing, whereas in

ADULT-ONSET DYSTONIA 491 the latter, tasks such as shaving or handling a knife and Etiology and differential diagnosis fork are also impaired. Some prefer the term “complex Excessive hand use is thought to have a potential role writer’s cramp” as dystonic writer’s cramp may sugin the development of focal hand dystonia as it develgest that simple writer’s cramp is not dystonic (Jedynak ops on the side and in the muscles most frequently et al., 2001). used. However, many people use their hands excessively and do not develop dystonia. Jedynak et al. Clinical features and natural history (2001) noted that less than half of their patients with writer’s cramp had a history of intensive writing before Most patients experience the onset of symptoms symptom onset. Although controversial, trauma has between the ages of 20 and 50 years (Sheehy and been suggested as a trigger for dystonia in susceptible Marsden, 1982). Unlike other adult-onset focal dystoindividuals (Jankovic, 2001). nias, writer’s cramp occurs more frequently in men than Even though most cases are sporadic, a positive women. Patients often initially note a subtle change in family history may be noted in 5%. Isolated unilateral the quality of their handwriting. Jedynak et al. (2001) or bilateral writer’s cramp, whether sporadic or famildescribed several dystonic features in 65 patients with ial, was only rarely a phenotypic manifestation of the writer’s cramp. Common patterns included excessive DYT1 GAG deletion (Kamm et al., 2000). However, pen pressure and hypertonia, excessive wrist flexion or the possibility should be considered if a clear family extension, elbow elevation, and excessive wrist pronahistory of early limb-onset dystonia was present or if tion. Writing becomes slow and tedious and the quality it occurred in juvenile cases. Recently three brothers of the handwriting deteriorates as writing continues. with very-late-onset dystonic writer’s cramp (age Some patients note that their hand “locks up,” while ranges from 65 to 75 years) were described with linkothers note their hand jerks across the page or exhibits age to the DYT7 locus on chromosome 18 (Bhidayasiri tremor. Patients may use compensatory movements et al., 2005). such as elevating the elbow or adducting the shoulder Common misdiagnoses include overuse syndrome to facilitate writing. Discomfort is not uncommon, due (repetitive stress injury), entrapment neuropathies, to excessive and inappropriate muscle contraction, but complex regional pain syndrome (CRPS), primary severe pain is unusual. Repeated dystonic spasms of writing tremor, and psychogenic dystonia. Overuse the wrist may cause carpal tunnel syndrome (Marsden syndrome causes hand pain, but without loss of funcand Sheehy, 1990). Tremor may be seen in about a third tion, and is most often due to tenosynovitis. It can be of patients with writer’s cramp, leading to a diagnosis precipitated by repetitive, stressful hand use. Treatof primary writing tremor (Sheehy and Marsden, 1982). ment is rest and anti-inflammatory medications (Karp, Patients may try a thicker pen to help their writing, 2004). CRPS is associated with pain, autonomic although this typically is ineffective. They may also dysfunction, and trophic changes, usually following learn to write with the other hand. However, in 25– an injury to the extremity. Dystonic-like posturing 30% of cases the opposite hand also becomes involved may be seen with CRPS, but it may be fixed, painful, within months to years (Marsden and Sheehy, 1990). and present during sleep. Treatment of CRPS focuses Patients may use a “sensory trick” to lessen dystonic on pain control and may include medications or sympasymptoms, including touching the writing hand with thetic block. the contralateral hand. Weakness or sensory loss in the distribution of the Neurologic examination is unremarkable except for median or ulnar nerves suggests entrapment neuropathe dystonic movements observed during writing. Labthy. Routine nerve conduction studies can be peroratory and neuroimaging tests are seldom needed in formed to help with the diagnosis. Carpal tunnel typical cases. Occasionally a slight reduction in arm syndrome does not appear to be related, but ulnar neuswing or a slight increase in tone may be noted. Mirror ropathy can be associated with changes similar to those movements may also be seen; this can be demonstrated of focal hand dystonia in musicians (Charness et al., by writing with the unaffected hand and provoking 1996). dystonic posturing of the affected hand (so-called mirPrimary writing tremor is a task-specific tremor that ror dystonia). Such maneuvers may be helpful in distinoccurs predominantly during writing. Some consider guishing compensatory movements from the primary this a form of focal dystonia, although patients with dystonic movements if botulinum toxin injections are primary writing tremor often do not exhibit dystonia planned. Spontaneous remissions are rare, but may (Lang, 1990). On the other hand, tremor is known to occur in the first few years in about 5% of patients. occur in writer’s cramp (Sheehy and Marsden, 1982). Although remissions may last for months or years, Finally, psychogenic dystonia should be considered recurrence is common (Marsden and Sheehy, 1990).

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when there is an abrupt onset, rapid progression to fixed postures, and nonphysiologic weakness or sensory loss (Lang, 1995).

Evaluation and treatment Alternative forms of treatment have been tried by some for various types of dystonia, including writer’s cramp. Many interventions have been tried to improve writer’s cramp, but the results have generally been disappointing for long-term success. It has been conjectured that sensory training could improve dystonia. Several patients with focal hand dystonia who learned to read Braille and practiced this skill (blindfolded) for 30–60 minutes daily showed improvement in writing for up to 1 year (Zeuner and Hallett, 2003). Siebner and colleagues (1999), using slow repetitive transcranial magnetic stimulation over the contralateral motor hand area, reported marked or moderate improvement in handwriting for 3 hours in eight of 16 patients. Their data supported the notion that this treatment can reinforce deficient intracortical inhibition (reducing excitability) of the underlying cortex. Transcutaneous electrical nerve stimulation (TENS) for writer’s cramp was studied in a randomized, placebo-controlled study by Tinazzi and colleagues (2005). The group, treated for 2 weeks, showed a significant improvement in various measures that lasted for 3 weeks. They hypothesized that TENS treatment improved dystonia by promoting a reshaping of reciprocal excitatory and inhibitory functions between agonist and antagonist muscles in the central nervous system that are impaired in dystonia. Pohl and colleagues (2002) studied the effect of cooled hand and forearm muscles after immersion in 1  C water for 5 minutes in 10 patients. They observed decreased writing speed and improved writing ability for 25 minutes in 7 patients. It was felt that improvement might be due to reduced muscle spindle activity. Upper-limb immobilization for 4–5 weeks was studied in eight patients with focal occupational dystonia (Priori et al., 2001). Patients wore a splint for 24 hours/day and removed it once a week for 10 minutes for local hygiene. Immediately after removing the splint all patients reported marked clumsiness and weakness, which resolved in 4 weeks. There was substantial improvement in one patient for up to 12 months and in six other patients for several months. The authors postulated that prolonged immobilization could normalize the abnormally enlarged cortical representation of dystonic muscles. Tas and colleagues (2001) used a thermoplastic hand orthosis on five patients with writer’s cramp and showed improved writing ability. They believed that, by applying the hand orthosis, patients substituted

the action of the distal muscles with the unaffected proximal muscles. Other alternative treatments included acupuncture, relaxation techniques, homeopathy, and massages. However, in a survey of dystonia patients who had used alternative therapies, only 6% preferred alternative treatments to conventional therapy (Junker et al., 2004). While some patients reported these treatments helpful, they are not considered routine and their effectiveness has not been rigorously evaluated.

NEUROANATOMY AND NEUROPHYSIOLOGY Historically, the anatomic substrate of dystonia has been presumed to be the basal ganglia, based on the occurrence of symptomatic dystonia (Marsden et al., 1985; Jankovic, 1986). However, cranial dystonia, particularly blepharospasm, data have pointed more to abnormal brainstem physiology (Jankovic and Patel, 1983; Aramideh et al., 1996; Nair, 1997). Postulated anatomic substrates for blinking include the cingulate, primary motor cortex and amygdalae (Hallett et al., 2008). Positron emission tomography (PET) imaging studies of idiopathic cases have attempted to elucidate whether cortical, basal ganglia, or brainstem circuitry changes are dominant (Table 37.4). Using fluorodexyglucose (FDG) tracer, one study of 11 blepharospasm patients and controls demonstrated increased metabolism in the right caudate nucleus, inferior frontal gyri, right posterior and left anterior cingulate, left occipital gyrus, and the fusiform gyrus of the right temporal lobe; decreased metabolism was seen in the inferior frontal gyri ventral to the area of increased activity, thalamus and left inferior cerebellar hemisphere (Kerrison et al., 2003). Another FDG-PET study of six patients and controls using statistical parametric mapping concluded that the frontal eye field abnormality was the functional substrate for the blepharospasm, similar to that seen in primary generalized dystonia, and the pons and cerebellum are important in generating the movements (Hutchinson et al., 2000). One additional paper on 10 patients with blepharospasm demonstrated increased metabolism in the striatum and thalami but there was no control group (Esmaeli-Gutstein et al., 1999). A case-control PET study with [18F]spiperone binding demonstrated a reduction in putaminal D2 receptors, suggesting dysfunction of the indirect pathway in cranial dystonia (Perlmutter et al., 1997). Taken together, these studies suggest abnormalities in all three components (cortex, basal ganglia, and brainstem).

Table 37.4 Imaging studies Reference

Imaging technique

Population

Kerrison et al. (2003)

FDG

Hutchinson et al. (2000)

FDG PET study

11 blepharospasm and ↑ metabolism in: controls right caudate nucleus, inferior frontal gyri, right posterior left anterior cingulated, left occipital gyrus, fusiform gyrus of the right temporal lobe # metabolism inferior frontal gyri (ventral to the area of increased activity, thalamus, left inferior cerebellar hemisphere Abnormal metabolic rates were 6 patients and found in the cerebellum and controls using pons while awake, and statistical superior frontal eye fields parametric while asleep mapping

EsmaeliGutstein et al. (1999) Perlmutter et al. PET study: [18F] (1997) spiperone binding Galardi et al. (1996)

PET study [18F]FDG

Etgen et al. (2006)

MRI – VBM

Obermann et al. MRI – VBM (2007)

10 patients with blepharospasm

Results

Comments

Frontal eye field abnormality was the functional substrate for the blepharospasm, similar to that seen in primary generalized dystonia, and the pons and cerebellum are important in generating the movements ↑ metabolism in the striatum and No control group thalami

21 patients with focal Demonstrated a reduction in limb and cranial putaminal D2 receptors dystonia and 13 controls ↑ metabolism in the basal 10 patients with ganglia, thalamus, premotoridiopathic motor cortex and cerebellum torticollis (6 drugin the patients compared with free and 4 drugnormal controls naive) and 15 normal controls 16 patients and controls

Suggesting dysfunction of the indirect pathway in cranial dystonia

Support the hypothesis that a dysfunction of a subcortical-cortical motor network may play a role in the pathogenesis of focal dystonia Increased gray matter in the caudate head and cerebellum and decreased in the putamen and thalamus (all bilateral) 11 BEB, 9 CD, and 14 CD subjects ↑ gray matter in the Idiopathic focal dystonias may have a structural thalamus, caudate head healthy control correlate bilaterally, superior temporal subjects Structural similarities of the lobe, and left cerebellum focal dystonias may reflect # gray matter in the putamen a shared common bilaterally pathophysiology BEB subjects ↑ gray matter in the caudate head and cerebellum bilaterally # in the putamen and thalamus bilaterally. Pathophysiological origin

fMRI Continued

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Table 37.4 Continued Reference

Imaging technique

Population

Results

Black et al. (1998)

High-resolution MRI

Draganski et al. (2003)

MRI – VBM voxel-based morphometry

13 adults with cranial Putamen was 10% larger in or hand dystonia patients and 13 normal individuals 10 patients with CD ↑ in gray-matter density with that of 10 bilaterally in the motor cortex healthy control and in the cerebellar flocculus subjects and unilaterally in the right globus pallidus internus

Comments

FDG, fluorodeoxyglucose; PET, positron emission tomography; MRI, magnetic resonance imaging; VBM, voxel-based morphometry; BEB, benign essential blepharospasm; CD, cervical dystonia; fMRI, functional magnetic resonance imaging.

MRI studies using different techniques have been used to study blepharospasm. Studies using voxelbased morphometry (VBM) demonstrated increased gray matter in the putamen and decreased gray matter in the left parietal lobe (Etgen et al., 2006), increased gray matter in the caudate head and cerebellum, and decreased in the putamen and thalamus (all bilateral) (Obermann et al., 2007). Several functional MRI (fMRI) studies have been reported. One examined 13 patients with blepharospasm, 13 patients with blepharospasm plus OMD (combined group), and 13 controls (Dresel et al., 2006). While whistling, the combined group demonstrated deficient activation of the primary motor and ventral premotor cortices specific to the oromandibular representation area. This phenomenon had the functional correlate of reduced cortical inhibition. In both groups (compared to controls) there was increased activation in the bilateral somatosensory areas and caudal supplementary motor areas, which indicated altered somatosensory representation in the orofacial region (Dresel et al., 2006). fMRI with correlated blood oxygenation level dependent signal was utilized in two small studies and demonstrated activation of subregions of the putamen in one and activation of the anterior visual cortex, anterior cingulate, primary motor cortex, thalamus, and cerebellum, but not putamen in the other (Baker et al., 2003; Schmidt et al., 2003). Much work remains in deciphering the results of these studies. Others have sought to find anatomic changes in patients with focal dystonias, although without autopsy confirmation. Using two different MRI volumetric methods, one study demonstrated that patients with

idiopathic focal dystonia had a 10% increase of putamen volume compared to controls (Black et al., 1998). They did not know if this was a cause of the dystonia or perhaps a consequence of it. Another study using VBM noted a significant gray-matter increase in the right globus pallidus internus (GPi) on MRI, as well as bilaterally in the motor cortex and cerebellar flocculus in patients with idiopathic CD (Draganski et al., 2003). They also noted that the increase in GPi gray matter could be the cause or the consequence of CD. LeDoux and Brady (2003) described 4 of their own cases and reviewed 21 others with secondary CD associated with central nervous system lesions. Eleven cases (44%) were associated with structural lesions of the brainstem and/or cerebellum while the cervical spinal cord and basal ganglia were both involved in six patients (24%). They postulated that the cerebellar afferent pathways may be important to the pathophysiology of CD. The pathophysiological changes that result in dystonic movements remain a mystery. Multiple environmental factors and/or genetic susceptibility may coalesce in a given patient to promote the development of focal dystonia. Stroke and traumatic brain injury are known causes of CD (Kwak and Jankovic, 2002; Zadro et al., 2008). However, whether peripheral trauma may contribute to CD has been debated (Jankovic, 2001; Weiner, 2001) and was recently reviewed by van Hilten et al. (2007). The existence of focal dystonias with autosomal-dominant reduced penetrance inheritance patterns, along with a positive family history in 12% of patients (Chan et al., 1991), suggests some patients may have a genetic predisposition to developing CD (Almasy et al., 1997a, b; Leube et al., 1996, 1997a, b, c).

ADULT-ONSET DYSTONIA However, the low penetrance rates in known kindreds also supports the idea that other factors are necessary for the development of CD. Although the physiology of CD is poorly understood, dopamine signaling, particularly of the D2 receptors, is thought to be deficient (Singer and Velickovic, 2008). The leading hypotheses are briefly described below, and more extensively reviewed by Singer and Velickovic (2008) and Hallett (2006).

Loss of inhibition Mink (2003) hypothesized that hyperactivity of the direct GABAergic striatopallidal pathway “overinhibits” the GPi, thereby disinhibiting cortical activity. Berardelli et al. (1998) proposed that loss of inhibitory input from the motor cortex is associated with hyperactivity of the direct striatopallidal pathway and thalamocortical disinhibition. These hypotheses could explain the co-contractions and overflow contractions into muscles not typically activated in a given task that characterize all forms of dystonia (Cohen and Hallett, 1988). EMG reveals findings of co-contraction of agonist and antagonist muscles with abnormally prolonged EMG bursts in the active muscles. At the spinal level, reciprocal inhibition is defective, leading to a diminished ability to inhibit antagonist muscle activity during agonist contraction. There are data to support this hypothesis in blepharospasm. There is an increased blink rate in patients with blepharospasm, especially during conversation as compared to at rest. This is the opposite of that seen in normal individuals (Bentivoglio et al., 2006; Hallett et al., 2008). Talking could represent a form of trick in blepharospasm patients. The blink reflex, elicited by electrical stimulation of the supraorbital nerve and recording from the orbicularis oculi bilaterally, has been a prime area for the study of the physiology of blepharospasm. It explores the trigeminofacial pathways in the brainstem. The response consists of two components, an early response (R1), which is ipsilateral and an oligosynaptic arc, and a late response (R2), which is bilateral, and a polysynaptic pathway, and is longer in duration. In patients with blepharospasm the R2 response of the blink reflex has increased amplitude and recovery cycle to single stimulation and paired stimulation leads to a shortened recovery cycle, indicating lack of inhibition and enhanced excitability of interneurons. Sensory tricks with fingers touching the face increase R1 and decrease area of R2 (Gomez-Wong et al., 1998). This indicates a sensory gating on the trigeminal afferents. High-frequency stimulation of the supraorbital nerve results in markedly increased facilitation of the R2 response in

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patients relative to controls, indicating increased plasticity of interneurons in the trigeminal reflex circuit (Berardelli and Curra, 2002; Hallett, 2002; Quartarone et al., 2006; Satija and Ondo, 2007; Hallett et al., 2008). Chen et al. (1995) investigated reciprocal inhibition between forearm muscles in 13 patients with writer’s cramp using median H-reflexes. They found the amplitudes of inhibition to be significantly less than the control group. Similar abnormal patterns of reciprocal inhibition have been reported in the asymptomatic hands of patients with writer’s cramp. Tempel and Perlmutter (1993), using PET and H2O15 blood flow scans, found that patients with unilateral writer’s cramp had bilateral brain dysfunction and the degree of abnormal cortical responses was equal in the two hemispheres. The findings of these two studies may help explain the increased propensity for the contralateral hand to develop writer’s cramp if the person switches hands to write, the occurrence of mirror dystonia, and also lends credence to the possibility of loss of inhibition contributing to the emergence of dystonic symptoms. Disturbance of surround inhibition may also be important in dystonia. The concept of surround inhibition involves the suppression of unwanted movements, allowing the production of a more precise movement (Hallett, 2006). Surround inhibition was studied in patients with focal hand dystonia (Sohn and Hallett, 2004). The authors showed, using transcranial magnetic stimulation, that the motor evoked potentials were enhanced in the flexor digitorum superficialis and abductor digiti minimi, indicating a failure of surround inhibition in the motor cortex.

Sensory deficit/sensorimotor mismatch Although commonly thought of as a motor disorder, more recently it has been suggested that dystonia could primarily be a sensory disorder (Hallett, 1995). An abnormality of the brain’s sensory spatial discrimination (Molloy et al., 2003) or an inability to “match” sensory input to motor output could explain the characteristic agonist-antagonist co-contraction seen in CD and other dystonias. Such a mechanism could also explain the gestes in so many CD patients. Patients may report sensory symptoms and “sensory tricks” may alleviate the involuntary movements. Kaji et al. (1995) showed that vibration in the palm or the tendon of the forearm muscles induced dystonic postures or movements typical of those seen during writing. Vibration activates many types of sensory fibers, but particularly spinal afferents. Blocking the action of muscle afferents with lidocaine abolished or markedly reduced

496 M.L. EVATT ET AL. symptoms in patients with writer’s cramp. A quantitareorganization of the motor cortex in CD patients, tive evaluation of somatosensory spatial frequency lending support to the notion that aberrant neuroplastiand single-touch localization demonstrated that city has a role in the pathophysiology of CD. patients with focal hand dystonia had decreased ability to discriminate stimuli closely related spatially, with PATHOLOGY OF PRIMARY FOCAL higher spatial localization error and an increased DYSTONIAS threshold for spatial frequency discrimination (BaraAlthough primary focal dystonias are commonly Jimenez et al., 2000). These results supported the seen in movement disorders clinics, not many pathoconcept that abnormal sensory processing may be logic descriptions exist. Tarlov (1970) reported a relevant in the pathogenesis of dystonia. 65-year-old woman who had a 6-year history of spasIn a study using magnetoencephalography, alteramodic torticollis prior to her death. At that time some tions in somatosensory representation of the digits in neurologists held the view that spasmodic torticollis patients with focal hand dystonia were demonstrated was a conversion disorder. The patient had a psychiatric (McKenzie et al., 2003). PET studies in writer’s cramp evaluation, but no apparent psychological cause was showed particularly notable overactivity for subjects noted for her problem. In addition to an unsuccessful with dystonia in the primary somatosensory cortex as trial of medications, an attempt at deconditioning was well as in the primary sensory cortex during a writing tried. She was fitted with a special collar which delivtask (Lerner et al., 2004). VBM showed a significant ered an electric shock when her head went to the abnorbilateral increase in gray matter in the hand representamal position; however, this did not help. Immediately tion area of primary somatosensory cortices in 36 after her death in 1962 an autopsy was performed. The patients with unilateral focal hand dystonia compared gross appearance of the brain and spinal cord was with 36 controls (Garraux et al., 2004). Brain structures normal. Microscopic examination was also normal with interconnected within the sensorimotor network, includno histological abnormalities to account for the torticoling the cerebellum and the cortical representation of the lis. Tarlov (1970) reasoned that this did not support affected body part, can demonstrate structural abnormthe diagnosis of conversion disorder, but noted that alities (Delmaire et al., 2007). All of these observations histological methods have certain limitations. seem to indicate that dystonia is a sensory as well as a Garcia-Albea et al. (1981) reported a patient who motor disorder. died with Meige’s syndrome. Their patient was a 62-year-old female with a 6-year history of jaw spasms Aberrant neuroplasticity and blepharospasm. A psychiatric examination was Neural plasticity is the term given to the process by normal. She was treated with various medications, which neuronal circuits are modified by experience but did not benefit. Autopsy findings were normal. and learning, and in response to brain lesions. The techThey felt that the mechanism of disease should be nique of paired associative stimulation – low-frequency searched for at the molecular level, and might be a median nerve stimulation with transcranial magnetic disorder of catecholamine metabolism or striatal dopastimulation – induced abnormal plasticity of the human mine preponderance. motor cortex in 10 writer’s cramp patients but not 10 Altrocchi and Forno (1983) describe a Filipino man controls (Quartarone et al., 2003). The magnitude of with spontaneous oral-facial dyskinesia. The main the increase of the motor evoked potential (from both microscopic abnormalities were limited to the dorsal the abductor pollicis brevis and first dorsal interosseus halves of the caudate and putamen. This showed a muscles) substantially exceeded that of the healthy conunique pattern of uneven neuronal loss and severe trols. The brain’s response to paired associative stimulagliosis involving the dorsal halves of the caudate and tion was exaggerated and its spatial specificity was putamen throughout their entire length, with small reduced in writer’s cramp. islands of unaffected normal cells giving a mosaic In a primate model of focal motor hand dystonia in appearance. The brainstem was normal. They noted which reorganization of sensory networks occurs (Byl that no other basal ganglia disease had shown this et al., 1996), patients improved cortical somatosensory unique mosaic pattern. responses and clinical motor function after individuaFactor and Barron (1997) similarly described the lized sensorimotor training consistent with neuroplastimosaic pattern of gliosis in the neostriatum of a North city (Byl et al., 2003). Intraoperative recordings American-born 51-year-old male with craniocervical demonstrate a higher prevalence of similar reorganizadystonia and parkinsonism. Brainstem findings were tion in patients with dystonia (Lenz and Byl, 1999). normal. Even though the patient had parkinsonism, Thickbroom et al. (2003) demonstrated reversible the substantia nigra showed no neuronal loss, Lewy

ADULT-ONSET DYSTONIA 497 bodies, or gliosis. The authors felt, based on the patholof onset was 59 years and the mean disease duration ogy of their case, that craniocervical dystonia could be was 17 years. They were unable to detect brainstem pericaused by lesions of the caudate and putamen. Striatal nuclear inclusion bodies, as had been seen in patients with mosaicism has also been described in a non-Filipino DYT1 dystonia (McNaught et al., 2004). There was no loss patient with severe generalized dystonia (Gibb et al., of the striatal striosome compartment. One case dis1992) and in a 34-year-old Filipino male with Lubag played Alzheimer pathology and a small number of Lewy (X-linked dystonia parkinsonism) (Waters et al., 1993). bodies in the brainstem. The authors concluded that, Kulisevsky et al. (1988) published the autopsy based on their pathology as well as lack of consistent results of a 72-year-old man with a 4-year history of pathologic findings from other reports, including normal Meige’s syndrome. The pathologic examination brain, functional and metabolic disturbances are likely showed abnormalities in several brainstem nuclei, to play a role in the pathogenesis of dystonia. including substantia nigra, locus ceruleus, and midTREATMENT brain tectum, as well as moderate neuronal loss and gliosis in the dentate nuclei. No abnormalities were Medical therapy noted in the striatum or other central nervous system Medical treatment for all forms of dystonia has not structures. Lewy bodies were noted in 1.7% of neurons changed in three decades. Unfortunately, less than half per section of pars compacta of the substantia nigra of dystonic patients respond to medical therapy, and and 14.4% of neurons of the locus ceruleus. The usually they respond incompletely (Greene et al., authors felt that brainstem pathology was important 1988a; Satija and Ondo, 2007). Table 37.5 lists medicain the pathophysiology of primary Meige’s syndrome. tions reported to have benefited patients with dystonia. Mark et al. (1994) reported a patient with Meige’s All these medications tend to have adverse effect syndrome with neuropathologic findings of typical profiles that limit their usefulness while offering relaand atypical Lewy bodies in pigmented nuclei of tively less effectiveness compared with botulinum the brainstem. They concluded that, even though the toxin injections. In general, these medications are not patient was not clinically parkinsonian, based on effective for writer’s cramp and SD. the autopsy results, Meige’s syndrome with Lewy Because of the dramatic effect of levodopa on bodies could be part of the spectrum of preclinical dopa-responsive dystonia and its phenotypic heterogeParkinson’s disease. neity, each patient with dystonia should be tried on In 1988 two papers described pathologic findings levodopa. Initial doses should be low, increasing to in patients with primary dystonia. Zweig et al. (1988) 600 mg/day for 3 months, although some patients have published autopsy results of four patients, one with required doses as high as 1000 mg/day for as long as Meige’s syndrome, one with spasmodic torticollis, and 6 months to respond (Jankovic, 1998; Robinson et al., two with dystonia muscularum deformans. Findings in 1999). If there is no benefit, withdraw levodopa and the patient with Meige’s syndrome showed moderate consider other therapeutic options. to severe neuronal cell loss in several brainstem nuclei, The most widely accepted group of medications including the substantia nigra, pars compacta, dorsal utilized in the treatment of dystonia is the anticholinerraphe, pedunculopontine nucleus, and locus ceruleus. gic group: trihexyphenidyl, benzatropine, or ethopropaNo abnormalities were noted in the basal ganglia. zine (Fahn, 1983a; Greene et al., 1988a). With the Neuropathology on the 50-year-old woman with a 3-year exception of trihexyphenidyl, none of the medical history of spasmodic torticollis was unremarkable. therapies has undergone double-blinded clinical trials Gibb et al. (1988) described the pathology of four with results reported in peer-reviewed literature (Burke patients presenting with cranial dystonia (two with blephet al., 1986). Pyridostigmine, a peripheral cholinesterase arospasm and OMD, one with blepharospasm, and one inhibitor, can be considered for managing cholinergic with OMD with retrocollis). The patient with only blephside-effects, though we are not aware of double-blind arospasm had a 5-mm angioma in the dorsal pontine trials confirming its efficacy. tegmentum without any other abnormal findings. The Both dopaminergic and dopa-blocking medications other three brains showed no abnormal findings. Bhatia have been reported to improve dystonia. Because dyset al. (1993) reported a patient with orofacial dystonia tonia appears to be due to increased activity in both and rest tremor with normal brain pathology. the indirect and direct striatopallidal pathways, in a Holton et al. (2008) described six patients who develgiven patient, dopaminomimetic or dopamine antagooped dystonia late in life affecting the neck (four nists could improve symptoms, depending on which patients), the eyes (blepharospasm, three patients), oroof the two pathways was dominant. Dopamine antagomandibular region (three patients), the paraspinal muscles nists are not recommended because of their propensity (one patient), and the arms (two patients). The mean age

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Table 37.5 Medications reported beneficial for adult-onset focal dystonia Medication

Reference

Most commonly prescribed Anticholinergic Burke et al. agents (1986)

Baclofen

Greene (1992)

Benzodiazepines

Greene et al. (1988b)

Other agents Clozapine

Mechanism of action

Dose

Data supporting their use

Comments

Side-effects often, Trihexyphenidyl Double-blind, Tertiary unblinded 1–10 mg given t.i.d. placeboantimuscarinic investigators and/or to q.i.d. controlled trial; agent patients to treatment dose range 5–120 Acetylcholine assignment mg daily receptor CNS side-effects are antagonism of common, and CNS and smooth elderly are muscle particularly sensitive Discontinue slowly to avoid NMS (Spivak et al., 1996) GABA-B agonist 10–30 mg t.i.d. Retrospective case Intrathecal baclofen to q.i.d. series reported in a case report (Dykstra et al., 2005) Long-acting Clonazepam “Delphinian” GABAergicbenzodiazepines are 0.25–2 mg daily agreement induced CNS typically preferred. Diazepam 0.5–30 mg No double-blind depression, Caution should be used daily randomized sedation, muscle in prescribing shortclinical trials relaxation acting demonstrating benzodiazepines, as efficacy rebound dystonia Single open-label effects may lead to trial (Greene escalating doses et al., 1988b) May be helpful in managing anxiety disorders that are a frequent comorbidity of CD

Burbaud et al. Atypical antipsychotic (1998), Karp et al. (1999)

Clozaril 12.5–100 mg

2 open-label trials; may be more effective for reducing spasmodic component (Burbaud et al., 1998)

Requires stringent monitoring of WBC

200–800 mg/day b.i.d.

2 open-label trials completed and reported. One randomized crossover trial completed

Side-effects include dizziness at higher doses

Dopaminergic medications Mexiletine

Ohara et al. Antiarrhythmic (1997, 1998), with properties Lucetti et al. similar to (2000) lidocaine – postulated central and peripheral mechanism

ADULT-ONSET DYSTONIA

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Table 37.5 Continued Medication

Reference

Mechanism of action

Dose

Data supporting their use

Riluzole

Muller et al. (2002c)

Glutamate antagonist thought to modulate glutamate release

50 mg b.i.d.

Tetrabenazine

Greene (1992), Benzoquinolizine Jankovic and derivative that Beach (1997) depletes catecholamines presynaptically

Reserpine

Fahn (1983b), Kang et al. (1986), Raffaele et al. (1988)

Open-label trial in 6 patients refractory to botulinum toxin type A and other oral pharmacotherapy Recently approved in Open-label the USA for the experience over treatment of 15 years shows Huntington’s chorea over 60% improvement in idiopathic dystonia, but has not been subjected to double-blinded trials in CD Retrospective chart Virtually all reports review use reserpine for tardive dystonia. Depression is a common side-effect

Dopaminedepleting

0.25–9 mg/day

Comments

CNS, central nervous system; NMS, neuroleptic malignant syndrome; GABA, gamma-amino butyric acid; CD, cervical dystonia; WBC, white blood cell counts.

to cause tardive dyskinesia. However, the dopaminedepleting agents tetrabenazine and reserpine are beneficial in approximately 30% of patients (Greene et al., 1988a, b; Jankovic and Nutt, 1988). Mixed results with baclofen, carbamazepine, benzodiazepines (particularly clonazepam and diazepam), mexilitine, and clozapine have been observed but these are frequently utilized nevertheless, especially in patients unresponsive to anticholinergics (Greene et al., 1988a).

Botulinum toxin injections For most focal or segmental dystonia patients whose symptoms are severe enough to warrant therapy, botulinum toxin injections are the treatment of choice. Two of the seven botulinum toxin serotypes, types A and B, are commercially available for treatment of CD. While the specific site of action differs between the toxins, the clinical effect is the same: botulinum toxins block the release of acetylcholine from the nerve terminals at the neuromuscular junction. The toxins are injected

into targeted muscles, with or without EMG guidance, depending on the muscles involved and injecting physician’s preference. Worldwide, three formulations of botulinum toxin A are commercially available: BotoxW, DysportW, and XeominW. One formulation of botulinum toxin type B is commercially available: MyoblocW (NeuroblocW outside the USA). Table 37.6 lists the commercially available serotypes and brands of botulinum toxin, along with common dosages. Importantly, even though the units for botulinum toxins are derived in a similar manner (1 unit represents the LD50 for a particular strain of mouse), the units for each brand name are not interchangeable. For cranial dystonia, botulinum toxin injections provide substantial improvement. Many of the data are available on the original formulation of botulinum toxin type A (BotoxW). While BotoxW has become the standard of care for blepharospasm, other type A toxins are currently being examined: DysportW, XeominW, and Prosigne. These have been compared to BotoxW in large controlled blinded trials and found to be similar

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Table 37.6 Botulinum toxins used in clinical practice – toxins available worldwide, including dose ranges reported effective in the literature Toxin serotype

Availability

Type of dystonia

Typical total dose

Reference

BotoxW (type A)

Worldwide

40–50 U 50–200 U 5–150 U (per muscle)

Myobloc/NeuroblocW (type B)

Worldwide

BEB OMD CD Limb BEB CD

DysportW (type A)

Europe

BEB CD

250 U (range 16–500 U) 400 U (range 63–1045 U)

XeominW (lyophilized preparation of type A)

Europe

BEB CD

Up to 70 U 70–300 U

Nussgens and Roggenkamper, (1997) Clark (2003) Pullman et al. (1996) Colosimo et al. (2003), Barnes et al. (2005), Berman et al. (2005), Bhidayasiri et al. (2006), Dutton et al. (2006) Van den Bergh et al. (1995), Marchetti et al. (2005), Truong et al. (2008) Benecke et al. (2005), Jost et al. (2005, 2007), Roggenkamper et al. (2006), Wohlfarth et al., (2007)

2400–6200 U reported 2500–5000 U initially Up to 28 000 U reported

BEB, benign essential blepharospasm; OMD, oromandibular dystonia; CD, cervical dystonia.

in efficacy, duration of effect, and safety (Nussgens and Roggenkamper, 1997; Roggenkamper et al., 2006; Rieder et al., 2007). For blepharospasm the earliest results of injection into the orbicularis oculi were reported by Frueh et al. (1984) in 22 patients and Scott et al. (1985) with 39 patients. Since then a number of open studies reported responsiveness of 70–93% of patients (Mauriello, 1985; Dutton and Buckley, 1986; Brin et al., 1987; Kraft and Lang, 1988; Jankovic et al., 1990; Calace et al., 2003). The effect was so dramatic that few double-blind trials have been completed and they were small in patient number (Simpson et al., 2008). One showed significant effects similar to the open trials:
70% improvement by clinical rating (Jankovic and Orman, 1987). An evidence-based review indicated that there was level B evidence because of lack of controlled trials (Simpson et al., 2008). The magnitude of effects in patients in open trials and lack of other effective therapies probably resulted in few controlled studies being done (Simpson et al., 2008). One open study demonstrated that botulinum injections improved not only motor features but also quality of life and depression secondary to the disorder (Ochudlo et al., 2007). Long-term responsiveness has been demonstrated (Calace et al., 2003). The frequency of secondary immunoresistance is low because of low dose requirements. Adverse effects include ptosis, diplopia, and increased tearing, all of which are transient. There have been few publications on the use of botulinum toxin type B (Myobloc/NeuroblocW) in

blepharospasm and those that are available are openlabel experience in small patient numbers and in mostly type A-resistant cases (Colosimo et al., 2003; Dutton et al., 2006). The effects have been considered good, similar to type A in some cases, with doses of approximately 3500 units. Although types A and B purportedly differ in the degree of injection site pain, due the relatively acid pH of type B (MyoblocW), no difference was found in the ABCD trial for CD (type A pain ¼ 4.9 (sd 2.6), discomfort ¼ 4.7 (sd 2.8); type B pain ¼ 5.1 (sd 3.1), discomfort ¼ 4.7 (sd 3.0); all P-values > 0.05) (Comella et al., 2005). Treatment of OMD is also frequently successful with type A toxin. The first double-blind study, in 1987 on nine patients, demonstrated improvement in 37.5% of patient’s evaluation, 20% improvement in examiner’s evaluation and video score, and 7% in self-assessment (Jankovic and Orman, 1987). The limited effects in these studies related to the injection of just masseters and digastrics without treatment of the pterygoids. Improvements are greater with the injection of these latter muscles. This was demonstrated in another study of 20 patients where all but one of the patients (95%) had some improvement (average 47%) of their symptoms with toxin injection (Blitzer et al., 1989). Long-term benefit has been demonstrated (Tan and Jankovic, 1999) and both jaw closing and opening respond equally. Injections can be made with EMG guidance into the pterygoid muscles (medial or lateral), the masseters, temporalis, and digastric muscles in varied combinations depending on whether the patient has jaw opening,

ADULT-ONSET DYSTONIA closing, or lateral deviation as the main manifestation. Doses for OMD range from 50 to 400 units botulinum toxin type A (BotoxW). In practice, 70–90% of patients improve and adverse effects are dysphagia and weakness of the soft palate that allows fluid to be regurgitated through the nose. Because high doses of the toxin are often necessary, secondary immunoresistance is a concern, although the actual frequency is unknown (Adler et al., 2002). We have also utilized type B toxin (MyoblocW) successfully in the same distributions at doses of 1000–20 000 units. Injection of toxin can also be beneficial for lingual protrusion dystonia. Two studies examined repeated injections in an open-label manner. The technique involves a submandibular approach with EMG guidance. Charles et al. (1997) treated nine patients with lingual protrusion dystonia: two idiopathic, six tardive, one neurodegenerative. Thirty-five injection sessions were completed over 5 years. Most of the patients (67%) reported improvement, and 83% of injections were ultimately successful. Dysphagia or dysarthria occurred in 14%. No significant weight loss was recorded. The authors used an average dose of 34 units (BotoxW botulinum toxin type A) and duration of effect was 15 weeks. In another study 10 patients – five idiopathic, four tardive, and one neurodegenerative – were treated (Esper et al., 2010). Of 96 total injections, 89% demonstrated improvement and 67% had excellent results. The dose of botulinum toxin type A (BotoxW) ranged from 5 to 30 units per genioglossus with an average of 12 units (total 24 units per session). Adverse effects, including dry mouth, dysphagia, and dysarthria, occurred in only 2.3% of the sessions. On one occasion, a patient developed severe dysphagia requiring feeding tube placement. Botulinum toxin is the most effective treatment available for SD. It was first utilized in 1984 with notable improvement (Blitzer et al., 1986; Hallett et al., 2009). There has been a single small (13 subjects) double-blind trial which demonstrated significant effectiveness compared to placebo (Truong et al., 1991). The rest of the studies are open-label; the largest experience reported is in 900 patients (Blitzer et al., 1998). It is likely that the dramatic results from open trials and lack of other effective therapies resulted in no further attempts at controlled trials. An evidencebased assessment suggested only level B recommendations for adductor dysphonia because of the lack of controlled trials and level U for abductor dysphonia because of insufficient evidence (Simpson et al., 2008). Injections can be given unilaterally (repetitive or alternating) or bilaterally (Brin et al., 1989; Adams et al., 1993; Koriwchak et al., 1996). The injections take 2–7 days to take effect, reach their peak in 9 days, and

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last 8–15 weeks (Hallett et al., 2009). For adductor injections, the thyroarytenoid is targeted and for abductor injection the posterior cricoarytenoid. The injections are done via the transcutaneous EMG-guided approach. Response for adductor dysphonia has been reported to be 90% recovery of the voice (Blitzer et al., 1998; Hallett et al., 2009). The average dose for bilateral injection is 1 unit (BotoxW botulinum toxin type A)/0.1 mL in each vocal cord and for unilateral 1.5 units (BotoxW botulinum toxin type A)/0.1 mL (Hallett et al., 2009). For abductor dysphonia the typical dose in the posterior cricoarytenoid is 3.75 units (BotoxW botulinum toxin type A). The response was 70% normal functioning with average onset in 4 days, peak in 10 days, and duration of 11 weeks (Blitzer et al., 1998). Long-term response has been demonstrated with a consistent dose over long periods (Damrose et al., 2004; Holden et al., 2007). Substantial improvement of quality of life has been demonstrated and it is independent of the time course of therapy (Bhattacharyya and Tarsy, 2001; Hogikyan et al., 2001; Rubin et al., 2004). Treatment of SD with botulinum toxin significantly lessened patients’ perception of dysphonia. In addition, it improved their social functioning and their perception of their mental health (Courey et al., 2000). The main adverse effects include a breathy voice (25%, usually mild) and dysphagia with coughing with fluids in 10% (Hallett et al., 2009). Resistance to type A toxin (BotoxW) is rare but has been reported (Smith and Ford, 2000; Park et al., 2003). In such cases botulinum toxin type B (MyoblocW) can be effective in doses up to 200 units per vocal cord (Park et al., 2003; Adler et al., 2004). Botulinum toxin injections are the treatment of choice for CD: both botulinum toxin A and B are approved by the Food and Drug Administration as effective and safe for the treatment of CD. BotoxW and Myobloc/NeuroblocW are equally effective for managing CD (Comella et al., 2005). Typically, muscle weakness and clinical improvement in pain and/or spasm are clinically evident 3–5 days postinjection. Maximal benefit occurs about 4 weeks postinjection and the benefit wanes about 8–12 weeks postinjection. Adverse reactions seen most commonly in injections for CD include dysphagia, dry mouth, and excessive neck muscle weakness. Controlled trials of botulinum toxin in CD demonstrated 60–90% relief of pain and/or spasm in most patients (Hallett et al., 2009). Dose of botoxW Botulinum toxin type A was first evaluated by Tsui et al. (1985) for treating CD in a single-blinded study of 12 patients. Subsequently, eight double-blind, placebo-controlled clinical trials have demonstrated effectiveness of botulinum toxin

502 M.L. EVATT ET AL. for the treatment of CD (Simpson et al., 2008). Three benefit at 5 years (Hsiung et al., 2002). Although botustudies demonstrated benefit of BotoxW for botulinum linum toxin injections can correct the abnormal posture toxin-naı¨ve patients (Greene et al., 1990; Brans et al., or relieve discomfort, patients may find normal hand 1996; Poewe et al., 1998) and one study demonstrated effifunction difficult to achieve. cacy of DysportW in previously treated patients (Truong et al., 2005). Three other studies assessed the safety and Surgery efficacy of Myobloc/NeuroblocW in patients known to Surgical therapy for cranial and CD can be divided into respond to botulinum toxin type A (Lew et al., 1997; peripheral and central procedures. Central procedures Brashear et al., 1999) as well as treatment-resistant involve either brain lesioning or deep-brain stimulation patients (Brin et al., 1999). (DBS) and peripheral procedures rely on selective Many years of experience have shown botulinum denervation or local dissection and removal of muscle toxin injections to be effective for writer’s cramp and tissue. other occupational dystonias. The patients should be Peripheral techniques have been described but are examined at rest and during writing as it is important diminishing in use and are utilized in patients who to identify the muscles causing the dystonia and distindevelop resistance to botulinum toxin (Satija and guish this from compensatory movements. Sometimes Ondo, 2007). They include: for blepharospasm, facial writing with the nondominant hand while the dominant nerve ablation and myectomy (Chapman et al., 1999; hand is at rest on the table will provoke mirror moveGeorgescu et al., 2008); for OMD, pterygoid myotments and help with correct muscle identification. omy (Balasubramaniam et al., 2008); and for SD, Injecting an appropriate dose in the muscle will assure selective denervation of the adductor branches of a good response without the potential side-effect of recurrent laryngeal nerve bilaterally with reinnervaweakness in the injected or neighboring muscles. tion using the ansa cervicalis (Berke et al., 1999). EMG use is critical for limb dystonia injections to idenPeripheral techniques for CD include a variety of tify the involved muscles. Injections are much less peripheral denervation surgeries (Bertrand et al., accurate without EMG guidance. 1987; Bertrand and Molina-Negro, 1988; Bertrand, Good results have been noted in open-label trials, but 1993; Chen et al., 2000; Munchau et al., 2001; Braun only four double-blind studies have been published and Richter, 2002; Taira et al., 2002). In one retro(Yoshimura et al., 1992; Tsui et al., 1993; Cole et al., spective review of cases, botulinum toxin responsive1995; Kruisdijk et al., 2007). Tsui et al. showed that 12 ness was not predictive of outcome (Cohen-Gadol of 20 patients had improvement in pen control with treatet al., 2003). It is premature to draw any conclusions ment, but only four had significant improvement in regarding these techniques (Meyer and Blitzer, 2007; writing. Yoshimura et al. evaluated 17 patients (10 with Hallett et al., 2009). occupational cramps) and showed significant subjective Lesioning of the basal ganglia or thalamus for improvement, but objective evaluation failed to demondystonia has been used for CD since the 1940s, with strate significant improvement with toxin compared to variable outcomes. The success of stereotactic proceplacebo. Cole et al. noted significant subjective improvedures in treating Parkinson’s disease has led to ment in eight of 10 patients, with improvement in objecrenewed interest in such procedures for dystonia. Postive testing in six patients. In an evidence-based review teroventral medial pallidotomy has been the preferred based on the three earlier studies, Balash and Giladi target for CD, and interestingly, responses may take (2004) rated botulinum toxin injections for writer’s weeks to months to evolve (Vitek, 1998; Yoshor et al., cramp a C (possibly effective for the given condition in 2001; Ford, 2004). the specified population). More recently, Kruisdijk The newest approach to treating CD, cranial cerviet al. (2007) noted that 14 of 20 patients receiving botulical and limb dystonia is DBS of the GPi. DBS has num toxin A reported a beneficial effect and chose to become an accepted therapy for primary generalized continue treatment, versus six of 19 in the placebo group. and segmental dystonia of various types (Vidailhet The changes in most of the clinical scales were signifiet al., 2005; Kupsch et al., 2006; Ostrem and Starr, cantly in favor of botulinum toxin A, and about half of 2008). In addition, cranial symptoms in patients with the patients were still under treatment after 1 year. generalized focal and segmental dystonia improve with Based on Balash and Giladi’s report, as well as the this procedure (Krauss et al., 2004; Bittar et al., 2005; many positive open-label studies and anecdotal experiKiss et al., 2007; Goto et al., 2008). Most published ence, botulinum toxin injections are considered the reports are single cases. These are generally patients first modality of treatment in most patients with writhat have lost responsiveness to botulinum toxins. Twelve ter’s cramp. Patients are typically injected every cases have been published. The largest experience 3 months and long-term follow-up has shown sustained

ADULT-ONSET DYSTONIA includes six patients followed for 6 months (Ostrem et al., 2007). These patients had bilateral implants placed in the sensorimotor region of the GPi. They were examined in an open-label fashion with the Burke–Fahn–Marsden (BFM) dystonia rating scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at presurgical assessment and 6 months postoperatively. Of the six patients, five had CD (craniocervical dystonia); only one was pure cranial. A 72% improvement in BFM and 54% in the TWSTRS scale was recorded. The movements of the eyes, mouth, and neck improved significantly. Complications were minimal. Similar results have been found in other cases of cranial (Capelle et al., 2003; Foote et al., 2005; Houser and Waltz, 2005) and craniocervical dystonia (Blomstedt et al., 2008). These cases demonstrated that blepharospasm, OMD, tongue dystonia, SD and CD can all be responsive to this treatment. Some cases have shown improvement in days (Capelle et al., 2003; Houser and Waltz, 2005; Ostrem et al., 2007) while others required longer, including one requiring a year (Blomstedt et al., 2008). Of 12 cases reported, 2 did not improve (Ostrem et al., 2007; Vagefi et al., 2008). How to determine which patients have the best chance for improvement is unknown. Many of the cases required high voltages when programmed in order to respond. Larger studies with blinded assessments are needed before GPi DBS can be considered routine as it is in generalized dystonia but it is expected that experience with this fairly safe procedure will grow rapidly in the next few years. In 1999, Islekel et al. reported benefit for a 42-yearold woman with CD. Within 3 years, others reported significant benefit for patients with CD from DBS (Bereznai et al., 2002; Yianni et al., 2003a, b). After analysis of eight patients with CD and GPi DBS, it was concluded that frequency and amplitude appear the most important factors in the acute antidystonic effects (Moro et al., 2009). Although not commonly used as a treatment for focal hand dystonia or writer’s cramp, thalamotomy and thalamic or pallidal DBS have been successfully performed in recent years. Taira and colleagues (2003) demonstrated improvement in seven of eight patients with writer’s cramp with a mean follow-up of 13 months. They performed stereotactic ventro-oral nucleus thalamotomy and felt it was safe and effective, but noted that longer follow-up is needed. Five patients who underwent thalamic DBS had sustained improvement up to 24 months (Fukaya et al., 2007). One patient had an electrode implanted in the GPi as well as the ventro-oral nucleus/nucleus ventrointermedius. However, improvement was more effective with

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thalamic stimulation compared to GPi stimulation in this patient. Goto and colleagues (2008) similarly implanted electrodes in the ventro-ocular nucleus complex and GPi in a patient with writer’s cramp and demonstrated immediate and complete relief of his symptoms after thalamic or pallidal stimulation. Upon discontinuation of the stimulation, his symptoms reappeared immediately. The patient has been followed for more than 3 years with beneficial effects.

FUTURE AND SUMMARY While much has been learned recently about the clinical characteristics and the pathophysiology of primary focal dystonias, further investigations are needed to delineate better the pathophysiology of dystonia. Although many medical treatments have been tried, botulinum toxin injections remain the main form of therapy. Unfortunately, these are symptomatic therapies that do not address the mechanism by which dystonia occurs. The mechanism of DBS remains unknown, but is becoming an important therapy for intractable and severe focal dystonia. Developing better rational medical therapies based on the pathophysiology of dystonia will depend on the development of improved animal models of disease and a better understanding of the role of genetics. Research in these directions will be the focus of the next decade (Jinnah and Hess, 2008).

ACKNOWLEDGMENT We gratefully acknowledge the assistance of Ms Pamela Best in the preparation of this manuscript.

REFERENCES Adams SG, Hunt EJ, Charles DA et al. (1993). Unilateral versus bilateral botulinum toxin injections in spasmodic dysphonia: acoustic and perceptual results. J Otolaryngol 22: 171–175. Adler CH, Zimmerman RS, Lyons MK et al. (1996). Perioperative use of botulinum toxin for movement disorderinduced cervical spine disease. Mov Disord 11: 79–81. Adler CH, Factor SA, Brin M et al. (2002). Secondary nonresponsiveness to botulinum toxin type A in patients with oromandibular dystonia. Mov Disord 17: 158–161. Adler CH, Bansberg SF, Krein-Jones K et al. (2004). Safety and efficacy of botulinum toxin type B (Myobloc) in adductor spasmodic dysphonia. Mov Disord 19: 1075–1079. Alm PA (2004). Stuttering and the basal ganglia circuits: a critical review of possible relations. J Commun Disord 37: 325–369. Almasy L, Bressman S, De Leon D et al. (1997a). Ethnic variation in the clinical expression of idiopathic torsion dystonia. Mov Disord 12: 715–721.

504

M.L. EVATT ET AL.

Almasy L, Bressman SB, Raymond D et al. (1997b). Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 42: 670–673. Altrocchi PH, Forno LS (1983). Spontaneous oral-facial dyskinesia: neuropathology of a case. Neurology 33: 802–805. Aramideh M, Ongerboer De Visser BW, Holstege G et al. (1996). Blepharospasm in association with a lower pontine lesion. Neurology 46: 476–478. Aronson AE, Brown JR, Litin EM et al. (1968a). Spastic dysphonia. I. Voice, neurologic, and psychiatric aspects. J Speech Hear Disord 33: 203–218. Aronson AE, Brown JR, Litin EM et al. (1968b). Spastic dysphonia. II. Comparison with essential (voice) tremor and other neurologic and psychogenic dysphonias. J Speech Hear Disord 33: 219–231. Asgeirsson H, Jakobsson F, Hjaltason H et al. (2006). Prevalence study of primary dystonia in Iceland. Mov Disord 21: 293–298. Baik JS, Park JH, Kim JY (2004). Primary lingual dystonia induced by speaking. Mov Disord 19: 1251–1252. Baker RS, Andersen AH, Morecraft RJ et al. (2003). A functional magnetic resonance imaging study in patients with benign essential blepharospasm. J Neuroophthalmol 23: 11–15. Balash Y, Giladi N (2004). Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol 11: 361–370. Balasubramaniam R, Rasmussen J, Carlson LW et al. (2008). Oromandibular dystonia revisited: a review and a unique case. J Oral Maxillofac Surg 66: 379–386. Bara-Jimenez W, Shelton P et al. (2000). Spatial discrimination is abnormal in focal hand dystonia. Neurology 55: 1869–1873. Barnes MP, Best D, Kidd L et al. (2005). The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A – initial experiences. Eur J Neurol 12: 947–955. Benecke R, Jost WH, Kanovsky P et al. (2005). A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 64: 1949–1951. Bentivoglio AR, Daniele A, Albanese A et al. (2006). Analysis of blink rate in patients with blepharospasm. Mov Disord 21: 1225–1229. Berardelli A, Curra A (2002). Pathophysiology and treatment of cranial dystonia. Mov Disord 17: S70–S74. Berardelli A, Rothwell JC, Hallett M et al. (1998). The pathophysiology of primary dystonia. Brain 121: 1195–1212. Bereznai B, Steude U, Seelos K et al. (2002). Chronic highfrequency globus pallidus internus stimulation in different types of dystonia: a clinical, video, and MRI report of six patients presenting with segmental, cervical, and generalized dystonia. Mov Disord 17: 138–144. Berke GS, Blackwell KE, Gerratt BR et al. (1999). Selective laryngeal adductor denervation-reinnervation: a new surgical treatment for adductor spasmodic dysphonia. Ann Otol Rhinol Laryngol 108: 227–231.

Berman B, Seeberger L, Kumar R (2005). Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord 20: 233–237. Bertrand CM (1993). Selective peripheral denervation for spasmodic torticollis: surgical technique, results, and observations in 260 cases. Surg Neurol 40: 96–103. Bertrand CM, Molina-Negro P (1988). Selective peripheral denervation in 111 cases of spasmodic torticollis: rationale and results. Adv Neurol 50: 637–643. Bertrand C, Molina-Negro P, Bouvier G et al. (1987). Observations and analysis of results in 131 cases of spasmodic torticollis after selective denervation. Appl Neurophysiol 50: 319–323. Bhatia K, Daniel SE, Marsden CD (1993). Orofacial dystonia and rest tremor in a patient with normal brain pathology. Mov Disord 8: 361–362. Bhattacharyya N, Tarsy D (2001). Impact on quality of life of botulinum toxin treatments for spasmodic dysphonia and oromandibular dystonia. Arch Otolaryngol Head Neck Surg 127: 389–392. Bhidayasiri R, Jen JC, Baloh RW (2005). Three brothers with a very-late-onset writer’s cramp. Mov Disord 20: 1375–1377. Bhidayasiri R, Cardoso F, Truong DD (2006). Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations. Eur J Neurol 13: 21–29. Bittar RG, Yianni J, Wang S et al. (2005). Deep brain stimulation for generalised dystonia and spasmodic torticollis. J Clin Neurosci 12: 12–16. Black KJ, Ongur D, Perlmutter JS (1998). Putamen volume in idiopathic focal dystonia. Neurology 51: 819–824. Blitzer A, Lovelace RE, Brin MF et al. (1985). Electromyographic findings in focal laryngeal dystonia (spastic dysphonia). Ann Otol Rhinol Laryngol 94: 591–594. Blitzer A, Brin MF, Fahn S et al. (1986). Botulinum toxin (BOTOX) for the treatment of "spastic dysphonia" as part of a trial of toxin injections for the treatment of other cranial dystonias. Laryngoscope 96: 1300–1301. Blitzer A, Brin MF, Fahn S et al. (1988). Clinical and laboratory characteristics of focal laryngeal dystonia: study of 110 cases. Laryngoscope 98: 636–640. Blitzer A, Brin MF, Greene PE et al. (1989). Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol 98: 93–97. Blitzer A, Brin MF, Stewart CF (1998). Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope 108: 1435–1441. Blomstedt P, Tisch S, Hariz MI (2008). Pallidal deep brain stimulation in the treatment of Meige syndrome. Acta Neurol Scand 118: 198–202. Bradley EA, Hodge DO, Bartley GB (2003). Benign essential blepharospasm among residents of Olmsted County, Minnesota, 1976 to 1995: an epidemiologic study. Ophthal Plast Reconstr Surg 19: 177–181. Brans JW, Lindeboom R, Snoek JW et al. (1996). Botulinum toxin versus trihexyphenidyl in cervical dystonia: a

ADULT-ONSET DYSTONIA prospective, randomized, double-blind controlled trial. Neurology 46: 1066–1072. Brashear A, Lew MF, Dykstra DD et al. (1999). Safety and efficacy of neurobloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology 53: 1439–1446. Braun V, Richter HP (2002). Selective peripheral denervation for spasmodic torticollis: 13-year experience with 155 patients. J Neurosurg 97: 207–212. Brin MF, Fahn S, Moskowitz C et al. (1987). Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 2: 237–254. Brin MF, Blitzer A, Fahn S et al. (1989). Adductor laryngeal dystonia (spastic dysphonia): treatment with local injections of botulinum toxin (Botox). Mov Disord 4: 287–296. Brin MF, Lew MF, Adler CH et al. (1999). Safety and efficacy of neurobloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 53: 1431–1438. Burbaud P, Guehl D, Lagueny A et al. (1998). A pilot trial of clozapine in the treatment of cervical dystonia. J Neurol 245: 329–331. Burke RE, Fahn S, Marsden CD (1986). Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 36: 160–164. Butler AG, Duffey PO, Hawthorne MR et al. (2004). An epidemiologic survey of dystonia within the entire population of northeast England over the past nine years. Adv Neurol 94: 95–99. Byl NN, Merzenich MM, Jenkins WM (1996). A primate genesis model of focal dystonia and repetitive strain injury: I. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys. Neurology 47: 508–520. Byl NN, Nagajaran S, Mckenzie AL (2003). Effect of sensory discrimination training on structure and function in patients with focal hand dystonia: a case series. Arch Phys Med Rehabil 84: 1505–1514. Calace P, Cortese G, Piscopo R et al. (2003). Treatment of blepharospasm with botulinum neurotoxin type A: longterm results. Eur J Ophthalmol 13: 331–336. Capelle HH, Weigel R, Krauss JK (2003). Bilateral pallidal stimulation for blepharospasm-oromandibular dystonia (Meige syndrome). Neurology 60: 2017–2018. Castelbuono A, Miller NR (1998). Spontaneous remission in patients with essential blepharospasm and Meige syndrome. Am J Ophthalmol 126: 432–435. Castelon Konkiewitz E, Trender-Gerhard I, Kamm C et al. (2002). Service-based survey of dystonia in Munich. Neuroepidemiology 21: 202–206. Chan J, Brin MF, Fahn S (1991). Idiopathic cervical dystonia: clinical characteristics. Mov Disord 6: 119–126. Chapman KL, Bartley GB, Waller RR et al. (1999). Follow-up of patients with essential blepharospasm who underwent eyelid protractor myectomy at the Mayo Clinic from 1980 through 1995. Ophthal Plast Reconstr Surg 15: 106–110. Charles PD, Davis TL, Shannon KM et al. (1997). Tongue protrusion dystonia: treatment with botulinum toxin. South Med J 90: 522–525.

505

Charness ME, Ross MH, Shefner JM (1996). Ulnar neuropathy and dystonic flexion of the fourth and fifth digits: clinical correlation in musicians. Muscle Nerve 19: 431–437. Chen RS, Tsai CH, Lu CS (1995). Reciprocal inhibition in writer’s cramp. Mov Disord 10: 556–561. Chen X, Ma A, Liang J, Ji S et al. (2000). Selective denervation and resection of cervical muscles in the treatment of spasmodic torticollis: long-term follow-up results in 207 cases. Stereotact Funct Neurosurg 75: 96–102. Chhetri DK, Merati AL, Blumin JH et al. (2008). Reliability of the perceptual evaluation of adductor spasmodic dysphonia. Ann Otol Rhinol Laryngol 117: 159–165. Clarimon J, Brancati F, Peckham E et al. (2007). Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm. Mov Disord 22: 162–166. Clark GT (2003). The management of oromandibular motor disorders and facial spasms with injections of botulinum toxin. Phys Med Rehabil Clin N Am 14: 727–748. Claypool DW, Duane DD, Ilstrup DM et al. (1995). Epidemiology and outcome of cervical dystonia (spasmodic torticollis) in Rochester, Minnesota. Mov Disord 10: 608–614. Cohen-Gadol AA, Ahlskog JE, Matsumoto JY et al. (2003). Selective peripheral denervation for the treatment of intractable spasmodic torticollis: experience with 168 patients at the Mayo Clinic. J Neurosurg 98: 1247–1254. Cohen LG, Hallett M (1988). Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology 38: 1005–1012. Cole R, Hallett M, Cohen LG (1995). Double-blind trial of botulinum toxin for treatment of focal hand dystonia. Mov Disord 10: 466–471. Colosimo C, Chianese M, Giovannelli M et al. (2003). Botulinum toxin type B in blepharospasm and hemifacial spasm. J Neurol Neurosurg Psychiatry 74: 687. Comella CL, Jankovic J, Shannon KM et al. (2005). Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 65: 1423–1429. Courey MS, Garrett CG, Billante CR et al. (2000). Outcomes assessment following treatment of spasmodic dysphonia with botulinum toxin. Ann Otol Rhinol Laryngol 109: 819–822. Critchley M (1939). Spastic dysphonia “inspiratory speech”. Brain 62: 96–103. Damrose JF, Goldman SN, Groessl EJ et al. (2004). The impact of long-term botulinum toxin injections on symptom severity in patients with spasmodic dysphonia. J Voice 18: 415–422. Das SK, Banerjee TK, Biswas A et al. (2007). Community survey of primary dystonia in the city of Kolkata, India. Mov Disord 22: 2031–2036. Dauer WT, Burke RE, Greene P et al. (1998). Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 121: 547–560. Defazio G, Berardelli A, Abbruzzese G et al. (1999). Risk factors for spread of primary adult onset blepharospasm:

506

M.L. EVATT ET AL.

a multicentre investigation of the Italian movement disorders study group. J Neurol Neurosurg Psychiatry 67: 613–619. Defazio G, Brancati F, Valente EM et al. (2003). Familial blepharospasm is inherited as an autosomal dominant trait and relates to a novel unassigned gene. Mov Disord 18: 207–212. Defazio G, Abbruzzese G, Livrea P et al. (2004). Epidemiology of primary dystonia. Lancet Neurol 3: 673–678. Defazio G, Martino D, Aniello MS et al. (2006). A family study on primary blepharospasm. J Neurol Neurosurg Psychiatry 77: 252–254. Delmaire C, Vidailhet M, Elbaz A et al. (2007). Structural abnormalities in the cerebellum and sensorimotor circuit in writer’s cramp. Neurology 69: 376–380. Dhaenens CM, Krystkowiak P, Douay X et al. (2005). Clinical and genetic evaluation in a French population presenting with primary focal dystonia. Mov Disord 20: 822–825. Draganski B, Thun-Hohenstein C, Bogdahn U et al. (2003). “Motor circuit” gray matter changes in idiopathic cervical dystonia. Neurology 61: 1228–1231. Dresel C, Haslinger B, Castrop F et al. (2006). Silent eventrelated fMRI reveals deficient motor and enhanced somatosensory activation in orofacial dystonia. Brain 129: 36–46. Duffey PO, Butler AG, Hawthorne MR et al. (1998). The epidemiology of the primary dystonias in the north of England. Adv Neurol 78: 121–125. Dutton JJ, Buckley EG (1986). Botulinum toxin in the management of blepharospasm. Arch Neurol 43: 380–382. Dutton JJ, White JJ, Richard MJ (2006). Myobloc for the treatment of benign essential blepharospasm in patients refractory to botox. Ophthal Plast Reconstr Surg 22: 173–177. Dykstra DD, Mendez A, Chappuis D et al. (2005). Treatment of cervical dystonia and focal hand dystonia by high cervical continuously infused intrathecal baclofen: a report of 2 cases. Arch Phys Med Rehabil 86: 830–833. Epidemiological Study of Dystonia in Europe (ESDE) Collaborative GROUP (2000). A prevalence study of primary dystonia in eight European countries. J Neurol 247: 787–792. Erjanti H, Marttila R, Rinne U (1996). The prevalence and incidence of cervical dystonia in south-western Finland. Mov Disord 11: A215. Esmaeli-Gutstein B, Nahmias C, Thompson M et al. (1999). Positron emission tomography in patients with benign essential blepharospasm. Ophthal Plast Reconstr Surg 15: 23–27. Esper CD, Freeman A, Factor SA (2010). Lingual protrusion dystonia: frequency, etiology and botulinum toxin therapy. Parkinsonism Relat Disord 16: 438–441. Etgen T, Muhlau M, Gaser C et al. (2006). Bilateral greymatter increase in the putamen in primary blepharospasm. J Neurol Neurosurg Psychiatry 77: 1017–1020. Factor SA, Barron KD (1997). Mosaic pattern of gliosis in the neostriatum of a North American man with craniocervical dystonia and parkinsonism. Mov Disord 12: 783–789. Factor SA, Podskalny GD, Molho ES (1995). Psychogenic movement disorders: frequency, clinical profile, and characteristics. J Neurol Neurosurg Psychiatry 59: 406–412.

Fahn S (1983a). High dosage anticholinergic therapy in dystonia. Neurology 33: 1255–1261. Fahn S (1983b). Treatment of tardive dyskinesia: use of dopamine-depleting agents. Clin Neuropharmacol 6: 151–158. Filipovic SR, Jahanshahi M, Viswanathan R et al. (2004). Clinical features of the geste antagoniste in cervical dystonia. Adv Neurol 94: 191–201. Fletcher NA, Harding AE, Marsden CD (1991). A casecontrol study of idiopathic torsion dystonia. Mov Disord 6: 304–309. Foote KD, Sanchez JC, Okun MS (2005). Staged deep brain stimulation for refractory craniofacial dystonia with blepharospasm: case report and physiology. Neurosurgery 56: E415; discussion E415. Ford B (2004). Pallidotomy for generalized dystonia. Adv Neurol 94: 287–299. Friedman A, Fahn S (1986). Spontaneous remissions in spasmodic torticollis. Neurology 36: 398–400. Frucht S, Fahn S, Ford B et al. (1999). A geste antagoniste device to treat jaw-closing dystonia. Mov Disord 14: 883–886. Frucht SJ, Fahn S, Greene PE et al. (2001). The natural history of embouchure dystonia. Mov Disord 16: 899–906. Frueh BR, Felt DP, Wojno TH et al. (1984). Treatment of blepharospasm with botulinum toxin. A preliminary report. Arch Ophthalmol 102: 1464–1468. Fukaya C, Katayama Y, Kano T et al. (2007). Thalamic deep brain stimulation for writer’s cramp. J Neurosurg 107: 977–982. Galardi G, Perani D, Grassi F et al. (1996). Basal ganglia and thalamo-cortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol Scand 94: 172–176. Garcia-Albea E, Franch O, Munoz D et al. (1981). Brueghel’s syndrome, report of a case with postmortem studies. J Neurol Neurosurg Psychiatry 44: 437–440. Garraux G, Bauer A, Hanakawa T et al. (2004). Changes in brain anatomy in focal hand dystonia. Ann Neurol 55: 736–739. Georgescu D, Vagefi MR, Mcmullan TF et al. (2008). Upper eyelid myectomy in blepharospasm with associated apraxia of lid opening. Am J Ophthalmol 145: 541–547. Ghika J, Regli F, Growdon JH (1993). Sensory symptoms in cranial dystonia: a potential role in the etiology? J Neurol Sci 116: 142–147. Gibb WR, Lees AJ, Marsden CD (1988). Pathological report of four patients presenting with cranial dystonias. Mov Disord 3: 211–221. Gibb WR, Kilford L, Marsden CD (1992). Severe generalised dystonia associated with a mosaic pattern of striatal gliosis. Mov Disord 7: 217–223. Gilbert GJ (1996). Brueghel syndrome: its distinction from Meige syndrome. Neurology 46: 1767–1769. Gomez-Wong E, Marti MJ, Cossu G et al. (1998). The ’geste antagonistique’ induces transient modulation of the blink reflex in human patients with blepharospasm. Neurosci Lett 251: 125–128. Goto S, Shimazu H, Matsuzaki K et al. (2008). Thalamic Vo-complex vs pallidal deep brain stimulation for focal hand dystonia. Neurology 70: 1500–1501.

ADULT-ONSET DYSTONIA Grandas F, Elston J, Quinn N et al. (1988). Blepharospasm: a review of 264 patients. J Neurol Neurosurg Psychiatry 51: 767–772. Green J, Factor SA (2007). Nonmotor symptoms in dystonia. In: M Stacy (Ed.), Handbook of Dystonia. Informa Healthcare, New York. Greene P (1992). Baclofen in the treatment of dystonia. Clin Neuropharmacol 15: 276–288. Greene P, Shale H, Fahn S (1988a). Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord 3: 46–60. Greene P, Shale H, Fahn S (1988b). Experience with high dosages of anticholinergic and other drugs in the treatment of torsion dystonia. Adv Neurol 50: 547–556. Greene P, Kang U, Fahn S et al. (1990). Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 40: 1213–1218. Gundel H, Busch R, Ceballos-Baumann A et al. (2007). Psychiatric comorbidity in patients with spasmodic dysphonia: a controlled study. J Neurol Neurosurg Psychiatry 78: 1398–1400. Hagenah JM, Zuhlke C, Hellenbroich Y et al. (2004). Focal dystonia as a presenting sign of spinocerebellar ataxia 17. Mov Disord 19: 217–220. Hall TA, Mcgwin G Jr., Searcey K et al. (2006). Healthrelated quality of life and psychosocial characteristics of patients with benign essential blepharospasm. Arch Ophthalmol 124: 116–119. Hallett M (1995). Is dystonia a sensory disorder? Ann Neurol 38: 139–140. Hallett M (2002). Blepharospasm: recent advances. Neurology 59: 1306–1312. Hallett M (2006). Pathophysiology of writer’s cramp. Hum Mov Sci 25: 454–463. Hallett M, Evinger C, Jankovic J et al. (2008). Update on blepharospasm: report from the BEBRF International Workshop. Neurology 71: 1275–1282. Hallett M, Benecke R, Blitzer A et al. (2009). Treatment of focal dystonias with botulinum neurotoxin. Toxicon 54: 628–633. Hogikyan ND, Wodchis WP, Spak C et al. (2001). Longitudinal effects of botulinum toxin injections on voicerelated quality of life (V-RQOL) for patients with adductory spasmodic dysphonia. J Voice 15: 576–586. Holden PK, Vokes DE, Taylor MB et al. (2007). Long-term botulinum toxin dose consistency for treatment of adductor spasmodic dysphonia. Ann Otol Rhinol Laryngol 116: 891–896. Holton JL, Schneider SA, Ganesharajah T et al. (2008). Neuropathology of primary adult-onset dystonia. Neurology 70: 695–699. Houser M, Waltz T (2005). Meige syndrome and pallidal deep brain stimulation. Mov Disord 20: 1203–1205. Hsiung GY, Das SK, Ranawaya R et al. (2002). Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period. Mov Disord 17: 1288–1293.

507

Hutchinson M, Nakamura T, Moeller JR et al. (2000). The metabolic topography of essential blepharospasm: a focal dystonia with general implications. Neurology 55: 673–677. Ishii K, Tamaoka A, Shoji S (2001). A case of primary focal lingual dystonia induced by speaking. Eur J Neurol 8: 507. Islekel S, Zileli M, Zileli B (1999). Unilateral pallidal stimulation in cervical dystonia. Stereotact Funct Neurosurg 72: 248–252. Jahanshahi M, Marion MH, Marsden CD (1990). Natural history of adult-onset idiopathic torticollis. Arch Neurol 47: 548–552. Jankovic J (1986). Blepharospasm with basal ganglia lesions. Arch Neurol 43: 866–868. Jankovic J (1998). Medical therapy and botulinum toxin in dystonia. Adv Neurol 78: 169–183. Jankovic J (2001). Can peripheral trauma induce dystonia and other movement disorders? Yes!. Mov Disord 16: 7–12. Jankovic J, Beach J (1997). Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology 48: 358–362. Jankovic J, Ford J (1983). Blepharospasm and orofacial-cervical dystonia: clinical and pharmacological findings in 100 patients. Ann Neurol 13: 402–411. Jankovic J, Nutt JG (1988). Blepharospasm and cranial-cervical dystonia (Meige’s syndrome): familial occurrence. Adv Neurol 49: 117–123. Jankovic J, Orman J (1987). Botulinum A toxin for cranialcervical dystonia: a double-blind, placebo-controlled study. Neurology 37: 616–623. Jankovic J, Patel SC (1983). Blepharospasm associated with brainstem lesions. Neurology 33: 1237–1240. Jankovic J, Schwartz K, Donovan DT (1990). Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 53: 633–639. Jankovic J, Leder S, Warner D et al. (1991). Cervical dystonia: clinical findings and associated movement disorders. Neurology 41: 1088–1091. Jedynak PC, Tranchant C, De Beyl DZ (2001). Prospective clinical study of writer’s cramp. Mov Disord 16: 494–499. Jinnah HA, Hess EJ (2008). Experimental therapeutics for dystonia. Neurotherapeutics 5: 198–209. Jost WH, Kohl A, Brinkmann S et al. (2005). Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT 201) compared with commercially available botulinum toxin type A (BOTOX) in healthy volunteers. J Neural Transm 112: 905–913. Jost WH, Blumel J, Grafe S (2007). Botulinum neurotoxin type A free of complexing proteins (XEOMIN) in focal dystonia. Drugs 67: 669–683. Junker J, Oberwittler C, Jackson D et al. (2004). Utilization and perceived effectiveness of complementary and alternative medicine in patients with dystonia. Mov Disord 19: 158–161. Kaji R, Rothwell JC, Katayama M et al. (1995). Tonic vibration reflex and muscle afferent block in writer’s cramp. Ann Neurol 38: 155–162.

508

M.L. EVATT ET AL.

Kamm C, Naumann M, Mueller J et al. (2000). The DYT1 GAG deletion is infrequent in sporadic and familial writer’ s cramp. Mov Disord 15: 1238–1241. Kandil MR, Tohamy SA, Fattah MA et al. (1994). Prevalence of chorea, dystonia and athetosis in Assiut, Egypt: a clinical and epidemiological study. Neuroepidemiology 13: 202–210. Kang UJ, Burke RE, Fahn S (1986). Natural history and treatment of tardive dystonia. Mov Disord 1: 193–208. Karp BI (2004). Botulinum toxin treatment of occupational and focal hand dystonia. Mov Disord 19: S116–S119. Karp BI, Goldstein SR, Chen R et al. (1999). An open trial of clozapine for dystonia. Mov Disord 14: 652–657. Kerrison JB, Lancaster JL, Zamarripa FE et al. (2003). Positron emission tomography scanning in essential blepharospasm. Am J Ophthalmol 136: 846–852. Kiss ZH, Doig-Beyaert K, Eliasziw M et al. (2007). The Canadian multicentre study of deep brain stimulation for cervical dystonia. Brain 130: 2879–2886. Kiwak KJ, Deray MJ, Shields WD (1983). Torticollis in three children with syringomyelia and spinal cord tumor. Neurology 33: 946–948. Kiziltan G, Akalin MA (1996). Stuttering may be a type of action dystonia. Mov Disord 11: 278–282. Koriwchak MJ, Netterville JL, Snowden T et al. (1996). Alternating unilateral botulinum toxin type A (BOTOX) injections for spasmodic dysphonia. Laryngoscope 106: 1476–1481. Kraft SP, Lang AE (1988). Botulinum toxin injections in the treatment of blepharospasm, hemifacial spasm, and eyelid fasciculations. Can J Neurol Sci 15: 276–280. Krauss JK, Yianni J, Loher TJ et al. (2004). Deep brain stimulation for dystonia. J Clin Neurophysiol 21: 18–30. Kruisdijk JJ, Koelman JH, Ongerboer De Visser BW et al. (2007). Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry 78: 264–270. Kulisevsky J, Marti MJ, Ferrer I et al. (1988). Meige syndrome: neuropathology of a case. Mov Disord 3: 170–175. Kupsch A, Benecke R, Muller J et al. (2006). Pallidal deepbrain stimulation in primary generalized or segmental dystonia. N Engl J Med 355: 1978–1990. Kwak CH, Jankovic J (2002). Tourettism and dystonia after subcortical stroke. Mov Disord 17: 821–825. Lang AE (1990). Writing tremor and writing dystonia. Mov Disord 5: 354–355. Lang AE (1995). Psychogenic dystonia: a review of 18 cases. Can J Neurol Sci 22: 136–143. Lang AE, Rogaeva EA, Tsuda T et al. (1994). Homozygous inheritance of the Machado-Joseph disease gene. Ann Neurol 36: 443–447. Le KD, Nilsen B, Dietrichs E (2003). Prevalence of primary focal and segmental dystonia in Oslo. Neurology 61: 1294–1296. Ledoux MS, Brady KA (2003). Secondary cervical dystonia associated with structural lesions of the central nervous system. Mov Disord 18: 60–69.

Lenz FA, Byl NN (1999). Reorganization in the cutaneous core of the human thalamic principal somatic sensory nucleus (Ventral caudal) in patients with dystonia. J Neurophysiol 82: 3204–3212. Lerner A, Shill H, Hanakawa T et al. (2004). Regional cerebral blood flow correlates of the severity of writer’s cramp symptoms. Neuroimage 21: 904–913. Leube B, Rudnicki D, Ratzlaff T et al. (1996). Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution. Hum Mol Genet 5: 1673–1677. Leube B, Hendgen T, Kessler KR et al. (1997a). Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe. Am J Med Genet 74: 529–532. Leube B, Hendgen T, Kessler KR et al. (1997b). Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p. Ann Neurol 42: 111–114. Leube B, Kessler KR, Goecke T et al. (1997c). Frequency of familial inheritance among 488 index patients with idiopathic focal dystonia and clinical variability in a large family. Mov Disord 12: 1000–1006. Lew MF, Adornato BT, Duane DD et al. (1997). Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia. Neurology 49: 701–707. Li SC, Schoenberg BS, Wang CC et al. (1985). A prevalence survey of Parkinson’s disease and other movement disorders in the People’s Republic of China. Arch Neurol 42: 655–657. Lo SE, Gelb M, Frucht SJ (2007). Geste antagonistes in idiopathic lower cranial dystonia. Mov Disord 22: 1012–1017. Lucetti C, Nuti A, Gambaccini G et al. (2000). Mexiletine in the treatment of torticollis and generalized dystonia. Clin Neuropharmacol 23: 186–189. Marchetti A, Magar R, Findley L et al. (2005). Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord 20: 937–944. Marion MH, Klap P, Perrin A et al. (1992). Stridor and focal laryngeal dystonia. Lancet 339: 457–458. Mark MH, Sage JI, Dickson DW et al. (1994). Meige syndrome in the spectrum of Lewy body disease. Neurology 44: 1432–1436. Marras C, Van Den Eeden SK, Fross RD et al. (2007). Minimum incidence of primary cervical dystonia in a multiethnic health care population. Neurology 69: 676–680. Marsden CD (1976). Blepharospasm-oromandibular dystonia syndrome (Brueghel’s syndrome). A variant of adultonset torsion dystonia? J Neurol Neurosurg Psychiatry 39: 1204–1209. Marsden CD, Sheehy MP (1990). Writer’s cramp. Trends Neurosci 13: 148–153. Marsden CD, Obeso JA, Zarranz JJ et al. (1985). The anatomical basis of symptomatic hemidystonia. Brain 108: 463–483. Martino D, Defazio G, Alessio G et al. (2005). Relationship between eye symptoms and blepharospasm: a multicenter case-control study. Mov Disord 20: 1564–1570.

ADULT-ONSET DYSTONIA Matsumoto S, Nishimura M, Shibasaki H et al. (2003). Epidemiology of primary dystonias in Japan: comparison with Western countries. Mov Disord 18: 1196–1198. Mauriello JA Jr. (1985). Blepharospasm, Meige syndrome, and hemifacial spasm: treatment with botulinum toxin. Neurology 35: 1499–1500. McKenzie AL, Nagarajan SS, Roberts TP et al. (2003). Somatosensory representation of the digits and clinical performance in patients with focal hand dystonia. Am J Phys Med Rehabil 82: 737–749. McNaught KS, Kapustin A, Jackson T et al. (2004). Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol 56: 540–547. Meige H (1910). Les convulsions de la face, une forme clinique de convulsion faciale bilateral et mediane. Rev Neurol 21: 437–443. Meyer TK, Blitzer A (2007). Spasmodic dysphonia. In: M Stacy (Ed.), Handbook of Dystonia. Informa Healthcare, New York. Mink JW (2003). The basal ganglia and involuntary movements: impaired inhibition of competing motor patterns. Arch Neurol 60: 1365–1368. Misbahuddin A, Placzek MR, Chaudhuri KR et al. (2002). A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm. Neurology 58: 124–126. Modi G, Modi M, Martinus I et al. (2000). The clinical and genetic characteristics of spinocerebellar ataxia type 7 (SCA 7) in three Black South African families. Acta Neurol Scand 101: 177–182. Molho ES, Feustel PJ, Factor SA (1998). Clinical comparison of tardive and idiopathic cervical dystonia. Mov Disord 13: 486–489. Moller E, Bakke M, Dalager T et al. (2007). Oromandibular dystonia involving the lateral pterygoid muscles: four cases with different complexity. Mov Disord 22: 785–790. Molloy FM, Carr TD, Zeuner KE et al. (2003). Abnormalities of spatial discrimination in focal and generalized dystonia. Brain 126: 2175–2182. Moro E, Piboolnurak P, Arenovich T et al. (2009). Pallidal stimulation in cervical dystonia: clinical implications of acute changes in stimulation parameters. Eur J Neurol 16: 506–512. Muller J, Wissel J, Masuhr F et al. (2001). Clinical characteristics of the geste antagoniste in cervical dystonia. J Neurol 248: 478–482. Muller J, Kemmler G, Wissel J et al. (2002a). The impact of blepharospasm and cervical dystonia on health-related quality of life and depression. J Neurol 249: 842–846. Muller J, Kiechl S, Wenning GK et al. (2002b). The prevalence of primary dystonia in the general community. Neurology 59: 941–943. Muller J, Wenning GK, Wissel J et al. (2002c). Riluzole therapy in cervical dystonia. Mov Disord 17: 198–200. Munchau A, Palmer JD, Dressler D et al. (2001). Prospective study of selective peripheral denervation for botulinumtoxin resistant patients with cervical dystonia. Brain 124: 769–783.

509

Nair KR (1997). Associated blepharospasm in lower pontine lesions. Neurology 48: 553. Nakashima K, Kusumi M, Inoue Y et al. (1995). Prevalence of focal dystonias in the western area of Tottori Prefecture in Japan. Mov Disord 10: 440–443. Nishioka GJ, Montgomery MT (1988). Masticatory muscle hyperactivity in temporomandibular disorders: is it an extrapyramidally expressed disorder? J Am Dent Assoc 116: 514–520. Nussgens Z, Roggenkamper P (1997). Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol 235: 197–199. Nutt JG, Muenter MD, Aronson A et al. (1988a). Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 3: 188–194. Nutt JG, Muenter MD, Melton LJ 3rd et al. (1988b). Epidemiology of dystonia in Rochester, Minnesota. Adv Neurol 50: 361–365. Obermann M, Yaldizli O, De Greiff A et al. (2007). Morphometric changes of sensorimotor structures in focal dystonia. Mov Disord 22: 1117–1123. Ochudlo S, Bryniarski P, Opala G (2007). Botulinum toxin improves the quality of life and reduces the intensification of depressive symptoms in patients with blepharospasm. Parkinsonism Relat Disord 13: 505–508. Ohara S, Miki J, Momoi H et al. (1997). Treatment of spasmodic torticollis with mexiletine: a case report. Mov Disord 12: 466–469. Ohara S, Hayashi R, Momoi H et al. (1998). Mexiletine in the treatment of spasmodic torticollis. Mov Disord 13: 934–940. Ostrem JL, Starr PA (2008). Treatment of dystonia with deep brain stimulation. Neurotherapeutics 5: 320–330. Ostrem JL, Marks WJ Jr., Volz MM et al. (2007). Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige syndrome). Mov Disord 22: 1885–1891. Papapetropoulos S, Singer C (2006a). Eating dysfunction associated with oromandibular dystonia: clinical characteristics and treatment considerations. Head Face Med 2: 47. Papapetropoulos S, Singer C (2006b). Primary focal lingual dystonia. Mov Disord 21: 429–430. Parkes D, Schachter M (1981). Meige, Brueghel or Black? Neurology 31: 498. Park JB, Simpson LL, Anderson TD et al. (2003). Immunologic characterization of spasmodic dysphonia patients who develop resistance to botulinum toxin. J Voice 17: 255–264. Pekmezovic T, Svetel M, Ivanovic N et al. (2009). Quality of life in patients with focal dystonia. Clin Neurol Neurosurg 111: 161–164. Perlmutter JS, Stambuk MK, Markham J et al. (1997). Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia. J Neurosci 17: 843–850. Poewe W, Deuschl G, Nebe A et al. (1998). What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo

510

M.L. EVATT ET AL.

controlled, dose ranging study using Dysport. German Dystonia Study Group. J Neurol Neurosurg Psychiatry 64: 13–17. Pohl C, Happe J, Klockgether T (2002). Cooling improves the writing performance of patients with writer’s cramp. Mov Disord 17: 1341–1344. Priori A, Pesenti A, Cappellari A et al. (2001). Limb immobilization for the treatment of focal occupational dystonia. Neurology 57: 405–409. Pullman SL, Greene P, Fahn S et al. (1996). Approach to the treatment of limb disorders with botulinum toxin A. Experience with 187 patients. Arch Neurol 53: 617–624. Quartarone A, Bagnato S, Rizzo V et al. (2003). Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 126: 2586–2596. Quartarone A, Sant’angelo A, Battaglia F et al. (2006). Enhanced long-term potentiation-like plasticity of the trigeminal blink reflex circuit in blepharospasm. J Neurosci 26: 716–721. Raffaele R, Patti F, Sciacca A et al. (1988). Effects of short-term reserpine treatment on generalized and focal dystonic-dyskinetic syndromes. Funct Neurol 3: 327–335. Raudino F (1994). Is temporomandibular dysfunction a cranial dystonia? An electrophysiological study. Headache 34: 471–475. Reimer J, Gilg K, Karow A et al. (2005). Health-related quality of life in blepharospasm or hemifacial spasm. Acta Neurol Scand 111: 64–70. Rieder CR, Schestatsky P, Socal MP et al. (2007). A doubleblind, randomized, crossover study of prosigne versus botox in patients with blepharospasm and hemifacial spasm. Clin Neuropharmacol 30: 39–42. Robinson R, Mccarthy GT, Bandmann O et al. (1999). GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness. J Neurol Neurosurg Psychiatry 66: 86–89. Roggenkamper P, Jost WH, Bihari K et al. (2006). Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 113: 303–312. Rubin AD, Wodchis WP, Spak C et al. (2004). Longitudinal effects of Botox injections on voice-related quality of life (V-RQOL) for patients with adductory spasmodic dysphonia: part II. Arch Otolaryngol Head Neck Surg 130: 415–420. Sankhla C, Lai EC, Jankovic J (1998). Peripherally induced oromandibular dystonia. J Neurol Neurosurg Psychiatry 65: 722–728. Satija P, Ondo WG (2007). Cranial dystonia. In: M Stacy (Ed.), Handbook of Dystonia. Informa Healthcare, New York, NY. Schmidt KE, Linden DE, Goebel R et al. (2003). Striatal activation during blepharospasm revealed by fMRI. Neurology 60: 1738–1743. Schneider SA, Bhatia KP (2007). The entity of jaw tremor and dystonia. Mov Disord 22: 1491–1495.

Schneider SA, Aggarwal A, Bhatt M et al. (2006). Severe tongue protrusion dystonia: clinical syndromes and possible treatment. Neurology 67: 940–943. Schramm A, Classen J, Reiners K et al. (2007). Characteristics of sensory trick-like manoeuvres in jaw-opening dystonia. Mov Disord 22: 430–433. Scolding NJ, Smith SM, Sturman S et al. (1995). Auctioneer’s jaw: a case of occupational oromandibular hemidystonia. Mov Disord 10: 508–509. Scott AB, Kennedy RA, Stubbs HA (1985). Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 103: 347–350. Sforza E, Montagna P, Defazio G et al. (1991). Sleep and cranial dystonia. Electroencephalogr Clin Neurophysiol 79: 166–169. Sheehy MP, Marsden CD (1982). Writers’ cramp-a focal dystonia. Brain 105: 461–480. Sieberer MG, Vieregge P, Klein C et al. (1999). Concordant late onset of craniocervical dystonia in a pair of monozygotic twins. Mov Disord 14: 1040–1043. Siebner HR, Tormos JM, Ceballos-Baumann AO et al. (1999). Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer’s cramp. Neurology 52: 529–537. Simpson DM, Blitzer A, Brashear A et al. (2008). Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70: 1699–1706. Singer C, Papapetropoulos S (2006). A comparison of jawclosing and jaw-opening idiopathic oromandibular dystonia. Parkinsonism Relat Disord 12: 115–118. Singer C, Velickovic M (2008). Cervical dystonia: etiology and pathophysiology. Neurol Clin 26: 9–22. Smith ME, Ford CN (2000). Resistance to botulinum toxin injections for spasmodic dysphonia. Arch Otolaryngol Head Neck Surg 126: 533–535. Sohn YH, Hallett M (2004). Disturbed surround inhibition in focal hand dystonia. Ann Neurol 56: 595–599. Sohtaoglu M, Ergin H, Ozekmekci S et al. (2007). Patient with late-onset Wilson’s disease: deterioration with penicillamine. Mov Disord 22: 290–291. Spivak B, Gonen N, Mester R et al. (1996). Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents. Int Clin Psychopharmacol 11: 207–209. Stacy M (2008). Epidemiology, clinical presentation, and diagnosis of cervical dystonia. Neurol Clin 26: 23–42. Suchowersky O, Calne DB (1988). Non-dystonic causes of torticollis. Adv Neurol 50: 501–508. Sveinbjornsdottir S, Pakkenberg H, Werdelin L (1993). Developmental stuttering followed by intermittent jaw opening dystonia. Mov Disord 8: 396–397. Taira T, Kobayashi T, Takahashi K et al. (2002). A new denervation procedure for idiopathic cervical dystonia. J Neurosurg 97: 201–206. Taira T, Harashima S, Hori T (2003). Neurosurgical treatment for writer’s cramp. Acta Neurochir Suppl 87: 129–131.

ADULT-ONSET DYSTONIA Tan EK, Chan LL (2005). Sensory tricks and treatment in primary lingual dystonia. Mov Disord 20: 388. Tan EK, Jankovic J (1999). Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up. Neurology 53: 2102–2107. Tan EK, Jankovic J (2000). Tardive and idiopathic oromandibular dystonia: a clinical comparison. J Neurol Neurosurg Psychiatry 68: 186–190. Tarlov E (1970). On the problem of the pathology of spasmodic torticollis in man. J Neurol Neurosurg Psychiatry 33: 457–463. Tas N, Karatas GK, Sepici V (2001). Hand orthosis as a writing aid in writer’s cramp. Mov Disord 16: 1185–1189. Tempel LW, Perlmutter JS (1993). Abnormal cortical responses in patients with writer’s cramp. Neurology 43: 2252–2257. Thickbroom GW, Byrnes ML, Stell R et al. (2003). Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia. Mov Disord 18: 395–402. Thomas M, Jankovic J (2004). Psychogenic movement disorders: diagnosis and management. CNS Drugs 18: 437–452. Thompson PD, Obeso JA, Delgado G et al. (1986). Focal dystonia of the jaw and the differential diagnosis of unilateral jaw and masticatory spasm. J Neurol Neurosurg Psychiatry 49: 651–656. Tinazzi M, Farina S, Bhatia K et al. (2005). TENS for the treatment of writer’s cramp dystonia: a randomized, placebo-controlled study. Neurology 64: 1946–1948. Tolosa E, Marti MJ (1988). Blepharospasm-oromandibular dystonia syndrome (Meige’s syndrome): clinical aspects. Adv Neurol 49: 73–84. Tolosa E, Kulisevsky J, Fahn S (1988). Meige syndrome: primary and secondary forms. Adv Neurol 50: 509–515. Tolosa ES, Klawans HL (1979). Meiges disease: a clinical form of facial convulsion, bilateral and medial. Arch Neurol 36: 635–637. Truong D, Duane DD, Jankovic J et al. (2005). Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, doubleblind, placebo-controlled study. Mov Disord 20: 783–791. Truong D, Comella C, Fernandez HH et al. (2008). Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of benign essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord 14: 407–414. Truong DD, Rontal M, Rolnick M et al. (1991). Doubleblind controlled study of botulinum toxin in adductor spasmodic dysphonia. Laryngoscope 101: 630–634. Tsui JK, Eisen A, Mak E et al. (1985). A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 12: 314–316. Tsui JK, Bhatt M, Calne S et al. (1993). Botulinum toxin in the treatment of writer’s cramp: a double-blind study. Neurology 43: 183–185.

511

Vagefi MR, Lin CC, Mccann JD et al. (2008). Exacerbation of blepharospasm associated with craniocervical dystonia after placement of bilateral globus pallidus internus deep brain stimulator. Mov Disord 23: 454–456. Van Den Bergh P, Francart J, Mourin S et al. (1995). Fiveyear experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve 18: 720–729. Van Hilten JJ, Geraedts EJ, Marinus J (2007). Peripheral trauma and movement disorders. Parkinsonism Relat Disord 13: S395–S399. Vidailhet M, Vercueil L, Houeto JL et al. (2005). Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 352: 459–467. Vitek JL (1998). Surgery for dystonia. Neurosurg Clin N Am 9: 345–366. Waters CH, Faust PL, Powers J et al. (1993). Neuropathology of lubag (x-linked dystonia parkinsonism). Mov Disord 8: 387–390. Weiner WJ (2001). Can peripheral trauma induce dystonia? No!. Mov Disord 16: 13–22. Weiss EM, Hershey T, Karimi M et al. (2006). Relative risk of spread of symptoms among the focal onset primary dystonias. Mov Disord 21: 1175–1181. Wenning GK, Kiechl S, Seppi K et al. (2005). Prevalence of movement disorders in men and women aged 50–89 years (Bruneck Study cohort): a population-based study. Lancet Neurol 4: 815–820. Wohlfarth K, Muller C, Sassin I et al. (2007). Neurophysiological double-blind trial of a botulinum neurotoxin type a free of complexing proteins. Clin Neuropharmacol 30: 86–94. Yianni J, Bain P, Giladi N et al. (2003a). Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov Disord 18: 436–442. Yianni J, Bain PG, Gregory RP et al. (2003b). Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur J Neurol 10: 239–247. Yoshimura DM, Aminoff MJ, Olney RK (1992). Botulinum toxin therapy for limb dystonias. Neurology 42: 627–630. Yoshor D, Hamilton WJ, Ondo W et al. (2001). Comparison of thalamotomy and pallidotomy for the treatment of dystonia. Neurosurgery 48: 818–824; discussion 824–826. Zadro I, Brinar VV, Barun B et al. (2008). Cervical dystonia due to cerebellar stroke. Mov Disord 23: 919–920. Zeuner KE, Hallett M (2003). Sensory training as treatment for focal hand dystonia: a 1-year follow-up. Mov Disord 18: 1044–1047. Zweig RM, Hedreen JC, Jankel WR et al. (1988). Pathology in brainstem regions of individuals with primary dystonia. Neurology 38: 702–776.