Historical highlights

In 1908, Schwalbe published his dissertation on a family with three affected children who are now recognized to have had primary generalized dystonia. An English translation of Schwalbe’s paper is available (Truong and Fahn, 1988). Three years later Oppenheim (1911) described the same disorder in four patients and coined the word “dystonia” to indicate that in this disorder, there would be hypotonia on one occasion and tonic muscle spasms on another, usually but not exclusively elicited on volitional movements. Oppenheim called this syndrome by two different names: “dystonia musculorum deformans” and “dysbasia lordotica progressiva.” The first name relates to the spasms and to the postural deformities that develop in these children; the second name emphasizes the dromedary gait and the progressive nature of the illness. Oppenheim described muscle spasms; bizarre walking with bending and twisting of the torso; rapid, sometimes rhythmic jerking movements; and progression of symptoms leading eventually to sustained fixed postural deformities.

Oppenheim, however, failed to recognize the inherited nature of the disorder, which was emphasized by Flatau and Sterling (1911) later that year; they suggested the name “progressive torsion spasm,” which perhaps would have been the preferred one, according to the full syndrome recognized today. The word “dystonia,” however, was immediately adopted by neurologists and has been used to describe both a distinctive motor phenomenology and a clinical syndrome in which these motoric features are present. Over time, different meanings were used for “dystonia” (for historical details, see Fahn et al., 1987). To clarify the definition, an ad hoc committee of the Dystonia Medical Research Foundation considered the clinical features described by Oppenheim (1911), Flatau and Sterling (1911) and other early observers, and developed the following definition: Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures (Fahn et al., 1987; Fahn, 1988). To emphasize the twisting quality of the abnormal movements and postures, the term “torsion” is often placed in front of the word “dystonia.” Such twisting is one feature that distinguishes dystonic movements from those of other dyskinesias, such as chorea, and distinguishes dystonic postures from other syndromes of increased muscle tone, such as rigidity, stiff-person syndrome, and neuromyotonia (Fahn, 1999). Exceptions to twisting are around joints that do not allow such torsion. Thus, dystonia involving the jaw, focusing on the temporomandibular joint, are jaw-opening and jaw-closing dystonias, rarely lateral jaw dystonia, but not twisting of the jaw.

The early observers described dystonia as a specific disease entity, but by the next decade, dystonia was recognized to be a feature in other neurologic disorders, such as Wilson disease and cerebral palsy, and following encephalitis. Soon, dystonia as a specific entity (today known as primary dystonia) was lost. It was Herz (1944a, 1944b, 1944c) who, in a masterful series of three papers, resurrected torsion dystonia as a specific neurologic entity as well as its presence within other neurologic diseases, who described the motor phenomenology and compared the duration of its contractions with those of chorea and athetosis, who utilized the analysis of cinematography to distinguish these differences in various movement disorders, and who showed the characteristic simultaneous contractions of agonist and antagonist muscles in dystonia. Another major pioneer in dystonia was Zeman (1970), who, along with his colleagues (Zeman et al., 1959, 1960; Zeman and Dyken, 1967), carried out the first epidemiologic study, emphasized the autosomal dominant pattern of inheritance, described the focal dystonias as formes frustes of generalized dystonia, and found the pathologic anatomy to be normal in primary torsion dystonia (PTD). The disparate varieties of focal dystonias were not linked as focal dystonias until Marsden placed them together (1976). Still, patients with dystonia, both generalized and focal, were often considered to be hysterical, i.e., to have a psychogenic disorder and not an organic one, as Lesser and Fahn (1978) pointed out, often with tragic consequences, as described in Cooper’s book (1976). Better awareness of the organic nature of dystonia, both generalized and focal (for torticollis and writer’s cramp were often considered hysterical), began to come about with the holding and publication of the first international symposium on dystonia (Eldridge and Fahn, 1976). The final proof came with the discovery of the gene locus for Oppenheim dystonia (Ozelius et al., 1989) and the discovery that dystonia in the Ashkenazi Jewish population was inherited in an autosomal dominant pattern (Bressman et al., 1989).

Other important events in the development of our understanding of dystonia are the formation of the Dystonia Medical Research Foundation in 1976, the creation of four international symposia on dystonia with their subsequent publications (Eldridge and Fahn, 1976; Fahn et al., 1988, 1998b, 2004), and the investigations of clinical and molecular genetics that are leading to the discovery of the mutated genes and clarifying the classification and clinical features of the dystonias (Bressman et al., 1989, 1994a; Ozelius et al., 1989, 1997; Nygaard et al., 1993; Ichinose et al., 1994). The advances in genetics have led to a better etiologic classification of the dystonias (Fahn et al., 1998a) and to the labeling of many of the dystonias using a “DYT” classification, as displayed in Table 12.1.

Table 12.1 Genetic classification of the dystonias

AD, autosomal dominant; AR, autosomal recessive.

A number of reviews covering the historical aspects are available to which the reader is referred for more details than are provided in this chapter (Fahn, 1984a; Fahn et al., 1987; Fahn and Marsden, 1987; Rothwell and Obeso, 1987; Fahn et al., 1988; Fahn, 1989a, 1990; Tsui and Calne, 1995; Jankovic and Fahn, 1998; Nemeth, 2002; Stacy, 2007; Breakefield et al., 2008). A collection of historical photographs about dystonia is available for perusal (Goetz et al., 2001).

Impact and overview of genetic discoveries

Perhaps the greatest advance in dystonia in the past 10 years has been the continual unraveling of an increasing number of distinct genetic forms of dystonia based on gene mapping and cloning. In turn, this has led to the beginning of molecular biology research in the dystonias and a more comprehensive classification of the dystonias based on etiology. The first genetic form of dystonia whose gene was mapped was the form described by Oppenheim (1911), which he called dystonia musculorum deformans and which is now called Oppenheim dystonia (Fahn et al., 1998a) and also DYT1 dystonia (because the mapped gene was given that designation). The gene for Oppenheim dystonia has been identified and cloned, but not before the gene responsible for another genetic form of dystonia was identified, namely, dopa-responsive dystonia (DYT5), or DRD, caused by a mutation in the gene for the enzyme guanosine triphosphate (GTP) cyclohydrolase I (GCH1). As genes are being mapped, the clinicians are able to use this information to better define the clinical features of each genetic type. Table 12.1 lists the currently known genetic designations for the dystonias. The last two genes identified in this nomenclature are those of NA-K-ATPase responsible for rapid-onset dystonia-parkinsonism (RDP) (DYT12) (de Carvalho Aguiar et al., 2004) and TAF1 (TATA box-binding protein-associated factor 1) for lubag (DYT3) (Makino et al. 2007). The official nomenclature committee has labeled 20 DYTs, but omitted other genetic forms of dystonia, which are listed in this section after the first 20. Moreover, clinical neurologists usually consider DYT8, DYT9, and DYT10 to be part of the category of movement disorders known as paroxysmal dyskinesias, and not the dystonia category. These are covered in Chapter 22. Also, the designation of DYT14 for a new form of DRD was incorrect. The family with “DYT14” was thought not to have the DYT5 gene deletion in GCH1 (Grotzsch et al., 2002), but subsequently a mutation in GCH1 was found (Wider et al., 2008). DYT14 has been eliminated in Table 12.1.

A number of other dystonias are known to be genetic, but have not received a “DYT” classification. Two new families with suspected DYT2 dystonia were reported (Khan et al., 2003; Moretti et al., 2005). Siblings from two families with consanguinity developed autosomal recessive childhood-onset generalized dystonia. Gene studies for other known genetic forms of dystonia were negative.

The gene causing lubag (DYT3) was reported to involve a multiple transcript system (Nolte et al., 2003). It was not initially possible to say which mutant protein (and there may be up to six from this mutation) is actually responsible for the disease. However, Makino and colleagues (2007) have subsequently found the mutation for lubag to be in the TAF1 gene.

The gene causing DYT6 was reported in 2009 as the THAP1 gene (Fuchs et al., 2009). Its function is unknown. Subsequently a search was made for familial dystonia with young onset and many more mutations were discovered in this gene, and the age at onset expanded to 49 years, with the majority still being young onset (Bressman et al., 2009). Screening for focal dystonia, singleton cases revealed far fewer cases, with a phenotype of young-onset spasmodic dysphonia that later spread to become generalized dystonia (Djarmati et al., 2009). The THAP1 gene was analyzed in a series of 362 British, genetically undetermined, primary dystonia patients, and nine mutations were found (Houlden et al., 2010). The main clinical presentation was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients); laryngeal or oromandibular dystonia was present in 3 cases. Thus, early-onset dystonia that includes involvement of the larynx or face should arouse suspicion of a THAP1 mutation. A search for THAP1 mutations in 1114 patients with adult-onset primary dystonia revealed different THAP1 sequence variants to be associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia (Xiao et al., 2010).

de Carvalho Aguiar and colleagues (2004) reported the identification of missense mutations in the gene for the Na+/K+-ATPase α3 subunit (ATP1A3) as a cause of RDP (DYT12).

A fuller description of the phenotype of DYT13 (craniocervical-brachial dystonia) has been reported in the only known family with this disorder (Bentivoglio et al., 2004). Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in the upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred in only two cases. There was no anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13 is an autosomal dominant disease, with incomplete penetrance (58%).

Two independent studies searched for mutations in the ε-sarcoglycan gene in patients with familial and sporadic myoclonus–dystonia and did not find any (Han et al., 2003; Valente et al., 2003). This finding, plus the report of one family having a mutation on a different chromosome, 18p11 (DYT15), provides additional evidence for genetic heterogeneity in myoclonus–dystonia.

Two unrelated consanguineous Brazilian families with early-onset dystonia–parkinsonism were found to have a mutation in the PRKRA gene for protein kinase, interferon-inducible double-stranded RNA-dependent activator and it has been labeled as DYT16 (Camargos et al., 2008).

DYT17 is the designation given to a large consanguineous Lebanese family in which three sisters had primary torsion dystonia beginning with torticollis at ages 14, 17, and 19 years, spreading to segmental and generalized in one of the sisters (Chouery et al., 2008).

DYT18, DYT19, and DYT20 are paroxysmal dyskinesias and are covered in Chapter 22. DYT21 is an autosomal dominant family from northern Sweden of adult onset manifesting combinations of focal, segmental and generalized dystonia (Holmgren et al., 1995; Norgren et al., 2011).

A number of dystonic conditions are not labeled as “DYT,” but dystonia is part of their features (Table 12.2).

Table 12.2 Unlabeled as “DYT” but dystonia is present as well as other neurologic features in some of these disorders

AD, autosomal dominant; AR, autosomal recessive.

The association with a polymorphism in the D5 receptor gene (DRD5) for primary focal dystonias could not be confirmed in German and French patients (Sibbing et al., 2003), but was seen in Italian patients (Brancati et al., 2003).

The autosomal recessive disorder of early-onset cerebellar ataxia with oculomotor apraxia associated with a mutation of the aprataxin gene on chromosome 9p13 can also cause generalized dystonia (Sekijima et al., 2003). Adult-onset craniocervical dystonia preceded ataxia in a case with spinocerebellar ataxia type 1 (SCA1) (Wu et al., 2004). Cervical dystonia was also seen in SCA10 (Gatto et al., 2007), and spasmodic dysphonia has been reported in SCA17 (Hagenah et al., 2004, 2007).

Some patients with adult-onset dystonia have been found to have a missense mutation in the mitochondrial complex I gene (Simon et al., 2003). In addition to dystonia, spasticity and core-type myopathy are present.

A screen for a combination of dystonia with cerebellar atrophy identified eight such families (Le Ber et al. 2006), which raises the possibility that the cerebellum could be involved in dystonia (Jinnah and Hess, 2006), but more likely these families suggest a phenotype of a newly recognized neurodegenerative disease.

Although the GAG mutation in torsinA (TOR1A) is rare and causes young-onset limb-onset dystonia, two polymorphisms in or near the TOR1A gene have been discovered to be common in idiopathic focal dystonia, raising the possible association of a risk factor for this gene and the common adult-onset focal dystonias (Kamm et al., 2006).

Phenomenology of dystonic movements

With few exceptions, the four clinically unifying, consistent, and predominant features of dystonic contractions are (1) their relatively long duration (compared to myoclonus and chorea), although short-duration contractions can occur in dystonia; (2) their simultaneous contractions of agonists and antagonists; (3) their resulting in a twisting of the affected body part; and (4) their continual contractions of the same muscle groups (called patterned movements, see Chapter 1). One exception to the twisting nature of dystonia is that dystonias in facial muscles are rarely twisting; they are patterned and involve sustained contractions of forehead, eyelids, and lower face. As it turns out, twisting facial muscles that move the mouth to one side or the other or back and forth to each side are usually psychogenic (see Chapter 25).

Although the durations of the patterned contractions are usually more sustained than those of chorea, sometimes they can be very short. The range from very short to very prolonged contractions results in the appearance of a wide range in the speed of the patterned dystonic movements from rapid to slow. The movements can be so fast that they have the appearance of repetitive myoclonic jerking. The term “myoclonic-dystonia” has been applied to such dystonia (Davidenkow, 1926; Obeso et al., 1983; Kurlan et al., 1988; Quinn et al., 1988), and the rapid jerks may respond to alcohol (Quinn et al., 1988). In some families, the phenomenology of the combination of myoclonus and dystonia is a major feature, and these families are genetically distinct from those of the originally described PTD (i.e., Oppenheim dystonia) (Wahlström et al., 1994) and have been called by different names, initially dystonia–myoclonus (Fahn et al., 1998a), but now myoclonus–dystonia (Klein et al., 1999; Nygaard et al., 1999). The relationship of familial myoclonus–dystonia and hereditary essential myoclonus, which can also include patients with some dystonic features, is not clear (Fahn and Sjaastad, 1991; Quinn, 1996), but will soon be settled, as the identification of a gene (ε-sarcoglycan) for myoclonus–dystonia has been discovered (Zimprich et al., 2001).

Primary dystonia almost always begins by affecting a single part of the body; this is focal dystonia (Video 12.1). Most patients’ dystonia remains as a focal dystonia without spreading to other parts of the body. However, even within that single body part, multiple muscles can be affected. Thus, in patients with dystonia of the neck (cervical dystonia, or torticollis) a combination of muscles are involved (Video 12.2). Moreover, even if the neck is postured to a stable position, there can be changes in muscle contraction patterns that can be detected with EMG recordings (Munchau et al., 2001a). In a sizeable minority of patients, dystonia that starts in one body part can spread to involve other parts of the body. Most often, the spread is to contiguous body parts; hence, the spread is from focal dystonia to segmental dystonia. The pattern of spread of adult-onset focal dystonias has been analyzed, especially blepharospasm (Fahn, 1985; Weiss et al., 2006), as has the spread of childhood-onset dystonia (Greene et al., 1995). In blepharospasm, spread to other body parts is faster in patients who carry at least one T allele in a polymorphism site on the TOR1A gene (Defazio et al. 2009). As a general rule, the younger the age at onset, the more likely it is that the dystonia will spread; for example, childhood onset with leg involvement usually leads to eventual generalized dystonia (Marsden et al., 1976; Fahn, 1986; Greene et al., 1995). Regardless of genetic etiology, the phenotypes of primary dystonias are affected by age at onset, with a caudal-to-rostral change in the site of onset as a function of age (O’Riordan et al., 2004). The severity of dystonia can be quantified by using clinical rating scales for generalized dystonia and the various focal dystonias (Burke et al., 1985; Fahn, 1989b; Comella et al., 1997, 2003).

Dystonic movements are almost always aggravated during voluntary movement. The appearance of dystonic movements with voluntary movement is referred to as “action dystonia.” Primary dystonia commonly begins with a specific action dystonia, that is, the abnormal movements appear with a special action (i.e., task-specific action) and are not present at rest, in contrast to secondary dystonias which are more likely to begin with dystonia at rest (Svetel et al., 2004). For example, a child who develops primary dystonia might have the initial symptom in one leg, but only when walking forward. It could be absent when the child runs or walks backward (Video 12.3). Other common examples are the task-specific dystonias that are seen with writing (writer’s cramp) (Video 12.4), playing a musical instrument (musician’s cramp) (Video 12.5), chewing (Video 12.6), and speaking, including auctioneering (Scolding et al., 1995). Often, these task-specific dystonias produce occupational disability; e.g., musicians usually no longer can play their instrument professionally. Robert Schumann’s career as a pianist was impaired, probably because of musician’s cramp (de Yebenes, 1995). Musician’s cramp and other occupational cramps can occur in any part of body that is engaged in repetitive, highly skilled tasks (Altenmüller and Jabusch, 2010). Embouchure (the pattern of lip, jaw, and tongue muscles used to control the flow of air into a mouthpiece) dystonia has been seen in horn and woodwind players (Frucht and Estrin, 2010). Patients with embouchure dystonia can be separated into several groups, including embouchure tremor, involuntary lip movements, and jaw closure (Frucht et al., 2001). The dystonia can spread to other oral tasks, often producing significant disability. Musician’s dystonia, like other focal dystonias (discussed below in pathophysiology of primary dystonia), is associated with increased sensorimotor activation (Haslinger et al., 2010). Focal task-specific tremors might be a form of focal dystonia rather than a manifestation of essential tremor (Soland et al., 1996b). Several reviews of musician’s cramps were presented at an international symposium on dystonia (Brandfonbrener and Robson, 2004; Charness and Schlaug, 2004; Frucht, 2004; Jabusch and Altenmuller, 2004; Pesenti et al., 2004).

As the dystonic condition progresses, less specific voluntary motor actions of the involved limb can bring out the dystonic movements (see Table 12.3). In the above example, the affected leg might also activate the dystonia when it is tapping the floor. With further evolution, actions in other parts of the body can induce dystonic movements of the involved leg, so-called “overflow.” Talking is the most common mechanism for causing overflow dystonia in other body parts. Such activation of involuntary movements by talking is also particularly common with levodopa-induced dyskinesias and in cerebral palsy. With still further worsening, the affected limb can develop dystonic movements while it is at rest. Eventually, the leg can have sustained posturing. Thus, dystonia at rest is usually a more severe form than pure action dystonia. Whereas primary dystonia often begins as action dystonia and may persist as the kinetic (clonic) form, symptomatic dystonia often begins as sustained postures (tonic form). Sustained postures may appear in specific placements of the body. For example, the trunk may be in normal posture when the patient is lying supine or prone, but develop into kyphosis, scoliosis, or lordosis when sitting or standing. Thus, this dystonia is not a fixed dystonia (non-changing with a change in body posture and unable to be altered by the examiner applying normal strength to move the affected body part). Fixed postures, with or without pain, are often psychogenic in origin (Fahn and Williams, 1988; Lang, 1995; Sa et al., 2003; Schrag et al., 2004), although there may be organic cases. Transcranial magnetic stimulation studies revealed similar physiologic alterations in the cerebral cortex as seen in patients with mobile dystonia (Avanzino et al., 2008), but as Espay and colleagues (2006) have shown, and as discussed in Chapter 25, the changes in the brain can be secondary to the abnormal psychogenic postures or sensory abnormalities.

Much less common than action dystonia or overflow dystonia is the reverse phenomenon, i.e., for dystonia at rest to be improved by talking or by other voluntary active movements, so-called paradoxical dystonia (Fahn, 1989c). With paradoxical dystonia the patient is usually observed moving the affected or non-affected body part. The patient does this to obtain relief of the dystonia. When the paradoxical dystonia involves the trunk, the observer can easily mistake the patient’s moving about as being due to restlessness or akathisia, which is the most common differential diagnosis (Video 12.7). The focal dystonia that is most commonly decreased by voluntary motor activity is blepharospasm (Fahn et al., 1985). About 60% of patients with blepharospasm obtain relief when talking; about 40% worsen with talking.

Dystonia usually is present continually throughout the day whenever the affected body part is in use; and as a sign of more severity, also when the body part is at rest. A notable phenomenologic feature of DRD is that of diurnal variation in many of the patients, with the dystonia being worse at the end of the day, and minimal in the morning hours (Segawa et al., 1976). Dystonic movements tend to increase with fatigue, stress, and emotional states; they tend to be suppressed with relaxation, hypnosis, and sleep (Fish et al., 1991). Dystonia may be precipitated or exacerbated by pregnancy (dystonia gravidarum) (Lim et al., 2006). Unless it is extremely severe, dystonia often disappears with deep sleep. For patients who appear to have persistent postural abnormalities that cannot be overcome by manual manipulation, it might be necessary to put them to sleep with anesthesia to determine whether a contracture is already present (Fahn, 2006). Propofol anesthesia, however, does not entirely suppress dystonia because recurrences occur even under deep propofol anesthesia (Zabani and Vaghadia, 1996).

One of the characteristic and almost unique features of dystonic movements is that they can often be diminished by tactile or proprioceptive “sensory tricks” (geste antagoniste). Thus, touching the involved body part or an adjacent body part can often reduce the muscle contractions (Video 12.8). For example, patients with torticollis will often place a hand on the chin or side of the face to reduce nuchal contractions, and orolingual dystonia is often helped by touching the lips or placing an object in the mouth (Blunt et al., 1994; Lo et al., 2007). In a study of 50 patients with cervical dystonia who were known to have at least one sensory trick, 54% of them had two to five different tricks and 82% had a reduction of head deviation by at least 30%, with a mean of 60% (Muller et al., 2001). In cervical dystonia, applying the trick when the head is in a neutral or even contralateral position was most effective, while no reduction of muscle activity occurs during trick application at the maximum dystonic head position (Schramm et al., 2004). Sometimes a mechanical device can be utilized therapeutically, especially for cervical dystonia (Krack et al., 1998) (Video 12.9). Greene and Bressman (1998) found that in some patients with torsion dystonia, simply thinking about a sensory trick or task affects the dystonia in the same way as actually performing the activity. A positron emission tomography (PET) study has shown that the sensory trick brings about a normalization of the abnormal cortical physiology that is seen in dystonia, and results in increasing activation of the ipsilateral superior and inferior parietal lobule and decreasing activity of the contralateral supplementary motor area and the primary sensorimotor cortex (Naumann et al., 2000). The presence of a sensory trick is not specific for primary dystonias; it can sometimes occur in secondary dystonias, including psychogenic dystonia (Munhoz and Lang, 2004).

Pain is uncommon in dystonia except in cervical dystonia; 75% of patients with cervical dystonia (spasmodic torticollis) have pain (Chan et al., 1991). The pain perception threshold appears to be lower in patients with primary cervical dystonia (Lobbezoo et al., 1996). Dystonia in most parts of the body rarely is accompanied by pain; when it is, it is not clear whether the pain is due to painful contractions of muscles or some other factor. The high incidence of pain in cervical dystonia appears to be due to muscle contractions because this pain is usually relieved by injections of botulinum toxin (Greene et al., 1990). It is believed that the posterior cervical muscles are rich in pain fibers, and that continual contractions of these muscles results in pain. On the other hand, because no correlation was found between the severity of motor signs and pain, some investigators hypothesize that central mechanisms are also involved (Kutvonen et al., 1997). Quality of life is negatively affected with cervical dystonia (Camfield et al., 2002). It has been difficult to explain fixed painful postural torticollis following trauma, but recent analysis indicates that many of these cases appear to be psychogenic (Sa et al., 2003). Fixed dystonia in other parts of the body is also usually associated with a peripheral injury and overlaps with chronic regional pain syndrome (reflex sympathetic dystrophy); many of these individuals fulfill strict criteria for a somatoform disorder or psychogenic dystonia (Schrag et al., 2004).

Patients with PTD sometimes have rhythmical movements, particularly in the arms (Video 12.10) and neck, manifested as a tremor (Yanagisawa et al., 1972; Jankovic and Fahn, 1980). In one survey, 68% of patients with cervical dystonia had head tremor (Pal et al., 2000). Two basic types of tremors are seen in dystonic patients: (1) an accompanying postural/action tremor of the upper limbs that resembles essential tremor or enhanced physiologic tremor and (2) a tremor that is a rhythmic expression of rapid dystonic movements (Yanagisawa and Goto, 1971); these occur at the site of the tremor, such as arms, neck, or jaw (Schneider and Bhatia, 2007). The latter can usually be distinguished from the former by showing that the tremor appears only when the affected body part is placed in a position of opposition to the major direction of pulling by the abnormal dystonic contractions and disappears when the body part is positioned where the dystonia wants to place it. Dystonic tremor appears to be less regular than essential tremor (Jedynak et al., 1991). Tremor of the hands in patients with cervical dystonia tends to be irregular and therefore dystonic, rather than an accompanying essential tremor (Shaikh et al., 2008). Sometimes, it is very difficult to distinguish between the two types, particularly with writing tremor and cervical tremor. Primary writing tremor can sometimes represent task-specific dystonia or task-specific essential tremor (Cohen et al., 1987; Rosenbaum and Jankovic, 1988; Elble et al., 1990). A family history of tremor (and stuttering) is increased in PTD (Fletcher et al., 1991a).

Although accompanying essential tremor is recognized in patients with dystonia (Lou and Jankovic, 1991), there is uncertainty as to how common this occurrence is. Tremor of the hands can be seen fairly often in patients with cervical dystonia (spasmodic torticollis) (Couch, 1976). Deuschl and colleagues (1997) analyzed this tremor in 55 patients with cervical dystonia. The mean amplitudes of postural tremor were only slightly higher than those of the controls and much smaller than those found in classic essential tremor; analytic measurements showed evidence of physiologic tremor mechanisms only. In another study, arm tremor in patients with cervical dystonia was found to develop either before or simultaneously with onset of the torticollis; such temporal relationships do not correspond to either dystonic tremor or tremor in the presence of dystonia (Munchau et al., 2001c).

What can be mistaken for tremor or rhythmic jerky movements is the tendency for patients with dystonia to fight the abnormal pulling of dystonic muscles into a sustained posture. Asking the patient not to resist the pulling of the muscles and just relax and let the muscles go where they seek to go will usually enlighten the examiner that those jerky movements are actually a directional pulling with the patient trying to overcome the pull. One can position the affected body part into different postures to determine if there is a “null point” where the jerky movements or tremor ceases, indicating the position the involved muscles are seeking.

Tics are another type of involuntary movement that appears to occur more commonly in patients with dystonia than in the general population (Shale et al., 1986; Stone and Jankovic, 1991; Damasio et al., 2011).

Although this is rare, some children and adolescents with primary and secondary dystonia can develop a crisis of sudden marked increase in the severity of dystonia, which has been called dystonic storm (Dalvi et al., 1998) and status dystonicus (Manji et al., 1998). It can cause rhabdomyolysis and myoglobinuria, with a threat of death by renal failure (Jankovic and Penn, 1982; Paret et al., 1995). Placing the patient in an intensive care unit and narcotizing him or her with barbiturates is usually necessary to treat this crisis. Intrathecal baclofen might be necessary if the dystonic storm persists and continues to be present when the patient is allowed to awaken (Jankovic and Penn, 1982; Dalvi et al., 1998). More recently, pallidotomy or pallidal stimulation has been utilized in place of intrathecal baclofen.

A case of orthostatic hemidystonia has been reported (Sethi et al., 2002). The patient developed hemidystonia on rising from the sitting position. It was due to poor vascular perfusion in the contralateral frontoparietal cortex and was the result of occlusion of the contralateral internal carotid artery and near-total occlusion of the ipsilateral internal carotid artery.

Dystonia patients are relatively free of psychopathology, as measured in patients with writer’s cramp (Sheehy and Marsden, 1982) and blepharospasm (Scheidt et al., 1996). However, a recent study reports a prevalence of obsessive-compulsive disorder in 20% of patients with primary focal dystonias (Cavallaro et al., 2002). Attentional-executive cognitive deficits have been found in patients with primary dystonia by using the Cambridge Neuropsychological Test Automated Battery (Scott et al., 2003), but not by using a host of other tests (Jahanshahi et al., 2003). Obsessive-compulsive disorder and alcohol dependence are not uncommon in individuals who carry the DYT11 gene for myoclonus–dystonia (Saunders-Pullman et al., 2002), and the DYT1 gene has been associated with an increase in depression, whether the person is a manifesting or nonmanifesting carrier (Heiman et al., 2004).

Site of body involvement is characteristic for many types of dystonia. Children usually have onset equally in a leg or an arm, at least for Oppenheim dystonia. Adult-onset dystonia is typically in the upper body, cranial, cervical, or brachial. A few adult patients may have focal truncal dystonia. Foot onset in adults is uncommon, but does occur (Schneider et al., 2006b). Isolated foot dystonia following exercise in adults is sometimes seen as the first symptom of Parkinson disease. This has now been verified in a patient with neuroimaging by using dopamine transporter single photon emission computed tomography (SPECT). Childhood-onset dystonia that begins in the cranial region is usually non-DYT1 dystonia (Bressman et al., 2000; Fasano et al., 2006). Dystonia may be the presenting or dominant feature of many parkinsonian disorders besides Parkinson disease (Jankovic, 2005; Ashour and Jankovic, 2006). Sometimes dystonia involving the foot can resemble a Babinski sign. This pseudo-Babinski (striatal toe) can be a dystonic phenomenon and should be differentiated from a true Babinski sign seen with pyramidal tract lesions (Horstink et al., 2007).

Epidemiology

Zeman and his colleagues (Zeman and Dyken, 1967; Zeman et al., 1959, 1960) carried out the first epidemiologic study in dystonia in the population of the state of Indiana and emphasized the autosomal dominant pattern of inheritance in PTD. They considered only generalized dystonia to be PTD, and viewed other types as formes frustes. Today, those other forms are viewed as focal and segmental dystonia, and part of the spectrum of PTD. An epidemiologic study of PTD in the population living in Rochester, Minnesota, found the prevalence of generalized PTD to be 3.4 per 100 000 population, and the prevalence of focal dystonia to be 30 per 100 000 (Nutt et al., 1988). In a study of dystonia in Israel, Zilber and colleagues (1984) estimated the prevalence of generalized dystonia among Jews of Eastern European ancestry to be 1/15 000 or 6.8/100 000, which is double the prevalence in the general population of Rochester. However, the analysis by Risch and colleagues (1995) indicates that the frequency in the Ashkenazim is much higher (between 1/6000 and 1/2000), and they suggest that the Ashkenazi population with PTD descends from a limited group of founders of the DYT1 mutation. These investigators also have traced the origin of the mutation to the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia), approximately 350 years ago. In Japan, the DYT1 mutation was looked for in 178 patients with various forms of dystonia and was found in 6 (3.4%) (Matsumoto et al., 2001) and phenotypically resembled Oppenheim dystonia seen in other populations.

In Japan the prevalence rate of focal dystonias was found to be 6.12 (Nakashima et al., 1995), 10.1 (Matsumoto et al., 2003), 13.7 (Fukuda et al., 2006), and 14.4 (Sugawara et al., 2006) per 100 000 population, all of which is considerably lower than the 30/100 000 found by Nutt et al. (1988) in Rochester, Minnesota. The prevalence of focal limb dystonia in India was higher, 49.06/100 000 (Das et al., 2007). In the north of England, the prevalence of focal dystonias was found to be 12 per 100 000, and the prevalence of generalized dystonia was found to be 1.6 per 100 000 (Duffey et al., 1998). A European consortium of investigators published their findings of 11.7 per 100 000 for focal dystonia and 3.5 per 100 000 for segmental and generalized primary dystonias (Warner et al., 2000). A survey of primary blepharospasm in the Puglia region of southern Italy found a prevalence of only 13.3 per 100 000 (Defazio et al., 2001). The incidence rate of primary blepharospasm was found to be 1.2 per 100 000 population per year in Olmsted County, Minnesota (Bradley et al., 2003). Incidence for cervical dystonia was higher in white individuals (1.23/100 000/year) than in persons of other ethnicities (0.15/100 000/year) (Marras et al., 2007).

In Belgrade, the prevalence rate for focal, segmental, and multifocal dystonia was 13.6 per 100 000 population (Pekmezovic et al., 2003). It was almost twice as common (25.4 per 100 000 population) in Oslo (Le et al., 2003). Gender appears to play a role in both the prevalence and the age at onset of focal dystonia, women being more at risk and having an earlier age at onset for writer’s cramp, but men having an earlier age at onset for cervical dystonia, blepharospasm, and laryngeal dystonia (Epidemiologic Study of Dystonia in Europe (ESDE) Collaborative Group, 1999; Marras et al., 2007).

Table 12.4 lists epidemiologic studies of PTD.

Classification of torsion dystonia

Table 12.5 presents the three ways to classify patients with torsion dystonia: by age at onset, by body distribution of abnormal movements, and by etiology. This method allows physicians and health-care providers some understanding of the nature of the dystonia, including prognosis.

Table 12.5 Three ways to classify torsion dystonia