Dystonia: Phenomenology, classification, etiology, pathology, biochemistry, and genetics

Historical highlights

Before the twentieth century, there are several suggestions in paintings, texts, and sculpture that dystonia was noted as far back Hippocrates and Celsus ( ). 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 ( ). Three years later 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 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 ). 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 after encephalitis. Soon, dystonia as a specific entity (today known as primary dystonia) was lost. It was Herz (1944a,b,c) who, in a masterful series of three papers, resurrected torsion dystonia as a specific neurologic entity and its presence within other neurologic diseases, described the motor phenomenology and compared the duration of its contractions with those of chorea and athetosis, and used the analysis of cinematography to distinguish these differences in various movement disorders and showed the characteristic simultaneous contractions of agonist and antagonist muscles in dystonia.

Another major pioneer in dystonia was , who, along with his colleagues ( , ; ), 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, that is, to have a psychogenic disorder and not an organic one, as pointed out, often with tragic consequences, as described in the book by . 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 ( ). The final proof came with the discovery of the gene locus for Oppenheim dystonia ( ) and the discovery that dystonia in the Ashkenazi Jewish population was inherited in an autosomal dominant pattern ( ).

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 ( ; , , ), 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 ( , ; , ; ; ). The advances in genetics have led to a better etiologic classification of the dystonias ( ) and to the labeling of many of the dystonias using a “DYT” classification. Reviews covering the historical aspects are available, to which the reader is referred for more details than are provided in this chapter ( ; 1989a, 1990; ; , 1988; ; ; ; ; ; ; ). A collection of historical photographs related to dystonia also has been published ( ).

Phenomenology of dystonic movements

Dystonia is a disorder that is diagnosed clinically. There are no clinically available diagnostic laboratory or imaging tests to confirm the diagnosis. Nor are there validated diagnostic criteria that can be applied. The diagnosis depends entirely on the recognition of the clinical features. Isolated (primary dystonia) usually begins by affecting a single part of the body; this is focal dystonia ( Video 11.1 ). Adult-onset focal dystonias are much more common than generalized dystonias ( ; ) ( Table 11.1 ). Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. ( ). Young-onset generalized isolated (primary) dystonia is frequently associated with a genetic mutation (see next section). Dystonia is a dynamic disorder and rarely a fixed posture. Dystonia may appear on some actions and not others. For example, walking forward may enhance a foot dystonia that disappears when walking backward ( Video 11.2 ). Dystonia is a chronic disorder but may fluctuate over time. Remissions do occur, have been assessed using a meta-analysis ( ), and are most frequent in cervical dystonia in which up to 12% may have complete remission and 4% a partial remission. Blepharospasm has a reduced remission rate, with 15% having complete and 6% partial remissions. These occurred approximately 4 to 5 years after onset, but recurrence rates were high, with approximately 64% having a relapse. A younger age of onset was associated with more frequent remissions ( ).

Video 11.1 Blepharospasm.

Video 11.2 Dystonia of leg, with active voluntary movement.

Generalized dystonia is defined as representing a combination of segmental crural dystonia (i.e., both legs or legs plus trunk) plus involvement of any other area of the body ( Video 11.3, Video 11.4, Video 11.5, Video 11.6 ). Isolated generalized dystonia rarely begins in adulthood. The typical clinical picture is onset as a focal dystonia in the limb of a child or adolescent. The dystonia worsens in the affected area and over years typically spreads to involve the body and becomes generalized dystonia. Although isolated generalized dystonia is motorically disabling, cognitive impairment is not a feature unless there is an underlying neurologic disorder. However, psychological disturbances are frequent in dystonia, including sleep disturbance, anxiety, depression and fatigue. Suicidal ideation was recently reported to affect up to 32% of patients, mostly those with generalized dystonia.

Video 11.3 Generalized dystonia.

Video 11.4 Generalized dystonia.

Video 11.5 Generalized dystonia that evolved into a fixed posture.

Video 11.6 Generalized dystonia with inability to walk or crawl.

Rarely, 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 ( ) and status dystonicus ( ). Status dystonicus is a medical emergency. It can cause rhabdomyolysis and myoglobinuria, with a threat of death by renal failure ( ; ). Status dystonicus may be triggered by several factors. One of the most frequent triggers is an infection. Other causes include malfunctioning of deep brain stimulation (DBS), adjustment of medications, surgical procedures, and metabolic disorders. However, up to one-third of patients will not have an identifiable precipitating factor. The dystonia storm may last up to 2 weeks, and the mortality is approximately 10%. The treatment of status dystonicus initially involves making the appropriate diagnosis. Medications are often used first, including tetrabenazine and anticholinergic agents. Sedation is often required, which may be achieved with propofol, benzodiazepines or anesthesia. DBS also has been successfully used to treat the symptoms. Early recognition and treatment are imperative. Intensive care monitoring is often necessary ( ; ; ; ; , ).

Focal dystonia may affect different regions of the body ( Table 11.2 ). Focal dystonia indicates that only a single area of the body is affected. Dystonia of the eyes is called blepharospasm. Blepharospasm is typically an adult-onset disorder. The facial muscles involved usually include the orbicularis oculi, procerus, and corrugator muscles. Blepharospasm is an involuntary blinking, narrowing, or closing of the eyes. Although usually symmetrical, asymmetry of eye closure can occur. Blepharospasm may have at onset a feeling of discomfort or grittiness in the eyes. It varies in severity and in severe cases may cause functional blindness. The spasms may be triggered by reading, bright light, and wind. Stress usually worsens the symptoms. Some patients may have alleviating maneuvers, such as touching the side of the face, yawning, or reading. Blepharospasm is a heterogeneous disorder that varies among individuals. It may remain focal, or it may spread to involve the lower face and jaw (craniofacial dystonia) ( , ).

Cervical dystonia (formally spasmodic torticollis) is a focal dystonia involving the neck muscles, causing a turning, tilting, or flexion of the head and neck ( Video 11.7 ). Cervical dystonia rarely consists of only a single head movement and is a complex disorder in which multiple postures may be present. Often shoulder movements are included, with shoulder elevation, or rotation. Cervical dystonia is frequently associated with pain in the neck region, and the pain may be more disabling than the movement. Cervical dystonia more frequently affects women than men (2–3 to 1). Over half are noted to have a head tremor, and in many there is an associated hand tremor. The onset of symptoms is usually in the mid-forties. Although most remain focal, approximately a third will develop more extensive spread of the dystonia to laryngeal muscles and arm ( , 2019).

Video 11.7 Cervical dystonia.

Oromandibular dystonia affects the muscles of the jaw, with involuntary jaw opening, deviation, or closing. A summary of clinical data from 240 patients indicates that the age of onset is typically in the 50s, with a 2:1 female predominance compared with men. In this study, lingual dystonia was present in approximately 27% of the patients, and most had associated segmental or generalized dystonia. Frequently, oromandibular dystonia is an isolated dystonia, with no identifiable underlying cause ( ). Jaw closing dystonia may be the most frequent form of oromandibular dystonia ( ). Severe jaw closing dystonia impairs speech and eating. The forced closure may cause trauma to the tongue and cheeks. The most frequently involved muscles are the masseter and medial pterygoids. Jaw opening dystonia is less common. The forced jaw opening is often painful and results in abnormal speech. The muscles frequently involved include the medial pterygoids and digastric. Jaw deviation is the least common form, but may be combined with either jaw opening or closing. Typically the pterygoid muscles contracting asymmetrically underlie this movement. In addition to the mechanical difficulties with feeding and speech, the social implications of oromandibular dystonia can be significant.

Laryngeal dystonia (spasmodic dysphonia) is a rare, task-specific dystonia that is triggered by speech. The most frequent is the adductor type, in which the voice is strained and effortful. There are intermittent breaks in vowels while speaking, and the symptoms may be reduced during whispering. Abductor laryngeal dystonia is characterized by intermittent breathy breaks particularly during ongoing speech. Both abductor and adductor types of laryngeal dystonia demonstrate normal structure and symmetry of the vocal cords during otolaryngoscopy but demonstrate the dystonic contractions during speech. Muscular tension dysphonia is characterized by a continuous strained voice quality that occurs consistently during speech. There are no breaks in the voice, and on direct examination there is a continuous supraglottic compression. Finally, the vocal tremor type of spasmodic dysphonia demonstrates oscillation of the voice particularly with sustained expression of vowels. This type of dysphonia is characterized by bobbing of various structures, including the vocal cords, tongue, and pharynx ( ; ; , ).

Lingual dystonia involves the tongue. Tongue movements may be lateral or vertical, and many involve tongue protrusion. It can be part of a segmental dystonia, most frequently jaw, lower face, and craniofacial dystonia with blepharospasm ( ). It can be seen as a part of other neurologic disorders, such as neuroacanthocytosis, where it manifests as a feeding dystonia with the tongue involuntarily pushing food out of the mouth. It is also seen in neurodegenerative diseases and has been described associated with corticobasal syndrome ( ; ).

Limb dystonia can involve the upper and lower extremities. In childhood-onset dystonia, the disorder frequently begins in the foot or leg. Approximately 50% will subsequently spread to become generalized dystonia. Limb dystonia is often action and posture dependent. As an example, at rest there may be no abnormal movements, but with assuming a posture with outstretched arms, the dystonic movements become manifest as a twisting, turning, extension, or flexion of the fingers, hand, or arm. Limb dystonia is often a task-specific dystonia. One that is common is called writer’s cramp, in which there is dystonic posturing of the hand and the fingers but restricted to the specific action of writing. ( Video 11.8 ), playing a musical instrument (musician’s cramp) ( Video 11.9 ), chewing ( Video 11.10 ), and speaking, including auctioneering ( ). Often, these task-specific dystonias produce occupational disability—for example, musicians usually no longer can play their instrument professionally. Robert Schumann’s career as a pianist was impaired, probably because of musician’s cramp ( ). Musician’s cramp and other occupational cramps can occur in any part of body that is engaged in repetitive, highly skilled tasks ( ). 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 ( ). Patients with embouchure dystonia can be separated into several groups, including embouchure tremor, involuntary lip movements, and jaw closure ( ). The dystonia can spread to other oral tasks, often producing significant disability. Musician’s dystonia, like other focal dystonias (discussed later in the section on pathophysiology of primary dystonia), is associated with increased sensorimotor activation ( ). Focal task-specific tremors might be a form of focal dystonia rather than a manifestation of essential tremor (ET) ( ). Several reviews of musician’s cramps were presented at an international symposium on dystonia ( ; ; ; ; ).

Video 11.8 Writer’s cramp.

Video 11.9 Musician’s cramp.

Video 11.10 Action focal dystonia of the jaw when chewing.

Focal dystonia can spread to involve two or more contiguous body parts and are then referred to as segmental dystonia. These are described in Table 11.3 .

Classification

The definition of dystonia was first formulated by a committee organized by the Dystonia Medical Research Foundation and led by Stanley Fahn. The definition was as follows:

Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Fahn, 1988

To emphasize the twisting quality of the abnormal movements and postures, the term torsion is placed in front of the word dystonia . This twisting characteristic and the patterned movement are features that distinguish 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 ( ). The four consistent and predominant features of dystonic contractions were described as (1) relatively long duration (compared with myoclonus and chorea), although short-duration contractions can occur in dystonia; (2) simultaneous contractions of agonists and antagonists; (3) resulting in a twisting of the affected body part; and (4) continual contractions of the same muscle groups. Dystonia was classified as primary with dystonia as the sole manifestation, which could be hereditary or sporadic; secondary with additional neurologic, genetic, or environmental causes; and psychological, arising from nonphysical conditions. Using this definition, dystonia was further classified according to the age of onset, distribution in body regions, and cause ( ( Table 11.6 ).

Classification by age at onset is useful because there are different implications for underlying genetic mutations and prognosis based on this feature. Age of onset may be the most important single factor related to prognosis of primary dystonia ( ; ; ). When dystonia begins at a young age (26 years or younger), it is likely to begin in the limb, often the leg, and will usually spread to other body areas and in most cases become generalized ( ) ( Video 11.15 ). When dystonia begins at an older age (older than 26 years), it typically will begin in one body area, usually the upper body, with some spread to adjacent body areas but typically not evolve into generalized dystonia ( ) ( Video 11.7 ).

Video 11.15 Generalized torsion dystonia.

Video 11.16 Onset of Oppenheim dystonia involving a leg.

Video 11.17 Worsening of dystonia over time.

Subsequently, the Dystonia Medical Research Foundation, the Dystonia Coalition and the European Dystonia Cooperation in Science and Technology organized a consensus committee to further delineate the phenomenology and propose a modification of the classification scheme for dystonia. The revised definition of dystonia was as follows:

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically pattered, twisting and may be tremulous.

The committee proposed a new classification system that consisted of two axes ( ) ( Fig. 11.1 ). The term primary dystonia was abandoned in favor of isolated dystonia, in which dystonia is the only motor feature besides tremor. If additional findings such as parkinsonism, ataxia, or myoclonus was present, the terminology used was combined dystonia. Axis I focused on the clinical characteristics of dystonia. Age of onset was divided into onset in infancy (birth to 2 years), childhood (3–12 years, adolescence (13–20 years), early adulthood (21–40 years), and late adulthood (older than 40 years). Body distribution included focal (single body region affected), segmental (two or more contiguous body regions affected), multifocal (two noncontiguous body areas affected) and generalized (trunk and at least two other sites involved, with or without leg involvement), and hemidystonia (dystonia restricted to one body side). Temporal pattern included persistent (severity stable throughout the day), action-specific (dystonia occurring only with a particular activity or task), diurnal fluctuations (discernible circadian variations in dystonia), and paroxysmal (sudden episodes of dystonia with return to preexisting neurologic status).

Axis II focused on underlying cause. There are two components of this axis. The presence or absence of nervous system pathologic features is the basis of the first component and is classified as degeneration (progressive structural abnormality), static lesions, (nonprogressive neurodevelopmental anomalies or acquired lesions), and no evidence of degeneration or structural lesion. The second component describes whether the dystonia is inherited or acquired. In the inherited forms, a genetic origin is identified through testing for specific gene mutations. Acquired dystonia is used for dystonia resulting from a known specific cause, including drugs, infections, brain injury, toxins, and vascular or neoplastic causes. Finally, idiopathic dystonia is used when there is no discoverable cause for the dystonia; this is further subdivided into sporadic or familial.

This classification system is appropriate for adults but also has been found to be relevant in children and adolescents ( ).

Although this new definition and classification system was designed to be more relevant to the clinical features of dystonia, the variable interpretation of its components has been an obstacle to its general use. Some investigators think that the use of this system could lead to ambiguity ( ).

A review of currently available literature showed that approximately 60% were using the classification correctly from 2013 to 2018 ( ).

Epidemiology

Epidemiologic studies ( Table 11.7 ) of dystonia are hampered by the lack of diagnostic criteria and laboratory confirmation. It often goes undiagnosed if the clinician or patient is not familiar with the clinical features. Hence epidemiologic studies are often based on clinical records and searching for diagnostic codes in patient databases. Zeman and colleagues ( ; , ) 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 ( ). In a study of dystonia by Israel, Zilber, and colleagues (1984) estimated the prevalence of generalized dystonia among Jews of Eastern European ancestry to be 1 per 15,000 or 6.8 per 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%) ( ) and phenotypically resembled Oppenheim dystonia seen in other populations.

In Japan the prevalence rate of focal dystonias was found to be 6.12 ( ), 10.1 ( ), 13.7 ( ), and 14.4 ( ) per 100,000 population, all of which are considerably lower than the 30 per 100,000 found by Nutt and associates (1988) in Rochester, Minnesota. The prevalence of focal limb dystonia in India was higher, 49.06 per 100,000 ( ). 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 ( ). 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 ( ). A survey of primary blepharospasm in the Puglia region of southern Italy found a prevalence of 13.3 per 100,000 ( ). The incidence rate of primary blepharospasm was found to be 1.2 per 100,000 population per year in Olmsted County, Minnesota ( ). Incidence for cervical dystonia was higher in white individuals (1.23/100,000 per year) than in persons of other ethnicities (0.15/100,000 per year) ( ). Using electronic medical records followed by chart review in a multiethnic population followed through the Kaiser Permanente health care maintenance organization consisting of 3 million members, Marras and colleagues estimated the minimum incidence of cervical dystonia to be 0.80 per 100,000 person years The incidence was higher in white individuals and 2.5 times higher in women than in men. The duration between onset of symptoms to diagnosis was 4 to 5 years ( , ). In a smaller study, the delay from symptom to diagnosis was approximately 7 years, with patients being evaluated by a mean of three physicians before diagnosis ( )

In Belgrade the prevalence rate for focal, segmental, and multifocal dystonia was 13.6 per 100,000 population ( ). It was almost twice as common (25.4/100,000 population) in Oslo ( ). Gender appears to play a role in both the prevalence and the age at onset of focal dystonia, with 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; ).

The prevalence of primary focal dystonia in the Faroe Islands was higher than in most studies at 602 per million, with the most common subtype of cervical dystonia ( ).

Genetics: isolated and combined dystonia

Isolated dystonia consists of familial and nonfamilial (sporadic) types. Although most patients with torsion dystonia have a negative family history for this disorder, the presence of other affected family members allows the family to be investigated in terms of localizing the abnormal gene(s) for dystonia. In primary dystonia, the only neurologic abnormality is the presence of dystonic postures and movements, with the exception of tremor that can resemble ET and can even be ET in some individuals. There is no associated loss of postural reflexes, amyotrophy, weakness, spasticity, ataxia, reflex change, abnormality of eye movements, disorder of the retina, dementia, or seizures except where they may be the result of a concomitant problem such as a complication from a neurosurgical procedure undertaken to correct the dystonia or the presence of some other incidental neurologic disease. Because many of the secondary dystonias have these neurologic findings, the presence of any of these findings in a patient with dystonia immediately suggests that one is dealing with a secondary dystonia, a dystonia-plus syndrome, or a heredodegenerative disorder ( Table 11.8 ). However, the absence of such neurologic findings does not necessarily exclude the possibility of a secondary dystonia, which may rarely manifest as a pure dystonia.