Movement disorders other than Parkinson’s disease

Movement disorders other than Parkinson’s disease - technical

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Essentials

Movement disorders are considered in five main categories—dystonia, chorea, tremor, tics, and myoclonus. Each disorder may occur in several diseases, and each may be the sole manifestation of a given neurological disease, but they also may only represent a component of a more widespread disorder.

Movement disorders characteristically involve the basal ganglia and under these circumstances, neuropsychiatric manifestations—often more significant than the disturbed movement—have the greater impact on well-being.

Most treatments for movement disorders are empirical, but with greater understanding of the molecular genetics and the application of functional imaging, a more rational neurochemical basis for several disorders is emerging. Ultimately this greater understanding may lead to the development of effective therapies based on rational principles.

Particular movement disorders

Dystonias—so-called idiopathic torsion dystonia is often inherited as an autosomal dominant trait; other causes include the Dopa-responsive dystonia-Parkinsonism (Segawa’s syndrome), writer’s cramp and oromandibular dystonia (which responds poorly to most drugs).

Chorea—occurs in many conditions and may be a consequence of any treatment for Parkinson’s disease. The most common other cause is Huntington’s disease. Sydenham’s chorea (St Vitus’s dance), for which dopamine D2 receptor blocking agents may be effective, and neuropsychiatric manifestations are associated with rheumatic fever and other complications of group A streptococcal infections.

Tremor—this includes ‘essential’ tremor, for which several candidate susceptibility gene loci have been identified.

Tics—these may be simple or complex, and arise in numerous disorders. When combined with copralalia and other sudden vocalization, Tourette’s syndrome—a genetic disorder showing autosomal dominant transmission with variable penetrance—is identified. The tics may respond to neuroleptic agents, and the associated obsessive-compulsive behavioural features often benefit from clomipramine (a tricyclic agent) or fluoxetine; deep brain stimulation has been used successfully in severe cases, but is not yet established as a routine treatment.

Myoclonus—this occurs in numerous neurological diseases. It may be solitary and static, as in benign essential myoclonus, or a progressive disease with encephalopathy (progressive myoclonic encephalopathy), and it is also a feature of epilepsy. Static myoclonus after action (Lance–Adam syndrome) may develop after cerebral anoxia.

Miscellaneous movement disorders—these include (1) psychogenic conditions; (2) numerous drug-induced conditions, usually induced by anti-psychotic or anti-emetic drugs; (3) the stiff man syndrome; and (4) restless legs (Ekböm’s) syndrome—a common condition.

Introduction

Movement disorders typically result from diseases of the basal ganglia and can be classified into one of five main categories: dystonia, chorea, tremor, tics, and myoclonus (see bullet list 1 below for definitions). Each type of abnormal movement may occur in several diseases and many treatments are empirical. However, the study of molecular genetics and the use of functional imaging have revealed subtle neurochemical abnormalities that should facilitate the development of more rational therapies.

In this section, attention is drawn to abnormal movements that are a principal manifestation of the disease. Movement disorders have been divided into hyperkinetic and hypokinetic conditions; however, this classification may be misleading because a given disease often evolves with time. Furthermore, the disorder may be ‘mixed’, with different movement types present in the same patient. It is probably more useful to classify movement disorders by type, as correct identification of the phenomenology is the first step towards correct diagnosis and management.

The dystonias

Definition

Dystonias are characterized by prolonged involuntary muscle contractions, causing abnormal movements and postures. Hermann Oppenheim first used the term ‘dystonia’ in 1911 to describe a childhood-onset form of generalized dystonia which he called ‘dystonia musculorum deformans’.

Classification

When no symptomatic cause for dystonia can be discovered, the syndrome is described as idiopathic or primary dystonia, and if generalized then the disorder is synonymous with idiopathic torsion dystonia. Secondary dystonia is due to a defined exogenous, structural, or metabolic disorder. A ‘dystonia plus’ syndrome constitutes dystonia in combination with other abnormalities (e.g. myoclonic dystonia) and heredodegenerative dystonia occurs when there is an underlying brain degeneration.

Dystonia may affect the whole body (generalized dystonia) or adjacent parts such as an arm and neck (segmental dystonia), or may be restricted to one part (focal dystonia) as in spasmodic torticollis, dystonic writer’s cramp, blepharospasm, oromandibular dystonia, and laryngeal dystonia. Age at onset may also be used to classify dystonia. Early onset disease (before the age of 26 years) usually begins in a leg or arm and less commonly in the craniocervical region.

Children often develop symptoms in the legs and frequently develop segmental or generalized dystonia. Late-onset primary dystonia (onset after 26 years) commonly affects the neck and cranial musculature, and onset in a limb, particularly the leg, is much less likely. In adults the dystonia is most likely to remain confined to its site of origin as a focal dystonia.

Idiopathic dystonia is frequently inherited (see below), but the focal dystonias usually occur sporadically in middle life. However, focal dystonias may be isolated fragments of the syndrome of idiopathic torsion dystonia.

Causes of pseudodystonia (conditions that may mimic dystonia) include tonic seizures, stiff person syndrome, and other neuromuscular disorders (e.g. neuromyotonia, myotonic disorders), carpopedal spasm, head tilt resulting from posterior fossa or retropharyngeal space mass lesions, and Sandifer’s syndrome (gastro-oesophageal reflux in young children with associated head tilt).

Bullet list 1 Movement disorders

  • Dystonia
    • Sustained spasms of muscle contraction that distort the limbs and trunk into characteristic postures—the twisted (torticollis), flexed (antecollis), or extended neck (retrocollis), the arched (lordosis) or twisted back (scoliosis), the hyperpronated arm, and plantar-flexed inverted foot. The spasms typically occur on willed action (action dystonia). Dystonic spasms may be intermittent, producing dystonic movements, which may be repetitive to give a rhythmic character or sustained to hold a fixed dystonic posture.
  • Athetosis
    • This term was originally used to describe the sinuous, writhing movements that may follow a stroke; it later became synonymous with cerebral palsy, resulting from perinatal anoxia or kernicterus. Affected infants are floppy, exhibit delayed motor milestones, and before the age of 5 years develop athetoid movements—athetoid cerebral palsy, or ‘athetosis’
  • Tremor
    • A rhythmic sinusoidal movement of a body part caused by regular muscle contractions.
  • Chorea
    • A continuous flow of irregular, jerky, and explosive movements, that flit randomly from one part of the body to another. Each muscle contraction is brief, often appearing as a fragment of what might have been a normal movement, and unpredictable in timing or site (see Fig. 5)
  • Myoclonus
    • Rapid shock-like muscle jerks, often repetitive and sometimes rhythmic.
  • Tics
    • Similar to myoclonic jerks, but are repetitive, stereotyped movements that can be mimicked voluntarily and can be held in check by an effort of will. Simple tics are confined to a few muscles; complex tics may include quasipurposeful movements.

Note: Nearly all dyskinesias disappear in sleep, are aggravated by anxiety, and improved by relaxation. Many movement disorders merge: e.g. Huntington’s disease may show chorea and dystonia, giving the appearance of ‘hanging chorea’.

Aetiology

The many metabolic and other inherited or sporadic diseases that can cause dystonia (Table 1 and Bullet list 2) usually produce other neurological symptoms and signs. A symptomatic cause for dystonia is found in about 50% of children with the condition, but is rare in those with adult onset. The recent identification of mutations in genes responsible for forms of dystonia gives hope for understanding its basis (Table 1). Abnormalities within the basal ganglia and associated cortical motor areas have been found in some patients with secondary dystonia.

Idiopathic (torsion) dystonia

Symptoms

Idiopathic (torsion) dystonia may present in childhood, when it is frequently inherited as an autosomal dominant trait, or in adult life, when a family history is unusual. In many families with early onset disease, genetic linkage studies have localized the abnormal gene mutation to the DYT1 locus on chromosome 9q34 which codes for torsin A, a protein of unknown function expressed in the brain (including the substantia nigra).

Ashkenazi Jews are particularly prone to this condition. It usually presents in children with dystonic spasms of the legs on walking, or sometimes of the arms, trunk, or neck. The condition is usually progressive when it starts in childhood; the spasms spread to all body parts, leading to severe disability within about 10 years. The intellect is preserved and there are no signs of pyramidal or sensory deficit. Speech is often spared, permitting the pursuit of intellectual employment despite severe physical disability. A spontaneous remission of symptoms occurs in about 10 to 20% of patients, usually within 5 years of onset. There is no way of predicting who will remit or when such a remission will occur. Most remissions are transitory, lasting a matter of weeks or months, but occasionally they may persist.

In adults, the condition usually presents as a focal dystonia (blepharospasm, oromandibular dystonia, spasmodic dysphonia, torticollis, axial dystonia, or dystonic writer’s cramp). The legs tend to be spared, and progression is slow, with the dystonia remaining confined to its site of origin. Segmental dystonia develops in some cases.

Treatment

Dystonia is distressing and difficult to treat. Every child and young adult with dystonia should receive a trial of levodopa (e.g. Sinemet-Plus up to two tablets three times a day for 3 months), as they may have the condition of dopa-responsive dystonia–parkinsonism (see below). Occasionally, other forms of childhood-onset dystonia may also show a response, albeit incomplete, to levodopa.

The drugs that most patients find helpful, and continue to take to suppress muscle spasm, are benzodiazepines such as diazepam, often in a large dose of 20 to 50 mg daily, and an anticholinergic such as benzhexol, again in large doses (up to as much as 120 mg/day). Fifty per cent of children and 10% of adults will be helped, but adults are more sensitive to anticholinergic side effects. Dopamine-blocking drugs such as sulpiride or dopamine depletors such as tetrabenazine may help some patients, but often at the expense of drug-induced parkinsonism and unacceptable sedation. Unfortunately, dystonia is far less responsive to neuroleptics than chorea. Many other drugs have been tried in dystonia, but none has gained wide acceptance. In life-threatening dystonic crises, combination therapy may be required.

The recent interest in neurosurgery for movement disorders has extended to the treatment of dystonia, especially when the disease is advanced and disabling. Originally the thalamus was targeted for surgery but of late the target has moved to the internal part of the globus pallidum and deep brain stimulation. This therapy seems to work well in young patients with dystonia due to DYT1 mutations.

Table 1 Classification of genetic dystoniasa
Disease Gene locus Inheritance Chromosome region/protein Clinical features
Primary torsion dystonia DYT1 Autosomal dominant Torsin A Late childhood. Limb, then generalized
X-linked dystonia–parkinsonian syndrome (Phillipines; Lubag’s disease) DYT3 X linked TATA-binding protein-associated factor 1 gene (TAF1) Onset typically 30–45 years with focal dystonia, becoming generalized, with abnormal gait, associated tremors, and parkinsonism (last may be dominant)
Dopa-responsive dystonia -parkinsonism (Segawa’s syndrome)b DYT5 Autosomal dominant GTP cyclohydrolase 1 gene Childhood. Lower limb dystonia with parkinsonism. Worse at end of day
Craniocervical dystonia parkinsonism (Mennonite/Amish) DYT6 Autosomal dominant 8q21–22 Early adulthood. Craniocervical dystonia becoming generalized
Familial torticollis DYT7 Autosomal dominant 18p31 Torticollis. Spasmodic dysphonia
Paroxysmal kinesiogenic or nonkinesiogenic dystoniab DYT8 Autosomal dominant Myofibrillogenesis regulator gene
  • Episodes of dystonia or chorea that last for seconds with movement or startle (kinesiogenic)
  • Nonkinesiogenic episodes last for minutes to hours and are provoked by stress and certain agents
Alcohol-responsive myoclonic dystoniab DYT11 Autosomal dominant ε-Sarcoglycan gene Myoclonic jerks compounded by dystonia. Young adults. Nonprogressive, relieved by alcohol
Rapid-onset dystonia-parkinsonism DYT12 Autosomal dominant Na+/K+ ATPase α3  
Cervical–cranial–brachial DYT13 Autosomal dominant 1p36 Italian family with reduced penetrance
Dopa-responsive dystonia DYT14 Autosomal dominant 14q13 Early onset lower limb dystonia, diurnal variation with later-onset parkinsonism
Myoclonus–dystonia DYT15 Autosomal dominant 18p11 Onset in first two decades with myoclonus and dystonia, alcohol responsive; depression may be a feature

a Does not include DYT2 and -4 where the chromosome region has not yet been mapped.

b Only a proportion of cases are due to the named genetic defect.

Dopa-responsive dystonia–parkinsonism (Segawa’s syndrome)

This condition is most commonly inherited as an autosomal dominant condition with incomplete penetrance and has as its defect mutations in the guanosine triphosphate cyclohydrolase 1 gene. This enzyme catalyses the production of tetrahydrobiopterin, an essential cofactor for maintaining the normal activity of tyrosine hydroxylase (TH), the rate-limiting step in the catecholamine biosynthetic pathway. The typical dopa-responsive dystonia phenotype affects the legs, which become worse as the day goes on.

Rest without sleep does not help, but sleep relieves the dystonia. Many patients also have features of parkinsonism, although focal dystonia may be the presenting feature. The disease can easily be mistaken for cerebral palsy (given its lower limb predominance) or an unexplained ‘spastic paraparesis’ (because of brisk reflexes and variable ankle clonus). Rarer genetic causes for this condition exist, including abnormalities in the genes coding for TH itself, but in these cases there are often more widespread neurological problems such as major cognitive deficits.

Bullet list  2 Symptomatic secondary dystonias

  • Inherited metabolic, e.g. Wilson’s disease
  • Acquired metabolic, e.g. kernicterus
  • Inherited possible metabolic, e.g. Hallervorden–Spatz disease or now renamed pantothenate kinase-associated neurodegeneration (PKAN)
  • Other inherited causes, e.g. neuroacanthocytosis, Huntington’s disease
  • Miscellaneous causes, e.g. Parkinson’s disease and its treatment, progressive supranuclear palsy, trauma including head trauma, cervical cord and peripheral nerve injury, anoxia/ischaemia, tumours of the basal ganglia, toxins, and drug induced
  • Psychogenic

This condition is characterized by a reduction in turnover of dopamine due to the abnormality in tyrosine hydroxylase activity; patients respond well to low doses of levodopa without showing any of the long-term complications encountered in Parkinson’s disease.

Although very rare, the importance of this condition is that it can be easily confused with cerebral palsy and is very easy to treat.

Spasmodic torticollis

Symptoms

Spasmodic torticollis may be the presenting feature of dystonia in childhood, but isolated spasmodic torticollis usually occurs in middle-aged or older people. The onset is usually insidious, often with initial pain, and sometimes appears to be precipitated by trauma. The dystonic spasms affect sternomastoid, splenius, and other neck muscles to cause the head to turn to one side (torticollis) (Fig. 1), or occasionally to extend (retrocollis) or to flex (antecollis) the neck. The spasms may be repetitive, causing a ‘no–no’ titubation, tremulous torticollis, or sustained hold of the posture. The trunk commonly shows a compensatory lordosis.

The condition is usually lifelong, but remissions of a year or more occur in about one-fifth of cases. Most patients are otherwise normal apart from their torticollis, although some may exhibit a postural tremor similar to that of essential tremor, and a minority may develop dystonia elsewhere. As with all types of dystonia, the frequency and intensity of the muscle spasms vary considerably, being particularly worse in conditions of mental or emotional stress. A feature characteristic of spasmodic torticollis is the ‘geste antagoniste’, a sensory trick in which the patient discovers some particular manual act that controls the deviation of the head. A light touch of the forefinger to the jaw may suffice, but other more complex and bizarre actions are common.

woman with spasmodic torticollis

Figure 1: Lady with spasmodic torticollis affecting right sternocleidomastoid muscle

Treatment

Spasmodic torticollis, similar to other types of adult-onset focal dystonia, does not usually benefit from conventional drug therapy. The best treatment is injection of botulinum toxin A into the most affected muscles. Botulinum toxin prevents the release of acetylcholine and causes functional denervation with localized muscle weakness. Identification of the overactive muscles is a prerequisite to the administration of localized injections of botulinum toxin, which, in the case of torticollis, typically involves injections into the sternomastoid and splenius muscles.

These injections usually have an effect within a week although the maximum benefit is not apparent until several weeks later. Repeat injections are required approximately every 3 months as relapse, by terminal sprouting, occurs. In about 10 to 20% of patients, antibodies eventually develop to the botulinum toxin A, making it less effective with time. In these cases a switch to a botulinum toxin type F or B may be desirable; the long-term efficacy of this treatment is under investigation.

Surgery is sometimes practised and local denervation procedures are still considered in patients with otherwise intractable cervical dystonias, although the outcome from such interventions is very variable.

Dystonic writer’s cramp

Symptoms

Inability to write (or to type, play a musical instrument, or use any manual instrument) has many causes but in most patients no objective neurological deficit is found other than abnormal posturing of the hand and arm on writing. Typically, the pen is gripped with great force and driven into the paper (Fig. 2). However, in some patients the arm adopts a typical dystonic posture and, in such cases of dystonic writer’s cramp, other manual acts such as wielding a knife or a screwdriver are similarly affected. Such dystonic writer’s cramp may be the initial symptom of generalized torsion dystonia, but in adults it often remains as an isolated disability. The same considerations apply to other occupational cramps, such as pianist’s cramp, all of which may have their origin in abnormal plasticity and mapping of the affected limb part in the sensorimotor cortex.

Treatment

Writer’s cramp, and related conditions, is usually a permanent disability. Advice to use a broad-based pen or a keyboard, or to learn to write with the opposite hand allows most to cope with everyday events, but approximately one patient in 20 will then develop dystonia in the nondominant hand. Drugs (such as benzhexol and diazepam) are rarely of benefit but botulinum toxin injections into the muscles of the affected forearm may help some patients. Electromyography may be used to guide the injections more precisely to the overactive muscles, although the functional benefits of this technique over conventional administration has yet to be clearly demonstrated. Recently some investigators have advocated restraint therapy in the affected limb with the hope that this will lead to a remapping of the sensorimotor cortex back to normal with relief of the focal task-induced dystonia. This therapy remains controversial.

Blepharospasm and oromandibular dystonia (cranial dystonia)

Symptoms

Blepharospasm refers to recurrent spasms of eye closure. Orbicularis oculi forcibly contracts for seconds or minutes, often repetitively and sometimes so frequently as to render the patient functionally blind (Fig. 3). Spasms of eye closure commonly occur while reading or watching television, or in bright light; they often decrease or disappear when the person is alerted or under scrutiny. Oromandibular dystonia refers to recurrent spasms of muscle contraction affecting the mouth, tongue, jaw, larynx, and pharynx, causing spasms of lip protrusion or retraction, jaw closure or opening (Fig. 24.7.3.4), and difficulty in speech and swallowing. Such patients may lacerate their lips and tongue or even dislocate their jaw, and are usually unable to cope with dentures. Speech may take on a characteristic, forced, strained quality, and chewing and swallowing may be impaired.

These two conditions are closely related, because the patient with blepharospasm may develop oromandibular dystonia and vice versa. The term ‘Brueghel’s syndrome’ is often used when the dominant (or only) feature is a dystonically opened jaw, whereas Meige’s syndrome has blepharospasm as its central feature. Both conditions may occur in generalized torsion dystonia, or result from drugs (often as a tardive dystonia); they also appear in isolation in late life without evident cause.

Treatment

Unfortunately, both blepharospasm and oromandibular dystonia are notoriously difficult to control with drugs (e.g. benzhexol, diazepam, and/or a neuroleptic). Surgery cannot improve oromandibular dystonia but can relieve blepharospasm. The best treatment for blepharospasm is to inject botulinum toxin into orbicularis oculi, which gives relief in about 70 to 80% of cases, thereby restoring normal vision for about 3 months. The injections can be repeated as necessary. Botulinum toxin injections can be used to control some jaw spasms, although care is needed not to induce dysphagia.

Spasmodic dysphonia

Dystonic spasms of the muscles controlling the vocal folds cause spasmodic dysphonia, which impairs speech and singing, and may be severe enough to prevent communication. The most common type involves the adductor muscles, leading to a ‘strangled’ speech quality with pitch breaks and stops. Less common is abductor dysphonia which produces a breathy, low-volume voice. Abductor dysphonia, in particular, is often misdiagnosed as a psychogenic disorder. The diagnosis can be established by direct noninvasive visualization of the vocal folds during talking. Spasmodic dysphonia may occur in association with cranial or generalized dystonia, or appear as an isolated focal dystonia in adult life. Speech can be restored by injection of botulinum toxin into the overactive vocal muscles, identified by electromyography in specialist centres.

Paroxysmal dystonia

Focal dystonias often commence with the appearance of a dystonic posture or spasm on only one motor act (action dystonia), but there are rare, usually familial, disorders in which dramatic dystonia occurs intermittently in attacks, the patient being normal in between. These conditions are thought to be caused by mutations in genes encoding ion channels. Several families with paroxysmal dystonic choreoathetosis have now been shown to have mutations in the myofibrillogenesis regulator gene (MR1).

Read more about dystonia:

Dystonia: a guide to assessment and management - technical

Movement disorders continued here: