Abstract
PURPOSE OF REVIEW:
This article discusses the most recent findings regarding the diagnosis, classification, and management of genetic and idiopathic dystonia.
RECENT FINDINGS:
A new approach to classifying dystonia has been created with the aim to increase the recognition and diagnosis of dystonia. Molecular biology and genetic studies have identified several genes and biological pathways involved in dystonia.
SUMMARY:
Dystonia is a common movement disorder involving abnormal, often twisting, postures and is a challenging condition to diagnose. The pathophysiology of dystonia involves abnormalities in brain motor networks in the context of genetic factors. Dystonia has genetic, idiopathic, and acquired forms, with a wide phenotypic spectrum, and is a common feature in complex neurologic disorders. Dystonia can be isolated or combined with another movement disorder and may be focal, segmental, multifocal, or generalized in distribution, with some forms only occurring during the performance of specific tasks (task-specific dystonia). Dystonia is classified by clinical characteristics and presumed etiology. The management of dystonia involves accurate diagnosis, followed by treatment with botulinum toxin injections, oral medications, and surgical therapies (mainly deep brain stimulation), as well as pathogenesis-directed treatments, including the prospect of disease-modifying or gene therapies.
INTRODUCTION
Dystonia is the third most common movement disorder after essential tremor and Parkinson disease (PD).1 Dystonia involves sustained or intermittent muscle contractions, often resulting in twisting and repetitive patterned movements and abnormal postures related to co-contraction of agonist and antagonist muscles.1 Dystonia may occur in isolation or in combination with other movement disorders or in the setting of other primary neurologic disorders or may be acquired; misdiagnosis frequently occurs.1,2 Most forms of dystonia are idiopathic; however, several genetic dystonias have been identified, and acquired forms are typically related to lesions in the basal ganglia or more global brain injury. The pathophysiology of dystonia is currently thought to represent a brain network disorder involving several brain regions, including the basal ganglia, cerebellum, thalamus, and sensorimotor cortex, resulting in abnormal neural motor programs.3 Treatment involves regular botulinum toxin injections, and oral medications are unreliable. Deep brain stimulation (DBS) can be highly effective in select cases.
CLINICAL FEATURES AND CLASSIFICATION OF DYSTONIA
The term dystonia can be used as both a clinical descriptor of an abnormal posture, frequently with a twisting quality, and a group of diseases in which dystonia is the main clinical feature. The dystonias result from idiopathic, genetic, acquired, and other causes. No reliable diagnostic test exists for idiopathic dystonia, as imaging and laboratory testing are typically normal in patients with dystonia; however, genetic testing may lead to a definitive diagnosis in forms of genetic dystonia.
KEY POINTS.
The term dystonia can be used as both a clinical descriptor of an abnormal posture, frequently with a twisting, patterned quality and a group of diseases, where dystonia is the main clinical feature.
The dystonias include idiopathic, genetic, acquired, and other causes. No reliable diagnostic test (outside of genetic testing) currently exists, as imaging and laboratory testing are typically normal in patients with dystonia.
Clinical features of dystonia include influence by voluntary action, overflow/mirror dystonia, and a “null point.” Sensory tricks should be specifically inquired about and assessed on examination.
Dystonia is classified based on clinical characteristics (age of onset, body distribution, temporal pattern, and associated clinical features) and etiology (underlying nervous system pathology or whether the condition is inherited, acquired, or idiopathic).
Nomenclature of genetic dystonias involves referring to the movement disorder type (including if combined) and gene name, not DYT locus, using recently updated criteria.
The diagnosis of dystonia is challenging. Common misdiagnoses occur in patients thought to have Parkinson disease, essential tremor, myoclonus, tics, functional (“psychogenic”) dystonia, headaches, and scoliosis.
Dystonia Phenomenology
Core clinical features of dystonia include influence by voluntary action, overflow dystonia (unintentional muscle contraction distinct anatomically from the primary movement), mirror dystonia (unilateral abnormal posturing elicited by contralateral movements), and, in some cases, dystonic tremor (movements are oscillatory but not strictly rhythmic, jerky, and patterned).4 Dystonia and dystonic tremor may also have a directional nature, with movements worse in certain positions and improved in others (a “null point”). Another core feature is the presence of alleviating maneuvers (sensory tricks, or geste antagoniste), typically involving simple movements but not forceful opposition to the dystonic movement.1 Dystonia is typically exacerbated by anxiety, stress, or heightened emotions or occurs when the patient is tired or fatigued; dystonia decreases with relaxation, generally resolving during sleep.5 A useful approach to the clinical diagnosis of dystonia was provided by Albanese and Lalli6 (TABLE 10–17).
TABLE 10–1.
Clinical Criteria for Examination Signs Observed in Dystoniaa
| Clinical examination sign | Description | Notes |
|---|---|---|
| Dystonic postures | Affected body part (neck, trunk, limb) is flexed or twisted along its longitudinal axis (not possible in cranial or laryngeal dystonia) | If concern exists for task-specific dystonia, the clinician must observe directly or examine a video of the patient performing the particular task (eg, writing, typing, playing a musical instrument [should be asked to bring instrument if possible] in the upper limbs, or walking, running, using a bicycle in the lower limbs). Similarly, in paroxysmal forms, replication of the movement (kinesigenic) is essential, so clinician should ask the patient to perform triggering movements or try to exercise, if possible (exercise/exertion induced). If not able to provoke an episode in the clinic, a video of the episode is essential to make a diagnosis (particularly in nonkinesigenic forms). |
| A sensation of tightness and traction (pulling) is present in the affected part | ||
| Incomplete phenomenology: at least one feature | ||
| Complete phenomenology: both features | ||
| Dystonic movements | Movements have a twisting nature or a pull in a preferred direction (including dystonic tremor) | In the case of vocal/laryngeal dystonia, the clinician must assess for the individual vocal features described in the section on adult-onset idiopathic focal/segmental isolated dystonia. Identifying dystonic movements may be more complex in combined dystonia, in which the presence of multiple superimposed abnormal movements may hamper assessment. |
| Movements are repetitive and patterned (ie, consistent and predictable) | ||
| Movements are often sustained at peak severity and lessen at a given posture (a “null point”), which may also be seen in dystonic tremor | ||
| Incomplete phenomenology: at least one feature | ||
| Complete phenomenology: at least two features | ||
| Geste antagoniste (sensory tricks) | Alleviation of dystonia occurs during the geste movement, usually soon after the patient performs the maneuver | Although not considered a geste, other alleviating maneuvers include walking backward, which can alleviate lower extremity dystonia, or lying flat, which can alleviate truncal and cervical dystonia. |
| Alleviation may last for the duration of the geste or slowly wanes in effectiveness spontaneously before its end | The presence of highly atypical or bizarre apparent “sensory tricks” in a suggestive clinical context, or specific examiner maneuvers leading to dramatic reduction or cessation of abnormal posture or spasms (such as a centrally placed tuning fork on the head) may suggest a diagnosis of functional dystonia.7 | |
| The geste is simple, natural, and “elegant,” but never forceful | ||
| The geste does not push or pull the affected body part, but simply touches it (sensory trick) or accompanies it during alleviation of dystonia (not physically resisting the movement) | ||
| Present: requires all features | ||
| Mirror dystonia | At least three different types of repetitive tasks are performed at slow and fast speeds in the nonaffected limb | Dystonia in one body part can be brought on when performing tasks in any other body part; for example, lower extremity tasks and walking, particularly with stress gait (walking on heels and tiptoes) can exacerbate or unveil not only lower extremity dystonia but also upper extremity dystonia. |
| Examples of tasks used to assess for upper extremity dystonia: sequential finger movements, piano-playing movements, hand opening/closing, hand pronation/supination, normal writing (ideally in cursive), specific writing tasks (writing with the nondominant hand, cursive ‘l’ loops across the page, Archimedean spirals) | ||
| Examples of tasks used to assess for lower extremity dystonia: leg agility (heel stomping), toe tapping, and alternating heel and toe tapping | ||
| Present: Dystonic posturing in the contralateral limb occurs during at least one task | ||
| Overflow dystonia | Dystonic movement or dystonic postures extend beyond the commonly involved body region (an unintentional muscle contraction that accompanies but is anatomically distinct from the primary dystonic movement) | |
| The movement is observed at least once, ipsilaterally or contralaterally, either by inspection or, if available, by EMG mapping, coinciding with the peak of the dystonic movements | ||
| Present: requires both features |
EMG = electromyography.
Modified with permission from Albanese A, Lalli S, Mov Disord.6 © 2009 Movement Disorder Society.
Classification of Dystonia
The 2013 consensus classification of dystonia involves two distinct axes1:
Axis I (clinical characteristics) involves (1) age of onset, (2) body distribution, (3) temporal pattern, and (4) associated clinical features.1
Axis II (etiology) addresses two complementary characteristics: (1) underlying nervous system pathology (imaging/diagnostic testing), and (2) whether the disorder is inherited, acquired, or idiopathic.1
CLINICAL CHARACTERISTIC CLASSIFICATION OF DYSTONIA.
Age of onset and body distribution can clinically differentiate dystonia (TABLE 10–28). Focal dystonia involves a single body region. Segmental dystonia involves two or more adjacent body segments, including the involvement of both arms or both legs. Multifocal dystonia involves at least two noncontiguous or more (contiguous/noncontiguous) body regions. Generalized dystonia has truncal involvement and at least two other distant sites. Hemidystonia involves multiple body regions restricted to a single side. Examples of dystonia phenomenology are shown in FIGURE 10–1.9
TABLE 10–2.
Classification of Dystonia by Body Distributiona
| Type of dystonia | Number of body parts affected | Examples and Details |
|---|---|---|
| Focal | 1 | Examples: |
| Eyelids (blepharospasm with eye closure spasms; may cause vision problems or, at worst, functional blindness) | ||
| Mouth/tongue/palate (oromandibular dystonia, which can impair speech and swallowing); task-specific forms include embouchure dystonia (occurring when engaging the embouchure when performing a wind instrument), and several other tasks generally involving repetitive heavy speech users have been identified, including telemarketers, bingo callers, people who are chanting/reciting prayers | ||
| Larynx (spasmodic dysphonia from dystonic involvement of the vocal cords); generally occurs as the patient begins to speak, but certain words and phrases may be more difficult than others; adductor-type spasmodic dysphonia (strained, strangled, and course voice, with variations in pitch and vocal breaks with or without vocal tremor); abductor-type spasmodic dysphonia (less common, with whispering and breathy speech); task-specific forms include singer’s dystonia (occurs only while singing, often in professional singers) and in other professional voice users | ||
| Neck (cervical dystonia, leading to abnormal neck posture and frequent cause of neck pain); subtypes include torticollis (neck rotation), laterocollis (tilting owing to lateral flexion), retrocollis (neck extension), and anterocollis (neck flexion) | ||
| Hand/arm (abnormal posturing and/or tremor of the hand or arm generally during daily activities or when performing specific hand tasks); task-specific forms (eg, writer’s cramp, musician’s focal hand dystonia) or other non-task-specific dynamic dystonia | ||
| Foot/leg (abnormal posturing of the lower extremity, typically when walking but can also be present when doing other seated tasks or at rest); task-specific runner’s or bicycling dystonia, or other non-task-specific dynamic lower extremity dystonia | ||
| Trunk (abnormal posturing of the trunk when walking and typically resolves when lying flat or when leaning against a wall or other surface); subtypes include bending forward (camptocormia), backward (opisthotonus), and sideways (Pisa syndrome, particularly in Parkinson disease) | ||
| Segmental | ≥2 contiguous body parts | Examples: |
| Meige syndrome (eyes and lower face with or without neck involvement) | ||
| Axial (neck and trunk) | ||
| Brachial (arm and trunk; both arms with or without neck or trunk involvement) | ||
| Crural (leg and trunk; both legs with or without trunk involvement) | ||
| Multifocal | ≥2 noncontiguous body parts | Example: |
| Faciobrachial (blepharospasm and writer’s cramp) | ||
| Hemidystonia | ≥2 | Ipsilateral arm and leg (dystonia only affects one side of the body) |
| Generalized | ≥3 | Trunk and ≥ 2 other sites; with or without leg involvement |
Modified with permission from Klein C, et al, Gene Rev.8 © 1993–2022 University of Washington, Seattle.
FIGURE 10–1.
Clinical phenomenology of dystonia. A, Oromandibular dystonia with tongue protrusion posturing is shown in a patient with tardive dystonia; B, in the same patient, the abnormal tongue posture, with curling in the mouth, is highlighted. C, In a patient with X-linked dystonia parkinsonism (DYT/PARK-TAF1, DYT3), severe jaw opening dystonia is shown as a part of multifocal dystonia, predominantly involving head and neck segmental dystonia. D, Image shows focal idiopathic cervical dystonia with laterocollis (lateral flexion) to the right, (E) with normalization of neck posturing in the same patient by using a sensory trick of wearing a scarf and applying tension to the posterior neck. F, Focal truncal dystonia with Pisa syndrome is shown in a patient with Parkinson disease. G, Image shows severe segmental dystonia involving truncal extension and neck extension (retrocollis). H, Segmental dystonia with idiopathic Meige syndrome is shown, highlighting bilateral eyelid spasm and lower facial spasm. I, Idiopathic left hemifacial spasm is shown, highlighting the left eyebrow elevation in keeping with the “other Babinski sign” (co-contraction of the orbicularis and frontalis muscles, causing ipsilateral eyebrow elevation during unilateral eye closure, which cannot be reproduced voluntarily) and (J) abnormal left lower facial posturing related to lower facial spasms in the same patient with a tortuous vertebrobasilar system, which may be an etiologic factor. K, Multifocal bilateral hand dystonia is shown in a patient with rapid-onset dystonia parkinsonism (DYT/PARK-ATP1A3). L, Multifocal bilateral arm dystonia is shown with notable abnormal wrist extensor posturing and right shoulder adduction in a patient with DYT-THAP1 (DYT6) dystonia. M, Task-specific focal hand dystonia is shown in a violinist who exhibits flexion dystonia of the left little greater than ring fingers. N, Focal left foot dystonia involves excessive plantarflexion in a patient with task-specific walking/running dystonia. O, Left foot dystonia with toe curling is shown in a patient with generalized dystonia in the setting of X-linked dystonia parkinsonism (DYT/PARK-TAF1, DYT3).
Reprinted with permission from Stephen CD, et al, Elsevier.9 © 2022 Elsevier.
The temporal pattern of dystonia is subdivided into four distinct types. In a persistent pattern, dystonia presence and severity are roughly similar throughout the day.8 Action-specific/task-specific dystonia only occurs during a particular activity, such as writing, typing, playing an instrument, or singing.10 Paroxysmal dystonia involves sudden, discrete episodes of dystonia, with return to neurologic baseline.11 Diurnal variation (mild symptoms on awakening and worsening as the day progresses) is classically seen in dopa-responsive dystonia.12
Dystonia can either be isolated or combined with another movement disorder. In isolated dystonia, dystonia is the only clinical motor feature other than tremor (generally phenomenologically dystonic in nature). In contrast, combined dystonia is associated with other movement disorders, including myoclonus, parkinsonism, ataxia, or chorea/dyskinesias. Dystonia is frequently associated with neuropsychiatric symptoms, whereas cognitive decline generally only occurs in degenerative/progressive dystonias.5,13 TABLE 10–314 lists the common isolated/combined genetic dystonias, and TABLE 10–413,15 lists more complex phenotypes. Dystonia can be differentiated by rate of symptomatic progression. Focal dystonias generally follow a subacute or slow worsening of symptoms, followed by a plateau, at least initially. Subsequent spread to segmental/multifocal distributions may occur but generally plateaus.13
TABLE 10–3.
Common Genetic Dystonia Subtypesa
| Classification | Designation (gene locus) | Onset | Pattern of inheritance | Dystonia distribution | Other relevant features |
|---|---|---|---|---|---|
| Isolated dystonia | DYT-TOR1A (DYT1) | Childhood | Autosomal dominant | Generalized | Most common genetic dystoniab |
| More common in Ashkenazi Jewish ancestry | |||||
| Focal onset, frequently in the lower limbs and subsequently generalizes | |||||
| Cranial involvement rare | |||||
| Reduced penetrance | |||||
| Deep brain stimulation highly effectiveb | |||||
| DYT-THAP1 (DYT6) | Adult/childhood | Autosomal dominant (rarely autosomal recessive) | Neck, limbs, orofacial, and larynx | Often prominent cranial involvement | |
| Also frequent onset in an arm | |||||
| Deep brain stimulation beneficialb | |||||
| DYT-ANO3 (DYT24) | Adult/childhood | Autosomal dominant | Neck, larynx, orofacial, and upper limbs | Onset typically cervical, followed by laryngeal | |
| Frequent tremor, may resemble essential tremor | |||||
| DYT-GNAL (DYT25) | Adult | Autosomal dominant (rarely autosomal recessive) | Neck, limbs, orofacial, and larynx | Onset typically cervical | |
| DYT-HPCA (DYT2) | Childhood | Autosomal recessive | Distal limbs, craniocervical, generalized | Generalized in childhood, segmental in adolescence onset | |
| Onset distally and later craniocervical involvement | |||||
|
Combined dystonia Parkinsonism |
DYT/PARK-TAF1 (DYT3) | Adult | X-linked recessive | Orofacial, neck, limbs, and trunk | Filipino ancestry,b often to Panay Island |
| Wide phenotypic spectrum ranging from severe generalized dystonia to pure parkinsonism or combination | |||||
| Unique dystonic parkinsonian gait14 | |||||
| MRI with striatal atrophy | |||||
| Deep brain stimulation beneficial | |||||
| DYT/PARK - GCH1 (DYT5a) | Childhood | Autosomal Dominant (rarely Autosomal recessive) | Limbs and trunk | Dopa responsiveb | |
| Diurnal variation (worse in evenings) | |||||
| Spasticity | |||||
| Familial cerebral palsy | |||||
| DYT/PARK-TH (DYT5b) | Childhood | Autosomal recessive | Limbs, trunk, and orofacial | Dopa responsiveb | |
| Diurnal variation | |||||
| Gait disorder | |||||
| Myoclonus | |||||
| Spasticity | |||||
| May be associated with oculogyric crises | |||||
| Deep brain stimulation beneficialb | |||||
| DYT/PARK-SPR | Childhood | Autosomal Recessive (rarely Autosomal dominant) | Variable | Dopa responsiveb | |
| Diurnal variation | |||||
| Intellectual/developmental delay (motor/speech) | |||||
| High CSF biopterin/dihydrobiopterin | |||||
| May be associated with oculogyric crises | |||||
| DYT/PARK-ATP1A3 (DYT12) | Adult/childhood | Autosomal dominant | Orofacial, cervical, larynx, and limbs | Considerable clinical heterogeneity: alternating hemiplegia of childhood; rapid-onset dystonia parkinsonism; common bulbar involvement; CAPOS syndrome | |
| Sudden onset after infection/febrile illness | |||||
| Fluctuating course | |||||
| Exacerbations with fever, physical stress, alcohol | |||||
| Chorea | |||||
| May have seizures | |||||
| DYT-PRKRA (DYT16) | Childhood | Autosomal dominant | Orofacial, larynx, neck, trunk, and limbs | Limb/cervical onset | |
| No response to levodopa | |||||
| Deep brain stimulation possibly beneficial | |||||
| DYT-VAC14 | Childhood | Autosomal recessive | Generalized | Clinical heterogeneity: dystonia parkinsonism, developmental delay, and retinitis pigmentosa, Yunis-Varón-like syndrome | |
| Can have limb onset and rapid generalization | |||||
| No documented response to levodopa | |||||
| Imaging may have brain iron accumulation | |||||
| Deep brain stimulation potentially beneficialb | |||||
|
Combined dystonia Myoclonus |
DYT-SGCE (DYT11) | Childhood | Autosomal dominant | Neck, upper limbs, and orofacial | Myoclonus is alcohol responsive (may lead to alcohol dependence) |
| Neuropsychiatric symptoms | |||||
| Deep brain stimulation beneficialb | |||||
| DYT-KCTD17 (DYT26) | Adult/childhood | Autosomal dominant | Cranial and cervical | Scarce response to alcohol | |
| Initial mild upper extremity myoclonus/jerky tremor | |||||
| Later upper limb/craniocervical dystonia | |||||
| Deep brain stimulation beneficialb | |||||
| DYT-KMT2B (DYT28) | Childhood | Autosomal dominant | Frequently generalized, orofacial, larynx, neck, limbs, and trunk | Increasingly recognized as a common cause of early-onset generalized dystonia (may have isolated dystonia)b | |
| Chorea and myoclonus | |||||
| Microcephaly | |||||
| Short stature | |||||
| Neuropsychiatric symptoms | |||||
| Intellectual/developmental delay | |||||
| Oculomotor apraxia | |||||
| Misdiagnosis as “cerebral palsy” | |||||
| Deep brain stimulation beneficialb | |||||
| Paroxysmal | PxMD-PRRT2 (DYT10/DYT19) | Childhood | Autosomal dominant | Variable | Paroxysmal kinesigenic dyskinesia |
| Attacks triggered by sudden voluntary movements, stress, startle, sleep deprivation | |||||
| Migraine (may be hemiplegic) | |||||
| May have epilepsy | |||||
| Possible role for deep brain stimulation | |||||
| TMEM151A | Childhood | Autosomal dominant | Variable | Paroxysmal kinesigenic dyskinesia | |
| Majority without a family history | |||||
| Attacks very brief, with a predominant, dystonic phenomenology | |||||
| May have epilepsy | |||||
| PxMD-PNKD (DYT8/DYT20) | Childhood | Autosomal dominant | Variable | Paroxysmal nonkinesigenic dyskinesia with choreoathetosis, ballismus | |
| Attacks triggered by alcohol, caffeine, stress, hunger, fatigue, tobacco | |||||
| Possible role for deep brain stimulation | |||||
| PxMD-SLC2A1 (DYT9/DYT18) | Childhood | Autosomal dominant | Legs most commonly | Paroxysmal exertional dyskinesia with choreoathetosis | |
| PxMD-ECHS1 | Childhood | Autosomal recessive | Variable | Paroxysmal exertional dyskinesia | |
| Severe developmental delay | |||||
| Infantile encephalopathy with choreoathetosis | |||||
| Optic atrophy | |||||
| Cardiomyopathy | |||||
| Sensorineural hearing loss | |||||
| Autosomal dominant frontal lobe epilepsy (CHRNA4) | Childhood | Autosomal dominant | Variable | Paroxysmal hypnogenic dyskinesia | |
| Other/complex | DYT-TUBB4A (DYT4) | Adult/childhood | Autosomal dominant | Orofacial, larynx, neck, limbs | Whispering dysphonia |
| Hobby horse gait | |||||
| Ptosis, edentulous, facial atrophy | |||||
| May have hypomyelinating | |||||
| leukodystrophy | |||||
| DYT-MECR (DYT29) | Childhood | Autosomal recessive | Generalized | Optic atrophy | |
| Basal ganglia abnormalities | |||||
| MxMD-ADCY5 | Childhood | Autosomal dominant, de novo, rare Autosomal recessive | Generalized | Axial hypotonia | |
| Developmental delay | |||||
| Facial twitching | |||||
| Chorea | |||||
| Myoclonus | |||||
| Oculomotor apraxia | |||||
| Triggered by sleep transitions, emotional stress, illness, sneezing, caffeine | |||||
| DYT-ACTB | Childhood | Autosomal dominant | Generalized | Sensorineural deafness | |
| Intellectual/developmental delay | |||||
| Dysmorphic facies | |||||
| Deep brain stimulation beneficialb |
CAPOS = cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (syndrome); CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
Modified with permission from Klein C, et al, Gene Rev.8 © 1993–2022 University of Washington, Seattle.
These are key features either pertaining to the diagnosis or high-yield treatment features, such as levodopa responsiveness or demonstrable efficacy of DBS.
TABLE 10–4.
Complex Genetic and Sporadic Dystoniasa
| Disorder | Pattern of inheritance | Gene(s) | Relevant clinical features |
|---|---|---|---|
| Disorders with predominant chorea or parkinsonism | |||
| Dopamine transporter deficiency syndrome (DYT/PARK-SLC6A3) | Autosomal recessive | SLC6A3 | Dystonia and parkinsonism, occasional chorea in infancy, mild developmental delay, truncal hypotonia, ocular flutter/oculogyric crises, saccade initiation failure |
| Disorders of heavy metal metabolism | |||
| Wilson disease (DYT-ATP7B) | Autosomal recessive | ATP7B | Dystonia, occasional parkinsonism/chorea, characteristic “flapping” tremor, orofacial dyskinesia,a liver diseasea |
| Kayser-Fleischer ringsa (slit-lamp examination; may be possible to be seen with naked eye) | |||
| Laboratory testing: low ceruloplasmin,b low serum copper,b high 24-hour urine copperb | |||
| MRI: face of the giant panda sign (in midbrain) and face of the miniature panda (in pons)b | |||
| Hypermanganesemia with dystonia, polycythemia, and cirrhosis (DYT/PARK-SLC30A10) | Autosomal recessive | SLC30A10 | Parkinsonism, hypermanganesemia,b polycythemia, chronic liver disease |
| MRI: T1 hyperintensities in the basal ganglia and cerebellumb | |||
| Hypermanganesemia with dystonia 2 (DYT-SLC39A14) | Autosomal recessive | SLC39A14 | Hypermanganesemiab |
| MRI: T1 hyperintensities in the basal ganglia and cerebellumb | |||
| Neurodegeneration with brain iron accumulation (NBIA) | |||
| Aceruloplasminemia (NBIA/DYT/PARK-CP) | Autosomal recessive | CP | Dystonia, ataxia, chorea, parkinsonism, tremors; cognitive impairment, psychiatric symptoms; diabetes mellitus; retinal degeneration |
| MRI with iron accumulation: hypointensity of basal ganglia, thalamus, red nucleus, occipital cortex, and cerebellar dentate nucleib | |||
| Woodhouse-Sakati syndrome (NBIA/DYT-DCAFI7) | Autosomal recessive | DCAF17 | Dystonia deafness syndrome,b hypogonadism,b alopecia; seizures, cognitive impairment; diabetes mellitus, thyroid dysfunction; acanthosis nigricans, keratoconus, camptodactyly |
| MRI with iron accumulation: involving the globus pallidus, substantia nigra, and other areas of the basal gangliab | |||
| Pantothenate kinase-associated neurodegeneration (NBIA/DYT-PANK2) | Autosomal recessive | PANK2 | Parkinsonism, chorea, spasticity, cognitive decline, gaze palsy, psychiatric symptoms, pigmentary retinopathy |
| MRI: eye of the tiger sign, with brain iron accumulationb | |||
| PLA2G6-associated neurodegeneration (NBIA/DYT/PARK-PLA2G6) | Autosomal recessive | PLA2G6 | Parkinsonism, cognitive decline, pyramidal signs, psychiatric symptoms (adults), ataxia (childhood) |
| MRI: may have brain iron accumulationb; cerebellar hypoplasia and T2 hyperintensities in the cerebellum | |||
| Lysosomal storage diseases | |||
| GM1-gangliosidosis (DYT/PARK-GLB1) | Autosomal recessive | GLB1 | Type III, chronic/adult form; dystonia, parkinsonism; pyramidal signs; cognitive deficits; skeletal abnormalities and short stature; corneal cloudingb; cardiomyopathyb |
| MRI: hyperintensity of caudate nucleus and putamen with signs of diffuse hypomyelination on T2-weighted sequencesb | |||
| Disorders of purine metabolism | |||
| Lesch-Nyhan syndrome (DYT/CHOR-HPRT7) | X-linked recessive | HPRT1 | Chorea, occasionally ballism; chronic liver disease; developmental delay/intellectual disability; abnormal eye movements; self-injurious behavior; hyperuricemia; renal failure |
| Mitochondrial disorders | |||
| Mitochondrial acetoacetyl-CoA thiolase deficiency (DYT/CHOR-ACAT1) | Autosomal recessive | ACAT1 | Metabolic decompensation and basal ganglia injury during acute stress resulting in dystonia and chorea |
| Mitochondrial complex IV deficiency nuclear type 11 (DYT-COX20) | Autosomal recessive | COX20 | Hypotonia, ataxia, dysarthria, sensory neuropathy |
| Leber hereditary optic neuropathy (DYT-mt-ND6) | Mitochondrial inheritance | Pathogenic variants in the mitochondrial DNA | Optic neuropathy/dystonia (G14459A mutation); juvenile-onset subacute vision loss; encephalopathy, spasticity, bulbar dysfunction; cognitive impairment |
| Deafness-dystonia-optic neuronopathy syndrome (Mohr-Tranebjaerg syndrome) (DYT- TIMM8A) | X-linked recessive | TIMM8A | Dystonia (particularly oromandibular) and sensorineural deafnessb (not necessarily present); visual impairment; cognitive impairment, behavioral problems; pyramidal signs |
| Mitochondrial disorders | |||
| SUCLA2-related mitochondrial DNA depletion syndrome (DYT-SUCLA2) | Autosomal recessive | SUCLA2 | Encephalomyopathic form, with mild methylmalonic aciduria; severe hypotonia, developmental delay, seizures; progressive spasticity, cerebral atrophy; sensorineural hearing lossb; ophthalmoplegia; feeding problems and postnatal growth retardation |
| Other dystonia-deafness syndromes | Autosomal dominant, autosomal recessive, X-linked recessive | SERACI, BCAP31, FITM2, DDP | Dystonia and deafnessb |
| Organic acidurias | |||
| Glutaric aciduria type 1 (DYT/CHOR-GCDH) | Autosomal recessive | GCDH | Newborn screening; chorea, parkinsonism, acute metabolic crises with basal ganglia injury, severe truncal hypotonia, macrocephaly, orofacial dyskinesia, spasticity; cognitive impairment (variable) |
| Imaging: enlarged subdural spaces,b subdural hygroma/hemorrhages | |||
| Methylmalonic acidemia including DYT/CHOR-MUT | Autosomal recessive | MCEE, MMAA, MMAB, MMADHC, MMUT | Newborn screening; chorea, occasional ataxia; seizures, lethargy, and hypotonia; ketoacidosis, hyperammonemia; developmental delay, spasticity |
| Acute metabolic crises,b with confusion/encephalopathy, basal ganglia injury (predominantly globus pallidus) | |||
| Propionic acidemia (DYT/CHOR-PCCA/PCCB) | Autosomal recessive | PCCA, PCCB | Dystonia, occasionally chorea; neonatal-onset vomiting, seizures, lethargy, and hypotonia; ketoacidosis, hyperammonemia; developmental delay; spasticity; cardiomyopathy |
| Acute metabolic crisesb with confusion/encephalopathy with basal ganglia injury (putamen/caudate) | |||
| Aminoacidurias | |||
| Aromatic l-amino acid decarboxylase deficiency (DYT-DDC) | Autosomal recessive | DDC | Dystonia, occasionally |
| Chorea; developmental delay, truncal hypotonia; oculogyric crises, ptosis; autonomic symptoms; sleep disorder with diurnal fluctuations and sleep benefit | |||
| Dihydropteridine reductase deficiency (DYT/PARK-QDPR) | Autosomal recessive | QDPR | Dystonia; parkinsonism; developmental delay, truncal hypotonia, seizures, autonomic dysfunction; hyperphenylalaninemia |
| Non-BH4-deficiency hyperphenylalaninemia (DYT-DNAJC12) | Autosomal recessive | DNAJCI2 | Dystonia, parkinsonism; developmental delay; hyperphenylalaninemia |
| 6-Pyruvoyl-tetrahydropterin synthase deficiency (DYT/PARK-PTS) | Autosomal recessive | PTS | Dystonia, parkinsonism |
| Disorders of biotin metabolism | |||
| Biotin-thiamine-responsive basal ganglia disease (DYT-SLC19A3) | Autosomal recessive | SLC19A3 | Dystonia, parkinsonism (mainly rigidity), occasionally ataxia, chorea; subacute encephalopathy/coma (often triggered by febrile illness); cranial nerve palsy, pyramidal signs; intellectual disability; epilepsy; responsive to thiamine and/or biotin therapyb |
| MRI: symmetric and bilateral edematous lesions in caudate nucleus, putamen, and cortexb | |||
| Other metabolic | |||
| Primary coenzyme Q10 deficiency | Autosomal recessive | COQ8A | May present with early-onset focal hand dystonia15; early-onset exercise intolerance, ataxia, tremor, epilepsy |
| Unpredictable responses to coenzyme Q10 supplementationb | |||
| Disorders with predominant ataxia | |||
| Spinocerebellar ataxias (SCAs) | Autosomal dominant | ATXN3, ATXN2, TBP, ATXNI, CACNAIA, PPP2R2B, PRKCG, ATXN7, 11q12, and others | Various presentations and can be associated with multiple movement disorders, including parkinsonism or action tremor; frequent prominent, sometimes generalized, dystonia particularly in early-onset SCA3; dystonia most common in SCA3, followed by SCA2, SCA17, and less frequent in SCA1, SCA6, SCA12 (often with cervical dystonia), and SCA14; rare in SCA7 and SCA20, but can be seen in others |
| Sporadic neurodegenerative disorders | |||
| Idiopathic Parkinson disease | N/A | Dystonia frequently in young-onset Parkinson disease; often involving a foot, or cervical dystonia; tends to remain focal | |
| Sporadic neurodegenerative disorders | |||
| Atypical parkinsonism | N/A | Focal/segmental dystonia most common distribution but can also involve the trunk | |
| Progressive supranuclear palsy: often blepharospasm or cervical dystonia (frequently retrocollis) | |||
| Multiple system atrophy: cervical dystonia, often anterocollis | |||
| Corticobasal syndrome: unilateral focal hand dystonia often spreading on affected side to become hemidystonia, associated with cortical sensory loss | |||
ETIOLOGIC CLASSIFICATION OF DYSTONIA.
The etiology of dystonia can be differentiated by identifiable anatomic changes and pattern of inheritance. In most causes of dystonia, brain degeneration or structural brain lesions are absent.
Important changes have occurred in the nomenclature of the genetic dystonias and other movement disorders16 and were updated in 2022.17 The previous system of assigning locus symbols (eg, DYT1 and DYT6) was used to provide names for conditions, frequently before identification of the disease-causing gene. Over time, this resulted in several issues, including erroneous, duplicated, missing, or unconfirmed loci; more than one designation applied to the same disorder; a discrepancy between risk factor versus disease-causing genes; and discordance between the predominant phenotypes of diseases.16 According to the new nomenclature, only isolated genetic dystonias (dystonia as the primary feature) were designated “DYT” followed by the gene name (eg, DYT-TOR1A, formerly DYT1), whereas combined dystonias have a double prefix, including both movement phenotypes (eg, DYT/PARK-TAF1, formerly DYT3). Paroxysmal dyskinesias/dystonias have the prefix PxMD,12 while those without a consistent core phenotype are designated mixed movement disorders (MxMD).17
DIAGNOSTIC CHALLENGES IN DYSTONIA
Diagnosing dystonia continues to be challenging, including differentiating dystonia from other mimics and because of the wide clinical spectrum.6 Lalli and Albanese4 have suggested clinical clues to guide the diagnosis of isolated dystonia, with common misdiagnoses occurring in patients thought to have PD, essential tremor, myoclonus, tics, functional (“psychogenic”) dystonia, headaches, and scoliosis.
PD can not only present with concurrent dystonia but parkinsonian features may be confused with dystonia in certain situations. Complicating diagnosis, dystonia is common in patients with PD: 30% develop off-state dystonia, and 10% to 15% may develop (generally lower) limb dystonia (which may be a presenting feature, particularly in early-onset parkinsonism), while blepharospasm, apraxia of eyelid opening (mainly in atypical parkinsonism), and truncal/axial dystonia (including camptocormia and Pisa syndrome) can occur.4 Additionally, dystonia may also resemble PD, as slowness of movement in a dystonic limb may be confused with parkinsonian bradykinesia, increased tone from dystonia may mimic rigidity, and a dystonic tremor, if observed at rest, may be misconstrued as a parkinsonian tremor. Even patients with genetic dystonia syndromes, such as DYT-TOR1A and dopa-responsive dystonia, can be misdiagnosed as having PD.4 However, in isolated dystonia, other than tremor, there is no development of diagnostic features of parkinsonism, without the essential presence of bradykinesia (a required criterion of parkinsonism, comprising slowness with specific characteristics of decrement/fatiguing with multiple iterations, or hesitations/interruptions), or true rigidity (the presence of “lead pipe” rigidity, with or without cogwheeling at the wrist), per the Movement Disorders Society criteria.18 Differentiating dystonia from PD is more challenging in combined forms of dystonia, particularly in dystonia parkinsonism, where true parkinsonism does occur. In general, causes of genetic dystonia parkinsonism have a much earlier age of onset than typical PD, although some cases may be clinically indistinguishable, in which case the clinician must instead rely on the presence of a family history, imaging, and other relevant features.19 Furthermore, the presence of task- or position-specific tremor, head or vocal tremor, normal dopamine transporter single-photon emission computed tomography (SPECT), and lack of symptomatic benefit with dopaminergic therapy (an exception being dopa-responsive dystonia) are all hallmarks of dystonia.
As a common diagnostic quandary, dystonia may be confused with essential tremor, particularly when essential tremor presents with head and vocal tremor, as cervical dystonic tremor with vocal tremor may present similarly.4 Essential tremor typically presents as a bilateral, largely symmetric, postural and kinetic tremor, frequently involving the head and voice (and less so, the face and jaw), which is commonly alcohol responsive (a nonspecific feature, as dystonia may also be alcohol responsive), and patients frequently have a positive family history. In comparison, dystonic tremor is not strictly rhythmic or oscillatory and is irregular, tends to involve the neck and less so a limb, and can improve with sensory tricks, particularly in cervical dystonia. Red flags indicating dystonia include an isolated head tremor, head tremor that is associated with neck pain or asymmetric neck muscle hypertrophy, vocal tremor with inability to change vocal pitch, and lack of tremor improvement with typical essential tremor treatments.6,20
Patients with myoclonus and dystonia may both have fast, jerky movements that can mimic tremor. The two forms of abnormal movement can be differentiated by EMG; spasm duration of less than 200 ms is found in myoclonus, and spasm duration of more than 200 ms is found in other forms.6 Myoclonus and dystonia co-occur in myoclonus-dystonia, while essential myoclonus has no associated dystonia.
Tics can have dystonic features and may coexist with dystonia. Features not present in dystonia include some more specifically associated neuropsychiatric symptoms (attention deficit hyperactivity disorder/obsessive-compulsive disorder are common in patients with tics but not dystonia) and a premonitory urge prior to the movements (not present in dystonia).4
Functional dystonia can be particularly challenging to differentiate from “organic” dystonia.7 Features suggestive of a diagnosis of functional dystonia, as described in detail by Frucht and colleagues,7 include an abrupt onset of symptoms, the hallmarks of inconsistency/incongruity, a resting dystonia at onset, no evidence of co-contraction/overflow dystonia, the presence of highly atypical or bizarre “sensory tricks,” or examiner maneuvers such as the placement of a vibrating tuning fork which result in dramatic improvement of posturing (which may also leverage suggestibility).21,22 The use of a risk score based on historical features has also been proposed to help facilitate a diagnosis.23 Clinical features of functional dystonia phenomenology are shown in FIGURE 10–2. In comparison, in dystonia, a gradual onset occurs (other than in rare exceptions, such as rapid-onset dystonia parkinsonism), movements and postures are consistent and congruous over time, typical sensory tricks occur, and no associated functional neurologic features exist (although clinicians should be aware that both “organic” and functional movement disorders can coexist).
FIGURE 10–2.
Examples of functional dystonia phenomenology, which is distinct from that seen in “organic” dystonia. A, Functional cranial dystonia is shown in a patient with bilateral lip pulling (pulling of this kind is typically unilateral in “organic” dystonia other than in the setting of risus sardonicus, which is phenomenologically distinct). B, Patient exhibits functional blepharospasm with eyes tightly shut (left) and forcefully open when concentrating (right) (distinct from “organic” dystonia, as the eye closure was sporadic and very severe; in this case, provocative maneuvers, such as tight eye closure, did not trigger spasms, which is highly atypical and highlights the inconsistency). C, Three examples of functional foot dystonia illustrating the typical posturing involving fixed dystonia with plantarflexion and inversion (left); in this same patient, extension of the great toe with flexion of the others toes is shown (middle); in a different patient, paroxysmal dystonia involving plantarflexion and toe curling is shown (right); this is distinct from organic dystonia, as fixed dystonia at onset is highly unusual and tends to occur in more advanced disease, and the symptomatology is inconsistent. D, Three examples are shown of varying dystonic upper extremity posturing in a patient with paroxysmal functional dystonia: the right arm extended with wrist flexion and fisting (left); elbow flexion with wrist flexion akin to carpopedal spasm (middle); and shoulder abduction, elbow flexion, and wrist flexion with a limp hand (right) (distinct from “organic” dystonia where the phenomenology of episodes in paroxysmal dystonia/dyskinesia is typically stereotyped).
Reprinted with permission from Frucht L, et al, Front Neurol.7 © 2020 Frontiers Media S. A.
Headache and neck pain are nonspecific symptoms but both are commonly found in craniocervical dystonia. While headaches can be associated with some head posturing (to reduce activation of muscles in spasm), the relief of pain by sensory tricks, the presence of asymmetric neck muscle hypertrophy, and an excellent response to botulinum toxin injections may suggest a dystonic cause.4
Finally, scoliosis may be either idiopathic or degenerative, with a family history in roughly 30%, suggesting genetic cause in some cases.4 Scoliosis may be an initial manifestation of dystonia, particularly in childhood-onset cases. Dystonic appearance of the movements/postures (eg, a tendency to spasmodically pull to one side versus a static fixed posture) and a family history of dystonia may instead suggest an underlying diagnosis of dystonia.4
Acquired dystonia includes many conditions, often involving lesions of the basal ganglia or more global injury (TABLE 10–5).12,24,25 Numerous pseudodystonias, which mimic dystonia, also exist and result from musculoskeletal disease or dysfunction in sensory, motor, or other neurologic pathways (TABLE 10–6).26 Therefore, all patients with dystonic symptoms should have a careful history and physical examination to look for “rule in” signs suggestive of dystonia,6 excluding conditions that mimic dystonia, as well as looking for the presence of additional movement disorders, which may suggest a combined phenotype. Challenges in combined dystonias are even more fraught than in isolated dystonias, given the rapidly expanding phenotypic spectrum of complex movement disorders (TABLES 10–3 and 10–4). In genetic dystonias, even if there are presumed pathognomonic findings on history, examination, or investigations suggesting a specific diagnosis, surprises can occur, as one phenotype can be related to many genes, and one gene can yield multiple phenotypes.27
TABLE 10–5.
Acquired Nongenetic Causes of Dystoniaa
| Cause | Etiology | Examples and clinical features |
|---|---|---|
| Acquired brain lesions | Prenatal and postnatal hypoxia/ischemia, hypoglycemia | Post-cardiac arrest |
| “Cerebral palsy”: dystonia may be unilateral but can be generalized depending on the severity and degree of hypoxia (caution: cases of genetic dystonias may mimic acquired cerebral palsy,25 most notably dopa-responsive dystonia12) | ||
| Bronchopulmonary dysplasia: dystonia may be unilateral but can be generalized depending on the severity and degree of hypoxia | ||
| Hypoglycemia | ||
| Infections (causing basal ganglia lesions)/encephalitis | Creutzfeldt-Jakob disease (and other prion diseases, often associated with ataxia and dementia), rapidly progressive: mainly focal dystonia in earlier stages followed later by generalized dystonia | |
| Mycoplasma pneumoniae: dystonia contralateral to lesion | ||
| Tuberculosis: dystonia contralateral to lesion | ||
| Japanese B encephalitis: dystonia or other movement disorders as part of viral encephalitis, with prominent basal ganglia involvement | ||
| Parainfectious disorders | Reye syndrome: varying degrees of dystonia | |
| Subacute sclerosing panencephalitis: dystonia (may be generalized) and parkinsonism | ||
| Autoimmune disorders | Multiple sclerosis: related to demyelinating lesion location and burden; most common movement disorders are tremor, ataxia, and restless legs syndrome, but tonic spasms involving paroxysmal dystonia associated with a spinal cord lesion are common, and other cases may have focal (and exceedingly rare generalized) dystonia | |
| Antiphospholipid-antibody syndrome: may have dystonia or chorea and may be unilateral | ||
| Paraneoplastic encephalitis (including faciobrachial dystonic seizures caused by anti-LGI1 encephalitis) | ||
| Metabolic disorders | Kernicterus: varying degrees of dystonia and may be generalized | |
| Hepatic encephalopathy: liver disease, often associated with ataxia, with MRI revealing T1 hyperintensity in the basal ganglia | ||
| Hypoparathyroidism | ||
| Osmotic demyelination syndrome: arises from inappropriate treatment of hyponatremia/hypernatremia and may have late dystonia, which may be focal (cases involving cervical, cranial, and laryngeal dystonia), as well as parkinsonism | ||
| Vascular disorders | Stroke sequelae of basal ganglia lesions, particularly involving the putamen (differentiation from the fixed posture related to spasticity), contralateral hemidystonia | |
| Arteriovenous malformation of the basal ganglia, contralateral hemidystonia | ||
| Traumatic brain injury | Often contralateral if unilateral injury but may have bilateral involvement | |
| Intraparenchymal space-occupying lesions (direct effects) | Brain abscess or tumor, with or without involvement of the basal ganglia | |
| Increased intracranial pressure | Brain abscess, tumor, or other space-occupying lesion, including from radiation | |
| Subdural/epidural hematoma | ||
| Physical interactions | Electrocution | |
| Ionizing radiation/radiation therapy | ||
| Toxic causes | Carbon monoxide, methanol, disulfiram, or cyanide poisoning; MRI with high T2 signal in basal ganglia; delayed dystonia parkinsonism | |
| Manganese (ephedrone abuse, chronic liver disease, or total parenteral nutrition) causing combined dystonia parkinsonism with T1 hyperintensity in the basal ganglia on MRI | ||
| Wasp sting encephalopathy: acute dystonic reaction with evidence of pallidostriatal necrosis on MRI | ||
| Drug-induced dystonia | Neuroleptic drugs (antipsychotics and other medications with action at the dopamine receptor) | Acute dystonic reactions |
| Tardive dystonia, which may be accompanied by other tardive movement disorders (dyskinesia, drug-induced parkinsonism) and may frequently present focally as isolated retrocollis or blepharospasm and less commonly oromandibular dystonia and can cause truncal dystonia with extension; may respond to deep brain stimulation | ||
| Anti-seizure medications | Tardive dystonia or other tardive movement disorders |
TABLE 10–6.
Distribution and Etiology of Pseudodystoniaa
| Dystonia-mimicking phenotype | Corresponding pseudodystonia |
|---|---|
| Blepharospasm | Dermatochalasis (eyebrow elevation to prevent ptosis, no spasms) |
| Ptosis (eyebrow elevation to prevent ptosis, no spasms) | |
| Myotonia (presence of myokymia) | |
| Functional dystoniab | |
| Oromandibular dystonia | Tetanus (severe pain and spasms; can become generalized) |
| Hypoglossal nerve damage (persistent tongue deviation, without dynamic element, ipsilateral tongue weakness on examination) | |
| Functional dystoniab | |
| Cervical dystonia | Klippel-Feil syndrome (abnormal posturing related to cervical vertebral fusion; can be seen on x-ray) |
| Congenital muscular torticollis (present from birth and fixed) | |
| Cervical soft tissue mass (need to examine neck, tilts away from mass) | |
| Sandifer syndrome (associated with esophageal reflex, in which head tilting relieves gastrointestinal distress) | |
| Vestibulopathy (causing secondary head tilt to avoid sensation, with associated vertigo/disequilibrium) | |
| Trochlear/abducens cranial nerve palsy (causing secondary head tilt given visual misalignment; brain imaging if not chronic) | |
| Head drop related to neuromuscular weakness (true neck weakness on examination, fatigability in myasthenic syndromes, associated weakness in other locations) | |
| Dystonic tics (presence of premonitory urge, history of tics in childhood [generally ≤10 years of age], other motor/vocal tics) | |
| Functional dystoniab | |
| Focal hand dystonia | Dupuytren contracture (fixed posturing, notable palmar nodule) |
| Trigger finger (intermittent, evidence of triggering when opening hand from a fist, palpable snap on palpating A1 pulley) | |
| Peripheral entrapment neuropathy (weakness of predominantly ulnar [flexion of ring/little fingers, claw hand], median [thumb dysfunction, causing “ape hand”], or radial [wrist and finger drop] muscles leading to abnormal postures); severe sensorimotor peripheral neuropathy or ganglionopathy can cause secondary abnormal hand posturing (eg, Friedreich ataxia causing fixed distal finger flexion deformities) | |
| Other causes of hand/finger weakness (such as amyotrophic lateral sclerosis, causing various abnormal postures) | |
| Carpopedal spasms (generally bilateral tonic spasms involving wrist, thumb, and finger flexion, seen in hypocalcemia [positive Trousseau and Chvostek signs] or other electrolyte imbalance) | |
| Functional dystoniab | |
| Focal foot dystonia | Carpopedal spasms (generally bilateral tonic spasms involving mainly hand and, less commonly, foot plantarflexion and toe flexion; seen in hypocalcemia [positive Trousseau and Chvostek signs] or other electrolyte imbalance) |
| Any cause of focal spasticity or foot weakness (including footdrop from fibular [peroneal] nerve palsy or radiculopathy) | |
| Functional dystoniab | |
| Hemidystonia | Intraparenchymal brain lesion (neoplasm, abscess, vascular, inflammatory, congenital; imaging important to assess for ipsilateral or intramedullary lesion)c |
| Stroke (sudden onset; brain imaging important to look for corresponding lesion in contralateral cortex or brainstem, with appearance related to a combination of weakness, spasticity, and other upper motor neuron pathology)c | |
| Spinal cord lesionc (may have associated tonic spasms; spinal imaging) | |
| Stiff person syndrome (focal limb onset and hyperlordosis, painful spasms; antibody testing; immunomodulatory therapy) | |
| Functional dystoniab | |
| Generalized dystonia | Progressive encephalomyelitis with rigidity and myoclonus (antibody testing; immunomodulatory therapy) |
| Tetanus (painful generalized muscle spasms and boardlike abdominal rigidity; tetanus vaccine status) | |
| Myelopathy (bilateral more than unilateral abnormal postures related to weakness, spasticity, or deafferentation; bowel/bladder dysfunction; back/spinal pain; spinal imaging)c | |
| Peripheral neuropathy (bilateral abnormal postures related to weakness with or without deafferentation; nerve conduction studies and EMG)c | |
| Subacute combined degeneration of the spinal cord (bilateral abnormal postures related to weakness, spasticity or deafferentation; spinal imaging; vitamin B12, folate, homocysteine, methylmalonic acid testing, with additional testing for mimics including copper and zinc [copper deficiency myeloneuropathy] and vitamin E)c | |
| Functional dystoniab |
EMG = electromyography.
Modified with permission from Berlot R, et al, Parkinsonism Relat Disord.26 © 2019 Elsevier.
Functional dystonia can mimic all forms of dystonia and may have a pathophysiologic overlap.
Related to deafferentation or corticospinal tract involvement.
EPIDEMIOLOGY OF DYSTONIA
Despite increasing recognition, limited data on dystonia epidemiology exist. A recent meta-analysis reported an overall prevalence of primary focal dystonia of 16.4 per 100,000 individuals.28 However, given diagnostic difficulties, current estimates likely represent an underestimate, with some studies suggesting a prevalence of up to 1 per 1000 individuals.29 Focal dystonia is more common than widespread involvement, and combined dystonias are very rare. Idiopathic isolated dystonias are the most common, with cervical dystonia generally the most common form (3 to 13 per 100,000)28 however, blepharospasm is the more prevalent form in Japan and Italy.28 Dystonia prevalence increases with age and is different between the sexes. While dystonia is more common in women overall, this is generally related to the high relative prevalence of focal craniocervical dystonias, which have a clear female predilection. There are also racial, ethnic, and geographic differences, including from founder mutations (eg, DYT-TOR1A is more common in people of Ashkenazi Jewish ancestry,30 and X-linked dystonia-parkinsonism [DYT-TAF1] is almost exclusively found in people of Filipino ancestry).31
KEY POINTS.
Despite increasing recognition, limited data exist on dystonia epidemiology. Given the common misdiagnoses, the prevalence of dystonia may be up to 1 in 1000 individuals. There are age, sex, racial, ethnic, and geographic variations.
ADULT-ONSET IDIOPATHIC FOCAL/SEGMENTAL ISOLATED DYSTONIA
Adult-onset idiopathic focal and segmental dystonias are the most common dystonic conditions (segmental less common than focal) and infrequently generalize, although they may progress to involve other tasks (if task specific) or spread to a more widespread distribution over time.13 Dystonia is generally persistent, with rare spontaneous remission, and 68% of remissions subsequently relapse.32 These are differentiated from early-onset dystonias, where symptoms begin before 26 years of age, frequently have a genetic cause, and often generalize.1
KEY POINTS.
Adult-onset idiopathic focal/segmental dystonias are the most common dystonic conditions and infrequently generalize, although there may be progression over time. These include cervical, cranial, oromandibular, laryngeal, limb, and truncal dystonia.
Of the adult-onset focal dystonias, cervical dystonia (“torticollis”) is generally the most common (FIGURES 10–1D through 1E) and is illustrated in CASE 10–1. Cervical dystonia generally presents in middle age (often in the forties), frequently with gradually worsening neck pain and eventually developing into abnormal neck posturing. This can involve torticollis (neck rotation), laterocollis (tilting from lateral flexion), retrocollis (extension), and anterocollis (flexion), as well as shoulder elevation, or a combination. Sensory tricks are frequently beneficial (eg, touching the chin, head, or face, or applying pressure/tension to the posterior neck) but may wane in effectiveness. Associated head tremor occurs in 30% to 60% of patients, and hand tremor, which can mimic essential tremor, occurs in 25% of patients5; 20% may develop segmental/multifocal dystonia, often cranial (blepharospasm/oromandibular), writer’s cramp, or truncal dystonia.33
CASE 10–1
A 54-year-old man presented with a 1-year history of subacute development of right neck and shoulder pain and right head tilting, which intensified in the setting of significant work-related/interpersonal stress. His symptoms were worse with anxiety, physical activities, and complex hand tasks.
On examination, he had a considerable right head tilt, with some left rotation; full active range of neck motion and tension in his right levator scapulae, splenius capitis, and upper trapezius; and hypertrophy of the right sternocleidomastoid. His neck posture worsened with walking, with certain hand tasks, and when looking down. The neck posturing significantly improved when he wore a scarf (ie, tension) around his neck (FIGURES 10–1D through 1E), and he experienced resolution when resting his head against a surface.
He improved with targeted botulinum toxin injections, stress reduction, and physical therapy. He experimented and harnessed further sensory tricks, which over time required less stimulus to produce benefit and had a wider area of effect.
COMMENT
This case provides a classic example of adult-onset idiopathic cervical dystonia, with typical sensory tricks. Although his symptoms occurred in the setting of stress and anxiety, his examination and disease course were inconsistent with a functional etiology.
Cranial dystonia can involve the eyelids, lower face, jaw, and tongue and c an occur in isolation or in combination (FIGURES 10–1A through 1C and 1H through 1J). Blepharospasm (involuntary spasms of orbicularis oculi/surrounding muscles) is the most common type of cranial dystonia. Blepharospasm may be preceded by a feeling of eye irritation and photophobia, generally with initially mild eye blinking in both eyes, which gradually worsens. Patients with severe cases can have episodes of prolonged eye closure, which may be sight limiting.5 Triggers include bright sunlight, stress and anxiety, computer work, watching television, and other eye strain.34 Lower facial spasms indicate the presence of Meige syndrome, a segmental craniocervical dystonia.
Oromandibular dystonia involves the jaw muscles, causing jaw opening (lateral pterygoids/digastrics), (FIGURE 10–1C) or closing (medial pterygoids, masseters, and temporalis), with asymmetric contraction causing lateral deviation, protrusion, or retraction, sometimes with jaw tremor.5 Talking and chewing typically worsen symptoms. Sensory tricks are present in one-third and include pressure on the lips/teeth, touching the tongue to the hard palate, or placing an item between the teeth or in the cheek.5 Tongue dystonia is a rare oromandibular dystonia involving tongue protrusion/curling (FIGURES 10–1A and 1B). Task-specific forms include embouchure dystonia (a subset of musician’s dystonia) and other forms in repetitive/heavy speech users.
Laryngeal dystonia (spasmodic dysphonia) involves vocal fold muscles affecting voice production during speaking. In some cases, singing and shouting are also affected.35 Laryngeal dystonia is more common in women (80%), and the adductor form is more common than abductor, singer’s dystonia, or adductor respiratory forms, with dystonic tremor occurring in up to 30% of patients.35 Adductor spasmodic dysphonia results in a strained, strangled, and coarse voice with variations in pitch and vocal breaks. In contrast, abductor spasmodic dysphonia involves voice breaks on voiceless consonants and a breathy voice quality. In both forms, innate vocalizations during laughing, crying, and whispering are unaffected. Singer’s dystonia occurs during singing, while adductor respiratory dystonia involves inspiration, causing dyspnea, stridor, or obstruction.
Upper and particularly lower limb dystonia (FIGURES 10–1K through 1O) are rare in adults and are frequently task-specific (FIGURES 10–1M and 1N).10 The most common cause of upper extremity dystonia is writer’s cramp, a task-specific dystonia affecting the hand, forearm, or upper arm that manifests as abnormal posturing with writing.10 Writer’s cramp is more common in men and may occur in the setting of excessive, repetitive hand use or overuse.10 Musician’s focal hand dystonia is a task-specific dystonia occurring when playing a musical instrument (FIGURE 10–1M), is more common in men, typically occurs at the peak of performance careers, is more common in professional musicians, and can be associated with excessive practicing, overuse, or hand injury.36 Task-specific lower extremity dystonia includes runner’s dystonia, in which abnormal posturing occurs in runners or joggers (can occur in high-level athletes or amateurs), frequently in those preparing for a race, or where there has been a precipitous escalation in the amount of running time. The posturing predominantly involves plantarflexion, or inversion, but can have more proximal involvement (FIGURE 10–1N).37 Although this can begin with running or jogging, the posturing can involve other tasks, including cycling or walking on certain terrain types, and frequently progresses to affect general walking.37
GENETIC FORMS OF DYSTONIA
The presence of a family history of dystonia (which may need to be specifically sought, as dystonic symptoms may frequently be misinterpreted as other conditions) should be carefully queried in any patient with dystonia, as this can indicate a potentially genetic cause or susceptibility. This is of particular relevance in younger-onset cases and especially in generalized or combined dystonia, where the index of suspicion for an underlying hereditary cause should always be high. Many genetic forms of dystonia exist, with the most common being isolated autosomal dominant dystonia and rare autosomal recessive forms. However, with the increased use and availability of next-generation exome and genome sequencing, new dystonic genes continue to be discovered.
KEY POINTS.
Many genetic forms of dystonia exist. Genetic isolated dystonias are mainly autosomal dominant.
Autosomal recessive dystonia is much less common than autosomal dominant cases and should be suspected if there are multiple affected individuals within the same generation, but not in their parents, or parental consanguinity.
Combined dystonias involve dystonia and other movement disorders, frequently parkinsonism or myoclonus. Considerable clinical and genetic heterogeneity exists.
Autosomal Dominant Isolated Dystonia
Autosomal dominant isolated dystonia is the most common form of genetic dystonia. The presence of an autosomal dominant etiology should be suspected when dystonia is present in multiple family members across generations and particularly if this involves cases of early-onset generalized dystonia. However, this may not always be the case, owing to de novo mutations or reduced penetrance.
DYT-TOR1A (DYT1), the most common early-onset generalized dystonia, involves a GAG in-frame deletion in TOR1A and is particularly prevalent in individuals of Ashkenazi Jewish ancestry, with reduced penetrance (30%).30 Onset frequently involves focal leg or later arm involvement, then rapidly generalizes, while 20% may remain focal, often involving writer’s cramp.30 DBS is very beneficial.38,39
DYT-THAP1 (DYT6) is another common early-onset isolated dystonia with reduced penetrance (48%).27 Onset is mainly craniocervical or in an arm, with infrequent oromandibular involvement, and may generalize,40 as illustrated in CASE 10–2. DBS is beneficial.38,39
CASE 10–2
A 10-year-old girl presented with slowly progressive difficulties with writing. In retrospect, she had an awkward pencil grip at preschool, causing her to change her writing hand. By age 8, she had developed tremulousness of her right hand, with abnormal posturing and a tendency to tuck her right arm into her side. By age 10, she developed similar symptoms on the left side. She tried different pencil grips and a wrist splint, but constraining the movements tended to aggravate them. She had a history of normal birth and development and no significant family history.
On examination, she had abnormal bilateral arm spasmodic posturing involving in-drawing of the arms with shoulder adduction and pronation; bilateral wrist and finger flexion; and mild leg posturing with foot inversion. Her gait was minimally affected. Handwriting triggered posturing (FIGURE 10–1L), but she could compensate well. Brain MRI was normal. Genetic testing revealed a heterozygous pathogenic variant in the THAP1 gene, consistent with DYT-THAP1.
COMMENT
This case illustrates the presentation of DYT-THAP1 disease with upper extremity onset, without involvement of the craniocervical region, and with slow generalization. Despite the absence of a family history, childhood-onset isolated dystonia should be evaluated with genetic testing. Certain THAP1 variants can also present in a recessive manner.40,41 Oral medications such as trihexyphenidyl can be useful and are generally well tolerated in early-onset generalized dystonia, but these were deferred in this case given parental concern for the side effects. She had occupational therapy with good effect. Over the ensuing 3 years, her symptoms plateaued, and she continued to compensate well at school.
DYT-GNAL dystonia mainly occurs in adults, presents with cervical dystonia, and may spread, leading to segmental dystonia.42 DYT-ANO3 dystonia also has a cervical onset, often involving head and limb tremor, which may resemble essential tremor.43
Autosomal Recessive Isolated Dystonia
Autosomal recessive dystonia is much less common than autosomal dominant cases and should be suspected if multiple affected individuals are present within the same generation, but not in their parents, or in the presence of parental consanguinity. Previously referred to as “DYT2 dystonia,” several genes have been identified in single families with autosomal recessive dystonia, although not all are confirmed. Compound heterozygous mutations in HPCA are associated with childhood-onset slowly generalizing dystonia, mainly in the craniocervical and upper extremity regions.44 Other genes include VPS16 (late childhood–onset cervical dystonia, later generalizing)29 and an uncertain role for COL6A3.45 There have been homozygous variants reported in THAP139,40 and GNAL,46 suggesting that these may also present in a recessive manner.
Genetic Combined Dystonia
Combined dystonias involve dystonia and other movement disorders, frequently parkinsonism or myoclonus. DYT-GCH1 (DYT5a) is an autosomal dominant (rarely autosomal recessive), typically childhood-onset dopa-responsive dystonia.47 It often begins as a focal foot dystonia and slowly spreads upward, sometimes generalizing.47 Characteristic diurnal variation is seen, with worsening in the evening, related to varying dopamine levels over the day.47 GCH1 carriers may develop later-life parkinsonism, mimicking PD.48 Patients have an excellent response to levodopa although this may be complicated by levodopa-induced dyskinesias.47,49
DYT/PARK-PRKRA (DYT16) involves early-onset limb or cervical dystonia that progresses to severe generalized dystonia (including opisthotonus, sardonic dystonic facies, and laryngeal involvement) and frequently mild levodopa-nonresponsive parkinsonism.50 DBS has potential benefit.51
X-linked dystonia-parkinsonism (DYT/PARK-TAF1) is caused by the insertion of a retrotransposon in intron 32 of TAF1 on the X chromosome in males of Filipino ancestry.52 This causes an adult-onset movement disorder (onset in the third to the fifth decades) with a considerable phenotypic spectrum, often initially presenting with dystonia (predominantly axial or segmental neck/jaw dystonia), which generalizes, and may have later-onset parkinsonism.31 Some cases of X-linked dystonia-parkinsonism may present with pure parkinsonism indistinguishable from PD,31 and others may have a characteristic knee bending dystonic and parkinsonian gait.14 DBS is beneficial.38,39
Rapid-onset dystonia parkinsonism (DYT/PARK-ATP1A3 [DYT12]), a rare autosomal dominant combined dystonia, presents in adolescence or early adulthood with acute/subacute dystonia and prominent bulbar features and follows a triggering event such as fever or physical or psychological stress.53 The dystonia has a rostrocaudal gradient and can be associated with parkinsonism, particularly involving bradykinesia and postural instability. The two other classic phenotypes include (1) infantile-onset alternating hemiplegia of childhood or (2) cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Myriad rarer phenotypes also exist.54 Alternating hemiplegia of childhood is an early childhood–onset disorder involving paroxysmal episodes of alternating hemiparesis or hemidystonia and seizures, with progressive motor and cognitive impairment.53 Trigger avoidance is important, and dystonic attacks may respond to benzodiazepines, anticholinergics (eg, trihexyphenidyl, diphenhydramine), or flunarizine (not currently approved in the United States).
Recently discovered VAC14 mutations cause pediatric-onset (ages 1.5–13 years) dystonia parkinsonism (DYT-VAC14), with striatonigral degeneration.55 Some cases show brain iron accumulation on neuroimaging,56 suggesting that this should be included as a form of neurodegeneration with brain iron accumulation.57 Prominent dystonia with rapid generalization generally occurs with or without parkinsonism, and younger-onset cases progress rapidly, with slower progression in older patients.55 Severe neuropsychiatric symptoms were also observed in an unpublished case from the author’s center. Beneficial medical treatments have not been reported, including levodopa55; however, a single case treated with DBS had substantial improvement in dystonia.56
KMT2B mutations have emerged as a common cause of autosomal dominant childhood-onset generalized dystonia, although this is generally a combined dystonia owing to complex features, including developmental delay, microcephaly, short stature, and choreoathetosis or myoclonus.58 Patients have good responses to DBS.38,39
Myoclonus-dystonia (DYT-SGCE) results in autosomal dominant, typically childhood-onset generalized myoclonus predominantly involving the head/arms, associated with mild dystonia, mainly involving cervical dystonia and writer’s cramp.59 The myoclonus is frequently alcohol responsive, which may lead to alcohol dependency, and patients should be counseled regarding this. Patients frequently exhibit psychiatric features (anxiety, depression, and obsessive-compulsive behavior).59,60
Paroxysmal Dystonias/Dyskinesias
The paroxysmal dystonias/dyskinesias are rare disorders involving episodic hyperkinetic movements, including dyskinesia or dystonic movements. These are typically early-onset disorders that arise in childhood or adolescence and very rarely occur after age 18.11 The three main forms of paroxysmal dystonia/dyskinesias include (1) paroxysmal kinesigenic dystonia/dyskinesia, (2) paroxysmal nonkinesigenic dystonia/dyskinesia, and (3) paroxysmal exercise/exertion-induced dystonia/dyskinesia. Clinical and genetic overlap are present.61
KEY POINTS.
The paroxysmal dystonias/dyskinesias are rare disorders involving episodic hyperkinetic movements, including dyskinesia or dystonic movements. These are typically early-onset disorders arising in childhood or adolescence, occurring very rarely after age 18.
In paroxysmal dystonia/dyskinesias (commonly PRRT2 mutations), episodes are triggered by sudden movement, involving brief (<1 minute), self-limiting episodes of dystonic/choreiform posturing.62 Episodes occur frequently (up to hundreds of times per day) and may be associated with seizures.62 TMEM151A mutations have recently been described as an additional cause for paroxysmal kinesigenic dystonia/dyskinesias63 and, based on limited evidence, may have a greater predilection for a dystonic presentation of episodes, although episodes appear to respond to the same medications as other forms of paroxysmal kinesigenic dystonia/dyskinesias.64
In paroxysmal exercise/exertion-induced dystonia/dyskinesia (commonly a result of glucose transporter type 1 [GLUT1] deficiency caused by SLC2A1 mutations), episodes involve dystonic posturing/dyskinesia after prolonged exercise, with a wide frequency range (often several per week) and generally lasting for 5 to 40 minutes.11 The most common phenomenology is exercise-induced foot dystonia (foot inversion after prolonged walking).2,11 Triggers include fasting, stress, and anxiety.11 Patients have normal blood glucose levels, but lumbar puncture (which should be performed in all suspected cases) reveals decreased CSF glucose (<60 mg/dL).65
In contrast, in paroxysmal nonkinesigenic dystonia/dyskinesia (commonly PNKD [formerly MR-1] mutations), no movement/exertion-related trigger is seen, and episodes are provoked by specific physical conditions (exertion, fatigue, ill health/fever, menstruation, and psychological stress) or ingestion of methylglyoxal-containing foods (eg, alcohol, coffee, tea, chocolate).11 Episodes generally last from 1 minute to 2 hours and evolution occurs, with earlier dystonic appearance becoming choreiform and abnormal speech from facial involvement.11
MANAGEMENT OF DYSTONIA
The management of dystonia involves first accurately diagnosing dystonia, identifying the form of dystonia (idiopathic, genetic, or acquired), and determining whether dystonia is isolated or combined with another movement disorder or neurologic features, which may require separate treatment. The therapeutic approach then involves the use of pathogenesis-directed treatments, where available,9 and appropriate symptomatic medical treatment, including botulinum toxin injections, rehabilitation, and consideration of surgical therapies, including DBS. Tardive and paroxysmal dystonia have separate treatment pathways. Status dystonicus/dystonic storm, which involves severe and prolonged dystonic posturing, is a neurologic emergency associated with systemic instability and frequently requires intensive care unit–level treatment.
Defining the Dystonia Diagnosis and Relevant Investigations
The first step of management requires accurate diagnosis. As most dystonia syndromes have normal imaging/laboratory findings, diagnosis relies on identifying the unique clinical signs of dystonia. If an idiopathic (generally late-onset) dystonia is suspected, further diagnostic workup is not typically necessary. Initial laboratory workup should include copper/ceruloplasmin/24-hour urinary copper to rule out Wilson disease. Neuroimaging with brain MRI is used to evaluate for a structural cause in adult-onset hemidystonia/generalized dystonia, in rapidly progressive or combined dystonia, or in young-onset cases and can guide further investigation.2 Younger-onset patients should have laboratory evaluation, particularly if complex features are present. EEG should be considered in patients with paroxysmal symptoms and if concern exists for seizures. EMG is rarely necessary, unless there is concern for a neuromuscular dystonia mimic, although this can be used to help identify dystonic features (TABLE 10–1). Other targeted investigations include CSF analysis (typically metabolic/neurotransmitter disorders) and disease-specific testing, including genetic testing, for young-onset, combined, or complex phenotypes with or without a family history, and all should have genetic counseling. Single-gene testing can be reasonable if the phenotype is highly suggestive of a specific genetic entity; however, the clinical heterogeneity frequently necessitates the use of dystonia gene panels, with broader testing in combined phenotypes and chromosomal microarray considered, particularly in early-onset dystonia with developmental delay.66 If compelling evidence is present of a genetic etiology despite negative testing, then next-generation exome or (if available) genome sequencing (with or without sequencing of the mitochondrial DNA) should be the next step, although these are more difficult to analyze (such as related to variants of unknown significance), and may result in unexpected incidental findings.66,67
KEY POINTS.
The first step of management requires accurate diagnosis. If an idiopathic (generally late-onset) dystonia is suspected, further diagnostic workup is not typically necessary.
Directed workup includes laboratory testing to rule out Wilson disease and neuroimaging followed by specific targeted testing, including genetic testing with concomitant genetic counseling.
Treatment of dystonia depends on the diagnosis (idiopathic versus genetic) and whether potential pathogenesis-directed treatments are available. Symptomatic medical therapy often involves botulinum toxin injections, oral medications, and rehabilitation, with deep brain stimulation considered for treatment-refractory cases or conditions where good evidence of efficacy exists.
Disorders for which pathogenesis-directed treatments are available include dopa-responsive dystonia, Wilson disease, the paroxysmal dyskinesias, and rare, complex metabolic dystonias. All young-onset cases should have a trial of levodopa to assess for dopa-responsive dystonia.
Pathogenesis-directed Treatment for Dystonia
Disorders for which pathogenesis-directed treatments are available include dopa-responsive dystonia, Wilson disease, the paroxysmal dyskinesias, and rare, complex metabolic dystonias (TABLE 10–7).8,68 Substrate reduction in Wilson disease involves oral penicillamine, trientine, and zinc therapy, coupled with avoiding hepatotoxic agents. Additional specific oral therapeutics include levodopa (GCH1, TH, FTPS, and SPR mutations), or 5-hydroxytryptophan (FTPS/SPR mutations) in dopa-responsive dystonias, and carbamazepine/other antiseizure medications in the paroxysmal dystonias.68 Therefore, in addition to testing for Wilson disease, all younger-onset patients, as well as adult-onset patients with atypical presentations, should also have a levodopa trial, as low-dose treatment in dopa-responsive dystonia typically provides significant symptom relief.47,49 Dietary interventions are important in metabolic disorders and help avoid or mitigate potentially irreversible neurologic damage (TABLE 10–4).68 Trigger avoidance is also important in paroxysmal dyskinesias/dystonias, as is reducing fevers or excessive physical and emotional stresses in rapid-onset dystonia parkinsonism or metabolic causes of dystonia.68 The prospect of gene therapy for hereditary dystonia is highly anticipated by patients and clinicians.69
TABLE 10–7.
Pathogenesis-directed Therapies in Dystoniaa
| Rationale for treatment | Movement disorder (gene[s]) | Treatment |
|---|---|---|
| Reduction of toxic substrates | Wilson disease (ATP7B) | Penicillamine, trientine, zinc |
| Dystonia/parkinsonism with manganese accumulation (SLC39A14, SLC30A10) | Ethylenediaminetetraacetic acid chelation therapy | |
| Specific drugs | Aromatic l-amino acid decarboxylase deficiency (AADC) | Dopamine agonists, monoamine oxidase B inhibitors, pyridoxine |
| Dopa-responsive dystonia (GCH1, TH) | Levodopa | |
| Dopa-responsive dystonia, complex (PTPS, SPR) | Levodopa, 5-hydroxytryptophan | |
| GLUT1 deficiency and paroxysmal exercise/exertion-induced dyskinesia (SLC2A1) | Ketogenic diet, triheptanoin | |
| Paroxysmal kinesigenic dyskinesia (most commonly PRRT2) | Carbamazepine, other antiseizure medications | |
| Dietary interventions | GLUT1 deficiency (SLC2A1) | Ketogenic diet, triheptanoin |
| Glutaric aciduria type 1 (GCDH) | Avoid or treat triggers, dietary lysine restriction, L-carnitine | |
| Homocystinuria (CBS) | Vitamin B6, dietary restriction of methionine, betaine | |
| Methylmalonic aciduria (MMUT) | Avoid or treat triggers, dietary protein restriction, L-carnitine | |
| Propionic acidemia (PCCA, PCCB) | Avoid or treat triggers, dietary protein restriction, L-carnitine | |
| Vitamin supplements | Biotin-thiamine–responsive basal ganglia disease (SLC19A3) | Biotin plus thiamine, avoid or treat triggers |
| Biotinidase deficiency (BTD) | Biotin | |
| Coenzyme Q10 deficiency (COQ8A and others) | Coenzyme Q10 (variable benefit) | |
| Homocystinuria (CBS) | Vitamin B6, dietary restriction of methionine, betaine | |
| Trigger avoidance | Alternating hemiplegia of childhood (DYT/PARK-ATP1A3) | Avoid stress, fatigue, and sleep deprivation (flunarizineb can help) |
| Biotin-thiamine-responsive basal ganglia disease (SLC19A3) | Avoid fasting and aggressively treat infection or fever, as this can lead to metabolic decompensation | |
| Glutaric aciduria type 1 (GCDH) | Avoid fasting and aggressively treat infection or fever, as this can lead to metabolic decompensation | |
| Methylmalonic aciduria (MMUT) | Avoid dietary noncompliance or fasting and aggressively treat infection or fever, as this can lead to metabolic decompensation | |
| Paroxysmal kinesigenic dyskinesia (most commonly PRRT2) | Avoid sudden voluntary movement, stress, startle, fatigue/sleep deprivation | |
| Paroxysmal nonkinesigenic dyskinesia (most commonly PNKD) | Avoid alcohol, caffeine, stress, excitement, chocolate, significant temperature changes; aggressively treat fever; menstruation may also be a trigger | |
| Paroxysmal exercise/exertion-induced dyskinesia (most commonly SLC2A1) | Avoid, when possible, excessive exercise (vast majority of attacks), fasting, stress, anxiety | |
| Propionic acidemia (PCCA, PCCB) | Avoid dietary noncompliance or fasting and aggressively treat infection or fever, as this can lead to metabolic decompensation | |
| Rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3) | Avoid, when possible, excess emotional or physical stress, fatigue, alcohol, excessive exercise, environmental stresses (eg, bright lights, excessive heat or cold, loud noises in alternating hemiplegia of childhood); aggressively treat infection/fever; childbirth may be a trigger |
Modified with permission from Stephen CD, et al, Elsevier.9 © 2022 Elsevier.
Flunarizine is not approved by the US Food and Drug Administration.
Symptomatic Treatment for Dystonia
The goal of symptomatic therapy is to provide relief from abnormal movements/postures, associated pain and discomfort, contractures or other orthopedic complications of sustained abnormal postures, and medical comorbidities, including neuropsychiatric symptoms (FIGURE 10–3). Treatment should be individualized (TABLE 10–8).70
FIGURE 10–3.
Treatment modalities in dystonia. Treatment approaches to focal, generalized, and combined dystonia, as well as for special cases involving paroxysmal dystonia/dyskinesia, dopa-responsive disorders, and specific pathogenesis-directed treatments.
DBS = deep brain stimulation; GPi = globus pallidus internus; OT = occupational therapy; PED = paroxysmal exercise-induced dyskinesia/dystonia; PKD = paroxysmal kinesigenic dyskinesia/dystonia; PNKD = paroxysmal nonkinesigenic dyskinesia/dystonia; PT = physical therapy; rTMS = repetitive transcranial magnetic stimulation; SLP = speech and language pathology; SPR: sepiapterin reductase; STN = subthalamic nucleus; tDCS = transcranial direct current stimulation; TMS = transcranial magnetic stimulation.
Modified with permission from Balint B, et al, Nat Rev Dis Primers.2 © 2018 Springer Nature Limited.
TABLE 10–8.
Factors Affecting Choice of Treatment in Dystonia
| Symptom severity |
|
| Patient age |
|
| Type of dystonia (isolated versus combined) |
|
| Distribution of dystonia (focal versus more widespread) |
|
KEY POINTS.
The goal of symptomatic therapy for dystonia is to provide relief from abnormal movements/postures, associated pain and discomfort, contractures or other orthopedic complications of sustained abnormal postures, and medical comorbidities, including neuropsychiatric symptoms. This should be individualized for each patient.
Treatment of drug-induced/tardive dystonia involves early diagnosis and discontinuation of the offending drug, discontinuation of anticholinergics, and specific antidyskinetic medications, with DBS considered in severe, refractory cases.
Botulinum toxin injections form the cornerstone of focal dystonia treatment. Serotypes A and B are approved for treatment. Patients generally receive injections every 12 weeks, although many patients experience a shorter duration of effect. Patients rarely develop neutralizing antibodies, and this can be assessed with a “frontalis test.”
Oral medications for dystonia treatment are generally considered in cases of generalized dystonia or more severe disease and are much better tolerated in younger patients. These mainly involve dopaminergic therapy, anticholinergics, baclofen, and benzodiazepines.
Encouraging the patient to identify and experiment with sensory tricks/gestes is important, as this can lead to sometimes substantial improvement of dystonic movements and complement other treatments. Rehabilitation with physical therapy, occupational therapy, or speech therapy is also important, depending on the dystonia subtype.70,71 Rehabilitation can improve functional ability, prevent contractures in persistent/fixed postures through targeted splinting and specific exercises/stretching, facilitate sensorimotor retraining, and more effectively harness sensory tricks.
Symptomatic treatment of focal dystonia begins with botulinum toxin injections and targeted rehabilitation therapy (depending on the distribution and focal symptoms), with DBS in severe, refractory cases.72 Oral medications, including benzodiazepines or anticholinergics, can also play an adjuvant role to botulinum toxin injections.49 In generalized dystonia, the first-line treatment should be oral medications; botulinum toxin injections are indicated if there is associated bothersome focal dystonia, and DBS is indicated in refractory cases. However, early DBS treatment should be implemented in cases known to have evidence of benefit, such as DYT-TOR1A and other genetic forms(TABLE 10–3).38,39,51
Drug-induced/tardive dystonia has separate treatment, involving early diagnosis and discontinuation of the offending drug, discontinuation of anticholinergics, and consideration of specific antidyskinetic medications. These include the dopamine-depleting vesicular monoamine transporter 2 inhibitors valbenazine, deutetrabenazine, and tetrabenazine.73 Botulinum toxin injections can be used in tardive focal dystonia, zolpidem can be used for tardive akathisia, and amantadine can potentially be used to treat mild symptoms. DBS may be beneficial in select treatment-refractory cases.73
Chemodenervation for Dystonia
The introduction of botulinum toxin, a highly potent biological toxin with seven major serotypes (A-G) and produced by Clostridium botulinum, revolutionized the treatment of focal dystonia.74 This results in local paresis of the injected muscles but likely also contributes to altering sensory feedback. All forms of focal dystonia are routinely injected, including the muscles of mastication, the tongue, and vocal folds. The main serotypes are serotype A (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and serotype B (rimabotulinumtoxinB).74 Units and doses between different formulations are generally not interchangeable, and transitioning to another form must be done carefully, using appropriate dose calculations. The effects of botulinum toxin generally last 12 to 24 weeks (mean duration, 15.5 weeks) in cervical dystonia.75 Patients therefore typically receive injections every 12 weeks, although many patients experience a shorter duration of efficacy.74 Appropriate muscle selection is important, as injection into extraneous muscles may result in inadequate therapeutic response or exacerbation of symptoms. Dosing is also important, with low doses having insufficient benefit and high doses causing excess weakness and spread into adjacent, unintended muscles, causing functional impairment. EMG and ultrasound guidance improve accuracy of muscle targeting and are commonly used. Despite frequent sustained efficacy, patients may discontinue treatment given inadequate efficacy, adverse effects, inconvenience, and financial considerations.76 Longer-acting formulations of botulinum toxin show potential promise, such as daxibotulinumtoxinA, which is currently in clinical trials for dystonia and has published data for cosmetic dermatology indications, with data suggesting a median duration of 24 weeks.77 Patients rarely develop neutralizing antibodies, resulting in greatly decreased efficacy, and can be assessed with a “frontalis test,” where one side of the forehead frontalis muscles are injected and unilateral reduction of eyebrow elevation suggests preserved efficacy.74
Oral Pharmacotherapy for Dystonia
Oral medications are generally considered in cases of generalized dystonia or more severe disease. Certain medications, particularly the anticholinergics, are more frequently trialed in younger patients, given better tolerability compared to when used in older patients. FIGURE 10–4 represents the major neurotransmitters serving as targets for oral medications.72
FIGURE 10–4.
Neurochemical pathways and targets for oral pharmacologic treatment in dystonia. The figure illustrates the three striatal neurotransmitters (cholinergic [pink], γ-aminobutyric acid–mediated (GABA-ergic) [yellow, brown], and dopaminergic [blue]), and targets relevant to oral dystonia medications. 1) Cholinergic system: Acetylcholine (ACh) is synthesized in presynaptic terminals, catalyzed by choline acetyltransferase (ChAT), and transported into vesicles. ACh then binds to muscarinic and/or nicotinic receptors for cellular effects. The remaining ACh is metabolized by acetylcholinesterase (AChE), with uptake into the presynaptic terminal by choline transporter [CHT]. 2) GABA-ergic system: GABA is synthesized from glutamate presynaptically and transported to vesicles by vesicular GABA transporter (VGAT), released into synaptic clefts, and binds to postsynaptic receptors. The remaining GABA at the synaptic clefts is transported to presynaptic terminals by direct reuptake and indirect transport. 3) Dopaminergic system: The medium spiny neurons receive input from substantia nigra pars compacta (SNc) neurons. Dopamine is presynaptically synthesized from tyrosine by tyrosine hydroxylase (TH), transported into vesicles by vesicular monoamine transporter 2 (VMAT2), and released into the synaptic cleft, binding to postsynaptic dopamine receptors. Dopamine is degraded by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), with remaining dopamine transported to presynaptic terminals by dopamine transporters (DAT). Anticholinergics are postsynaptic muscarinic antagonists. Baclofen is a GABAB agonist acting presynaptically and postsynaptically. Benzodiazepines (BZDs) bind to GABAA receptors, causing increased chloride channel opening and inhibitory signals. Levodopa is postsynaptically converted to dopamine for direct effects. Dopamine-depleting agents (eg, tetrabenazine [TBZ]), are VMAT2 inhibitors, impairing dopamine transport into vesicles, while dopamine receptor blocking agents block postsynaptic dopamine receptors.
BH4 = tetrahydrobiopterin; ChI = cholinergic interneurons; DA = dopamine; DDC = dopa decarboxylase; DOPAC = 3, 4-dihydroxyphenylacetic acid; GAT = GABA transporter; L-DOPA = levodopa; MSN = medium spiny neuron; 3-MT = 3-methoxytyramine;TAN = tonically active neuron; VAChT = vesicular ACh transporter.
Reprinted with permission from Termsarasab P, et al, J Clin Mov Disord.72 © 2016 The Authors.
Dopaminergic therapy commonly involves levodopa therapy at low doses (200 mg/d to 400 mg/d). Although mainly used for the treatment of dopa-responsive dystonia, these may be beneficial in other forms of combined dystonia (X-linked dystonia-parkinsonism and rapid-onset dystonia parkinsonism), although with a less robust response.71
Antidopaminergic therapy (antipsychotics/neuroleptics), despite previous extensive use, should be avoided given the high risks of sedation and extrapyramidal side effects.70 Dopamine depleters, such as vesicular monoamine transporter 2 inhibitors, have potential evidence for efficacy, such as in the treatment of dystonia in Huntington disease, although the mainstay is for use in tardive dystonia.70 Side effects may include transient acute dystonic reactions, drug-induced parkinsonism, or akathisia, and given potential exacerbation of depressive symptoms, dopamine depleters are contraindicated in patients who have inadequately treated depression or suicidal ideation.70 Anticholinergic therapy is beneficial in most types of dystonia, although is mainly used in generalized and less frequently segmental forms.70 Examples include trihexyphenidyl (starting at 1 mg/d and gradually increasing to 2 mg 3 times a day; higher doses may be required) or benztropine and are the most effective oral medications overall, with a response rate of 71%, which wanes over time.78 Anticholinergic medications can have a bothersome side effect profile, including dry mouth, constipation, blurred vision, and most problematically, cognitive changes, hallucinations, and drowsiness, limiting their use in older patients, and can cause a crisis of anticholinergic delirium, which may require hospitalization.79
Baclofen (starting at 5 mg/d and typically increasing to 30 mg/d to 120 mg/d in three to four divided doses) is frequently used in segmental/generalized dystonia but also with certain focal dystonias.69 This may be particularly beneficial in secondary dystonia in PD and complex dystonias, including dystonic cerebral palsy.69,70 Use of intrathecal baclofen has decreased considerably since the advent of DBS but can be useful in spastic dystonia, particularly if there is trunk/leg involvement; however, side effects are common.71
Benzodiazepines (second- and third-line agents) are commonly used as adjunctive medications. The drug of choice is clonazepam, given its longer half-life and twice-daily dosing, and is particularly beneficial in myoclonus-dystonia.70 Benzodiazepines may provide synergistic benefit in patients with unsatisfactory responses to anticholinergics. However, sedation, particularly in older patients, and risks of abuse (11% in a cervical dystonia cohort)80 limit their use. Other muscle relaxants with evidence of possible efficacy in dystonia include cyclobenzaprine, metaxalone, carisoprodol, methocarbamol, orphenadrine, or chlorzoxazone for muscular pain/spasms.69 Other medications include sodium oxybate (in alcohol-responsive dystonia) and zolpidem (for blepharospasm, up to 5 mg/d to 20 mg/d) and zonisamide (for myoclonus dystonia).2
In comparison, the paroxysmal dystonias/dyskinesias have specific treatments.81 In paroxysmal kinesigenic dystonia/dyskinesias, low-dose carbamazepine (50 mg/d to 200 mg/d) is frequently highly effective, and other antiseizure medications include oxcarbazepine (75 mg/d to 300 mg/d), phenytoin (100 mg/d to 200 mg/d, limited by side effects and need for long-term use), and lacosamide (50 mg/d to 100 mg/d), with some benefit with valproic acid, lamotrigine, levetiracetam, and topiramate.81 In paroxysmal nonkinesigenic dystonia/dyskinesia, treatment is less effective but includes low-dose benzodiazepines (eg, clonazepam, diazepam), with reports of partial success with gabapentin and levetiracetam, and rare benefit from oxcarbazepine.81 In paroxysmal exercise/exertion-induced dystonia/dyskinesia, treatment involves dietary modification with the ketogenic diet, L-carnitine supplementation, and triheptanoin, and partial benefit noted with levodopa, trihexyphenidyl, and benzodiazepines.81 Minimal evidence exists for surgical management, involving right ventro-oral thalamotomy in paroxysmal nonkinesigenic dystonia/dyskinesia, globus pallidus internus (GPi) DBS in clinical paroxysmal nonkinesigenic dystonia/dyskinesia, and right posteroventral pallidotomy in paroxysmal exercise/exertion-induced dystonia/dyskinesia.81
KEY POINTS.
The paroxysmal dystonias/dyskinesia have specific treatments: Paroxysmal kinesigenic dystonia/dyskinesia is treated with anti-seizure medications, (typically carbamazepine or oxcarbazepine); paroxysmal nonkinesigenic dystonia/dyskinesia is typically treated with low-dose benzodiazepines; and paroxysmal exercise/exertion-induced dystonia/dyskinesia is treated with ketogenic diet, L-carnitine supplementation, and triheptanoin.
Noninvasive brain stimulation is a developing area of potential therapy for dystonia but has mainly been used for research purposes and includes transcranial magnetic stimulation and transcranial direct current stimulation.
Surgical treatments of dystonia include intrathecal baclofen pumps, ablative lesioning, and deep brain stimulation.
Focused ultrasound has evidence for efficacy for dystonia, although symptom recurrence is possible, requiring repeat lesioning. This is only approved for unilateral use.
Noninvasive Brain Stimulation in Dystonia
Noninvasive brain stimulation is a developing area of potential therapy for dystonia but is currently investigational and mainly used for research purposes. These include repetitive transcranial magnetic stimulation and transcranial direct current stimulation, which may be used as an adjunct to neurorehabilitation.82
Surgical Treatment of Dystonia
Surgical treatments of dystonia include intrathecal baclofen pumps, ablative lesioning (thalamotomy/pallidotomy), focused ultrasound, and DBS, targeting the GPi, subthalamic nucleus (STN), or thalamus. Previously, peripheral denervation was extensively used in cervical dystonia; however, this was poorly tolerated and resulted in a high rate of recurrence and considerable side effects, including weakness and dysphagia and hence is not recommended.
LESIONING THERAPY.
Pallidal and thalamic lesioning were the first effective treatments for dystonia and are still used in a small number of well-selected patients. MRI-guided focused ultrasound has evidence of efficacy, although there may be symptom recurrence, requiring repeat lesioning. Similar to other ablation techniques, it is unclear whether this will prove safe for bilateral use, and hence all current cases have been performed unilaterally. There have been reports of benefit in musician’s focal hand dystonia83 and task-specific writing tremor.84
DEEP BRAIN STIMULATION FOR DYSTONIA.
DBS has potential advantages over focused ultrasound, including a more favorable side effect profile, the potential for reversibility, and ability to adjust the stimulation direction and field. Indications include severe medication-refractory generalized/segmental dystonia (class 1 evidence)85 and some focal dystonias, including medication-refractory cervical dystonia.86 Although the bulk of data in DBS has involved targeting the GPi, evidence is growing for efficacy of STN DBS in dystonia, which appears similarly effective as the GPi, in isolated, segmental, and generalized dystonia, including in genetic forms.71 In comparison, thalamic DBS (eg, targeting the thalamic ventralis intermedius nucleus) may be more effective than GPi DBS for the treatment of dystonic tremor, and thalamic DBS also has potential efficacy in acquired dystonia and spasmodic dysphonia.71
KEY POINTS.
DBS has potential advantages over focused ultrasound, including a more favorable side effect profile, the potential for reversibility, and the ability to adjust the stimulation direction and field. The main stimulation site is the globus pallidus internus; however, efficacy has also been demonstrated in targeting the subthalamic nucleus and thalamus. Cerebellar stimulation is currently under investigation.
Status dystonicus/dystonic storm is a medical emergency, fatal in 10%. Precipitants include infection, medication changes, or deep brain stimulation hardware failure. Management involves treating triggers and oral dystonia therapies followed by intensive care unit–level care and consideration of rescue deep brain stimulation.
There are differential effects of DBS, with the best evidence of efficacy for isolated generalized dystonia (particularly DYT-TOR1A), younger age at surgery, shorter disease duration, and higher baseline severity.71 In contrast, older age, longer duration, genetic forms that are less amenable to DBS, the presence of functional dystonia, and fixed posture/contractures portend a poor response (TABLE 10–9).81,87 Combined dystonia has a robust response to DBS in specific genetic forms (KMT2B, SGCE, TAF1 mutations); a variable response in ADCY5, GNAL, and THAP1 mutations; and reports of efficacy in PRKRA and VAC14 mutations, while ATP1A3 does not tend to respond.38,39,51,56 There is preliminary evidence of efficacy in acquired dystonia.88
TABLE 10–9.
Predictors of Deep Brain Stimulation Outcome in Dystonia
| Disease factor | Positive outcome | Negative outcome |
|---|---|---|
| Patient selection | Isolated generalized dystonia | Acquired/complex dystonia |
| Younger age of onset | Older age of onset | |
| Judicious and appropriately selected treatment of idiopathic or tardive dystonia | Erroneous placement in functional dystonia/other pseudodystonia (TABLE 10–6) | |
| No prior brain surgery | Prior brain surgery | |
| No other significant medical comorbidities | Any significant medical, cognitive/neuropsychiatric comorbidities | |
| Dystonia phenomenology | Mobile dystonia | Fixed posturing or contractures |
| No other movement disorders or concomitant spasticity | Concomitant spasticity or ataxia | |
| Disease duration | Short symptom duration | Long symptom duration |
| Type of genetic dystonia | DYT-TOR1A and other genetic dystonias with robust efficacy data (TABLE 10–3) | Genetic dystonias without data for efficacy (eg, DYT/PARK-ATP1A3 and others as outlined in TABLE 10–3) |
| Imaging pathology | Normal brain MRI | Abnormal brain MRI |
| Lead placement | Appropriate lead placement | Lead not in ideal location |
| Stimulation settings | Optimal stimulation settings | Inappropriate stimulation settings |
MRI = magnetic resonance imaging.
Electrode location is an important predictor of response, with signs that the optimal GPi electrode location is the posterior ventral region.89 Limitations to GPi placement include a 20% nonresponder rate, modest response in acquired/complex dystonia, slow response to stimulation, requiring high energy settings for sufficient benefit, and risks of stimulation-induced bradykinesia.71 Other potential DBS targets have included the STN, thalamus, and cerebellum.71,90
Treatment of Status Dystonicus/Dystonic Storm
Status dystonicus/dystonic storm involves acute decompensation of generalized dystonia, with severe hyperkinetic movements, generally dystonia with or without dyskinesias.91 This rare but serious situation represents the most dangerous manifestation of dystonia and is a movement disorder emergency, which is fatal in 10%.92 The uncontrolled movements cause muscle breakdown/rhabdomyolysis, which can lead to renal failure, and the syndrome is frequently associated with systemic symptoms, including fever, hypertension, tachycardia/tachypnea, autonomic instability, which, paired with bulbar dysfunction, may lead to respiratory failure, all of which contribute to its high mortality.93 Potential differential diagnoses can include neuroleptic malignant syndrome, serotonin syndrome, malignant hyperthermia, and drug intoxication or withdrawal.93 Status dystonicus is more common in men and children and is subacute, often occurring in the setting of an intercurrent infection or recent change in medication.92 Other precipitating events include trauma, anesthesia, surgery, metabolic abnormalities, stress, and hormonal changes.92 DBS hardware failure is a common iatrogenic cause.92 Dystonic storm generally occurs in acquired dystonia (dystonic cerebral palsy); however, it can also occur in isolated (DYT-TOR1A, DYT-THAP1) and combined (DYT/PARK-TH, X-linked dystonia-parkinsonism) genetic dystonias and complex dystonia, and severe dystonic paroxysms may rarely occur in paroxysmal nonkinesigenic dystonia/dyskinesia.91
Management involves a stepwise approach. The first 24 hours involve supportive therapy, treating potential triggers, followed by oral dystonia therapies (mainly tetrabenazine and trihexyphenidyl).92,93 During this stage, patients should be assessed regarding candidacy for surgical treatment (DBS ideally, or if unavailable, intrathecal baclofen), particularly in DYT-TOR1A or other isolated dystonia.93 This should be promptly followed by intensive care unit–level care, with treatment involving IV midazolam, followed as needed by propofol anesthesia, and as a third line, the use of barbiturates, nondepolarizing neuromuscular blockers, or botulinum toxin.92,93 If this is ineffective, bilateral GPi rescue DBS should be considered (successful in 33.7%),92 and where unavailable, ablative pallidotomy has been used.92 The goal over subsequent weeks is adequate symptomatic treatment.93
CONCLUSION
Substantial challenges are associated with the clinical diagnosis of dystonia, although great advances have occurred regarding its etiologic underpinnings. Symptomatic treatment for focal dystonia currently involves chemodenervation, oral therapies, and rehabilitation. In DBS, therapeutic indications and potential stimulation targets continue to expand. Future pathogenesis-based therapies, including gene therapy, are on the horizon.
ACKNOWLEDGMENT
This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (1K23NS118045–01A1).
RELATIONSHIP DISCLOSURE:
Dr Stephen has received personal compensation in the range of $500 to $4999 for serving on a scientific advisory or data safety monitoring board for SwanBio Therapeutics, Inc, has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (1K23NS118045–01A1), and has received honoraria in the range of $500 to $4999 from the International Parkinson and Movement Disorder Society. The institution of Dr Stephen has received research support from Sanofi.
Footnotes
UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Stephen discusses the unlabeled/investigational use of medications and therapies, none of which are approved by the US Food and Drug Administration (FDA) except for botulinum toxin injections; medications and therapies for the treatment of paroxysmal dystonia, none of which are approved by the FDA for this indication; medications and therapies for the treatment of status dystonicus/dystonic storm, none of which are approved by the FDA for this indication; dopamine agonists for the treatment of dystonia parkinsonism; ethylenediaminetetraacetic acid chelation therapy for the treatment of dystonia/parkinsonism with manganese accumulation; dopamine agonists, monoamine oxidase inhibitors, and pyridoxine for the treatment of aromatic L-amino acid decarboxylase deficiency; levodopa and 5-hydroxytryptophan for the treatment of complex dopa-responsive dystonia; L-carnitine for the treatment of glutaric aciduria type 1, methylmalonic aciduria, and propionic acidemia; vitamin B6 for the treatment of homocystinuria; biotin and thiamine for the treatment of biotin-thiamine–responsive basal ganglia disease and biotinidase deficiency; and coenzyme Q10 for the treatment of coenzyme Q10 deficiency.
REFERENCES
- 1.Albanese A, Bhatia K, Bressman SB, et al.Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28(7): 863–873. doi: 10.1002/mds.25475 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers 2018;4(1):25. doi: 10.1038/s41572-018-0023-6 [DOI] [PubMed] [Google Scholar]
- 3.Battistella G, Termsarasab P, Ramdhani RA, Fuertinger S, Simonyan K. Isolated focal dystonia as a disorder of large-scale functional networks. Cereb Cortex 2017;27(2):1203–1215. doi: 10.1093/cercor/bhv313 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lalli S, Albanese A. The diagnostic challenge of primary dystonia: evidence from misdiagnosis. Mov Disord 2010;25(11):1619–1626. doi: 10.1002/mds.23137 [DOI] [PubMed] [Google Scholar]
- 5.Evatt ML, Freeman A, Factor S. Adult-onset dystonia. Handb Clin Neurol 2011;100:481–511. doi: 10.1016/b978-0-444-52014-2.00037-9 [DOI] [PubMed] [Google Scholar]
- 6.Albanese A, Lalli S. Is this dystonia? Mov Disord 2009;24(12):1725–1731. doi: 10.1002/mds.22597 [DOI] [PubMed] [Google Scholar]
- 7.Frucht L, Perez DL, Callahan J, et al. Functional dystonia: differentiation from primary dystonia and multidisciplinary treatments. Front Neurol 2020;11:605262. doi: 10.3389/fneur.2020.605262 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Klein C, Lohmann K, Marras C, et al. Hereditary dystonia overview. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews. University of Washington, Seattle; 1993-2022. [PubMed] [Google Scholar]
- 9.Stephen CD, Simonyan K, Ozelius L, Breakefield XO, Sharma N. Dystonia. In: Zigmond M, Wiley C, Chesselet MF, editors. Neurobiology of brain disorders. 2nd ed. Elsevier; 2022. [Google Scholar]
- 10.Stahl CM, Frucht SJ. Focal task specific dystonia: a review and update. J Neurol 2017;264(7): 1536–1541. doi: 10.1007/s00415-016-8373-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification. Mov Disord 2014;29(9):1108–1116. doi: 10.1002/mds.25933 [DOI] [PubMed] [Google Scholar]
- 12.Wijemanne S, Jankovic J. Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat Rev Neurol 2015;11(7):414–424. doi: 10.1038/nrneurol.2015.86 [DOI] [PubMed] [Google Scholar]
- 13.Klein C, Münchau A. Progressive dystonia. Handb Clin Neurol 2013;113:1889–1897. doi: 10.1016/b978-0-444-59565-2.00059-9 [DOI] [PubMed] [Google Scholar]
- 14.Stephen CD, Go CL, Acuna P, Sharma N. Phasic knee bending dystonic and parkinsonian gait: a characteristic finding in X-linked dystonia parkinsonism. Mov Disord Clin Pract 2020;7(4): 448–452. doi: 10.1002/mdc3.12929 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Galosi S, Barca E, Carrozzo R, et al. Dystoniaataxia with early handwriting deterioration in COQ8A mutation carriers: a case series and literature review. Parkinsonism Relat Disord 2019; 68:8–6. doi: 10.1016/j.parkreldis.2019.09.015 [DOI] [PubMed] [Google Scholar]
- 16.Marras C, Lang A, van de Warrenburg BP, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord 2016;31(4):436–457. doi: 10.1002/mds.26527 [DOI] [PubMed] [Google Scholar]
- 17.Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. ; on behalf of the Task Force on Genetic Nomenclature in Movement Disorders. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force - an update. Mov Disord 2022;37(5):905–935. doi: 10.1002/mds.28982 [DOI] [PubMed] [Google Scholar]
- 18.Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30(12):1591–601. doi: 10.1002/mds.26424 [DOI] [PubMed] [Google Scholar]
- 19.Morales-Briceno H, Fung VSC, Bhatia KP, Balint B. Parkinsonism and dystonia: clinical spectrum and diagnostic clues. J Neurol Sci 2022;433:120016. doi: 10.1016/j.jns.2021.120016 [DOI] [PubMed] [Google Scholar]
- 20.Quinn NP, Schneider SA, Schwingenschuh P, Bhatia KP. Tremor—some controversial aspects. Mov Disord 2011;26(1):18–23. doi: 10.1002/mds.23289 [DOI] [PubMed] [Google Scholar]
- 21.Munhoz RP, Lang AE. Gestes antagonistes in psychogenic dystonia. Mov Disord 2004;19(3): 331–332. doi: 10.1002/mds.10628 [DOI] [PubMed] [Google Scholar]
- 22.Baizabal-Carvallo JF, Jankovic J. Examiner manoeuvres “sensory tricks” in functional (psychogenic) movement disorders. J Neurol Neurosurg Psychiatry 2017;88(5):453–455. doi: 10.1136/jnnp-2016-315120 [DOI] [PubMed] [Google Scholar]
- 23.Stephen CD, Perez DL, Chibnik LB, Sharma N. Functional dystonia: a case-control study and risk prediction algorithm. Ann Clin Transl Neurol 2021;8(4):732–748. doi: 10.1002/acn3.51307 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Dressler D Nonprimary dystonias. Handb Clin Neurol 2011;100:513–538. doi: 10.1016/b978-0-444-52014-2.00038-0 [DOI] [PubMed] [Google Scholar]
- 25.Chopra M, Gable DL, Love-Nichols J, et al. Mendelian etiologies identified with whole exome sequencing in cerebral palsy. Ann Clin Transl Neurol 2022;9(2):193–205. doi: 10.1002/acn3.51506 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Berlot R, Bhatia KP, Kojović M. Pseudodystonia: a new perspective on an old phenomenon. Parkinsonism Relat Disord 2019;62:44–50. doi: 10.1016/j.parkreldis.2019.02.008 [DOI] [PubMed] [Google Scholar]
- 27.Lange LM, Junker J, Loens S, et al. Genotypephenotype relations for isolated dystonia genes: MDSGene systematic review. Mov Disord 2021; 36(5):1086–1103. doi: 10.1002/mds.28485 [DOI] [PubMed] [Google Scholar]
- 28.Steeves TD, Day L, Dykeman J, Jette N, PringsheimT. The prevalence of primary dystonia: a systematic review and meta-analysis. Mov Disord 2012;27(14): 1789–1796. doi: 10.1002/mds.25244 [DOI] [PubMed] [Google Scholar]
- 29.Cai X, Chen X, Wu S, et al. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci Rep 2016;6:25834. doi: 10.1038/srep25834 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Ozelius LJ, Bressman SB. Genetic and clinical features of primary torsion dystonia. Neurobiol Dis 2011;42(2):127–135. doi: 10.1016/j.nbd.2010.12.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Lee LV, Rivera C, Teleg RA, et al. The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, “Lubag”). Int J Neurosci 2011; 121 Suppl 1:3–11. doi: 10.3109/00207454.2010.526728 [DOI] [PubMed] [Google Scholar]
- 32.Mainka T, Erro R, Rothwell J, Kühn AA, Bhatia KP, Ganos C. Remission in dystonia—systematic review of the literature and meta-analysis. Parkinsonism Relat Disord 2019;66:9–15. doi: 10.1016/j.parkreldis.2019.02.020 [DOI] [PubMed] [Google Scholar]
- 33.Dauer WT, Burke RE, Greene P, Fahn S. Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 1998;121(Pt 4):547–560. doi: 10.1093/brain/121.4.547 [DOI] [PubMed] [Google Scholar]
- 34.Tolosa E, Martí MJ. Blepharospasm-oromandibular dystonia syndrome (Meige’s syndrome): clinical aspects. Adv Neurol 1988;49:73–84. [PubMed] [Google Scholar]
- 35.Guiry S, Worthley A, Simonyan K. A separation of innate and learned vocal behaviors defines the symptomatology of spasmodic dysphonia. Laryngoscope 2019;129(7):1627–1633. doi: 10.1002/lary.27617 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Conti AM, Pullman S, Frucht SJ. The hand that has forgotten its cunning—lessons from musicians’ hand dystonia. Mov Disord 2008;23(10): 1398–1406. doi: 10.1002/mds.21976 [DOI] [PubMed] [Google Scholar]
- 37.Cutsforth-Gregory JK, Ahlskog JE, McKeon A, et al. Repetitive exercise dystonia: a difficult to treat hazard of runner and non-runner athletes. Parkinsonism Relat Disord 2016;27:74–80. doi: 10.1016/j.parkreldis.2016.03.013 [DOI] [PubMed] [Google Scholar]
- 38.Alterman RL, Filippidis AS. Genetic subtypes and deep brain stimulation in dystonia. Mov Disord Clin Pract 2018;5(4):357–360. doi: 10.1002/mdc3.12660 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Artusi CA, Dwivedi A, Romagnolo A, et al. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2020;91(4):426–433. doi: 10.1136/jnnp-2019-322169 [DOI] [PubMed] [Google Scholar]
- 40.Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 2010;74(10): 846–850. doi: 10.1212/WNL.0b013e3181d5276d [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Schneider SA, Ramirez A, Shafiee K, et al. Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Mov Disord 2011;26(5):858–861. doi: 10.1002/mds.23561 [DOI] [PubMed] [Google Scholar]
- 42.Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013;45(1):88–92. doi: 10.1038/ng.2496 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Charlesworth G, Plagnol V, Holmström KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet 2012;91(6): 1041–1050. doi: 10.1016/j.ajhg.2012.10.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Charlesworth G, Angelova PR, Bartolomé-Robledo F, et al. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am J Hum Genet 2015;96(4):657–665. doi: 10.1016/j.ajhg.2015.02.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Zech M, Lam DD, Francescatto L, et al. Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am J Hum Genet 2015; 96(6):883–893. doi: 10.1016/j.ajhg.2015.04.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Masuho I, Fang M, Geng C, et al. Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol Genet 2016;2(3):e78. doi: 10.1212/nxg.0000000000000078 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Segawa M Dopa-responsive dystonia. Handb Clin Neurol 2011;100:539–557. doi: 10.1016/b978-0-444-52014-2.00039-2 [DOI] [PubMed] [Google Scholar]
- 48.Mencacci NE, Isaias IU, Reich MM, et al. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain 2014;137(Pt 9):2480–2492. doi: 10.1093/brain/awu179 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Jankovic J Treatment of dystonia. Lancet Neurol 2006;5(10):864–872. doi: 10.1016/s1474-4422(06)70574-9 [DOI] [PubMed] [Google Scholar]
- 50.Camargos S, Scholz S, Simón-Sánchez J, et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 2008;7(3):207–215. doi: 10.1016/s1474-4422(08)70022-x [DOI] [PubMed] [Google Scholar]
- 51.Quadri M, Olgiati S, Sensi M, et al. PRKRA mutation causing early-onset generalized dystonia-parkinsonism (DYT16) in an Italian family. Mov Disord 2016;31(5):765–767. doi: 10.1002/mds.26583 [DOI] [PubMed] [Google Scholar]
- 52.Bragg DC, Mangkalaphiban K, Vaine CA, et al. Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proc Natl Acad Sci U S A 2017;114(51):E11020–E11028. doi: 10.1073/pnas.1712526114 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Brashear A, Sweadner KJ, Cook JF, et al. ATP1A3-related neurologic disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews. University of Washington, Seattle; 1993-2022. [PubMed] [Google Scholar]
- 54.Salles PA, Mata IF, Brünger T, Lal D, Fernandez HH. ATP1A3-related disorders: an ever-expanding clinical spectrum. Front Neurol 2021; 12:637890. doi: 10.3389/fneur.2021.637890 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Liao S, Chen T, Dai Y, Wang Y, Wu F, Zhong M. Novel VAC14 variants identified in two Chinese siblings with childhood-onset striatonigral degeneration. Mol Genet Genomic Med 2020; 8(2):e1101. doi: 10.1002/mgg3.1101 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.de Gusmao CM, Stone S, Waugh JL, et al. VAC14 gene-related parkinsonism-dystonia with response to deep brain stimulation. Mov Disord Clin Pract 2019;6(6):494–497. doi: 10.1002/mdc3.12797 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Baumann H, Tunc S, Günther A, et al. Altered homodimer formation and increased iron accumulation in VAC14-related disease: case report and review of the literature. Parkinsonism Relat Disord 2020;80:41–46. doi: 10.1016/j.parkreldis.2020.09.012 [DOI] [PubMed] [Google Scholar]
- 58.Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017; 49(2):223–237. doi: 10.1038/ng.3740 [DOI] [PubMed] [Google Scholar]
- 59.Nardocci N Myoclonus-dystonia syndrome. Handb Clin Neurol 2011;100:563–575. doi: 10.1016/b978-0-444-52014-2.00041-0 [DOI] [PubMed] [Google Scholar]
- 60.Timmers ER, Smit M, Kuiper A, et al. Myoclonus-dystonia: distinctive motor and non-motor phenotype from other dystonia syndromes. Parkinsonism Relat Disord 2019;69:85–90. doi: 10.1016/j.parkreldis.2019.10.015 [DOI] [PubMed] [Google Scholar]
- 61.Gardiner AR, Jaffer F, Dale RC, et al. The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain 2015;138(Pt 12):3567–3580. doi: 10.1093/brain/awv310 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Scheffer IE, Grinton BE, Heron SE, et al. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 2012;79(21):2104–2108. doi: 10.1212/WNL.0b013e3182752c6c [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Tian WT, Zhan FX, Liu ZH, et al. TMEM151A variants cause paroxysmal kinesigenic dyskinesia: a large-sample study. Mov Disord 2022;37(3): 545–552. doi: 10.1002/mds.28865 [DOI] [PubMed] [Google Scholar]
- 64.Chen YL, Chen DF, Li HF, Wu ZY. Features differ between paroxysmal kinesigenic dyskinesia patients with PRRT2 and TMEM151A variants. Mov Disord 2022;37(3):608–613. doi: 10.1002/mds.28939 [DOI] [PubMed] [Google Scholar]
- 65.Verrotti A, D’Egidio C, Agostinelli S, Gobbi G. Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 2012;16(1):3–9. doi: 10.1016/j.ejpn.2011.09.005 [DOI] [PubMed] [Google Scholar]
- 66.Di Fonzo A, Monfrini E, Erro R. Genetics of movement disorders and the practicing clinician; who and what to test for? Curr Neurol Neurosci Rep 2018;18(7):37. doi: 10.1007/s11910-018-0847-1 [DOI] [PubMed] [Google Scholar]
- 67.Donohue KE, Gooch C, Katz A, et al. Pitfalls and challenges in genetic test interpretation: an exploration of genetic professionals experience with interpretation of results. Clin Genet 2021; 99(5):638–649. doi: 10.1111/cge.13917 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Jinnah HA, Albanese A, Bhatia KP, et al. Treatable inherited rare movement disorders. Mov Disord 2018;33(1):21–35. doi: 10.1002/mds.27140 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Merola A, Kobayashi N, Romagnolo A, et al. Gene therapy in movement disorders: a systematic review of ongoing and completed clinical trials. Front Neurol 2021;12:648532. doi: 10.3389/fneur.2021.648532 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Jankovic J Medical treatment of dystonia. Mov Disord 2013;28(7):1001–1012. doi: 10.1002/mds.25552 [DOI] [PubMed] [Google Scholar]
- 71.Bledsoe IO, Viser AC, San Luciano M. Treatment of dystonia: medications, neurotoxins, neuromodulation, and rehabilitation. Neurotherapeutics 2020;17(4):1622–1644. doi: 10.1007/s13311-020-00944-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Termsarasab P, Thammongkolchai T, Frucht SJ. Medical treatment of dystonia. J Clin Mov Disord 2016;3:19. doi: 10.1186/s40734-016-0047-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 2: treatment of tardive dyskinesia. Drugs 2016;76(7):779–787. doi: 10.1007/s40265-016-0568-1 [DOI] [PubMed] [Google Scholar]
- 74.Jankovic J Botulinum toxin: state of the art. Mov Disord 2017;32(8):1131–1138. doi: 10.1002/mds.27072 [DOI] [PubMed] [Google Scholar]
- 75.Brashear A, Watts MW, Marchetti A, et al. Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review. Clin Ther 2000;22(12): 1516–1524. doi: 10.1016/s0149-2918(00)83049-0 [DOI] [PubMed] [Google Scholar]
- 76.Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol 2015; 262(4):837–848. doi: 10.1007/s00415-014-7586-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Solish N, Carruthers J, Kaufman J, et al. Overview of daxibotulinumtoxinA for injection: a novel formulation of botulinum toxin type A. Drugs 2021;81(18):2091–2101. doi: 10.1007/s40265-021-01631-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36(2):160–164. doi: 10.1212/wnl.36.2.160 [DOI] [PubMed] [Google Scholar]
- 79.Cloud LJ, Jinnah HA. Treatment strategies for dystonia. Expert Opin Pharmacother 2010;11(1): 5–15. doi: 10.1517/14656560903426171 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Mahajan A, Jankovic J, Marsh L, et al. Cervical dystonia and substance abuse. J Neurol 2018; 265(4):970–975. doi: 10.1007/s00415-018-8840-9 [DOI] [PubMed] [Google Scholar]
- 81.Latorre A, Bhatia KP. Treatment of paroxysmal dyskinesia. Neurol Clin 2020;38(2):433–447. doi: 10.1016/j.ncl.2020.01.007 [DOI] [PubMed] [Google Scholar]
- 82.Rosset-Llobet J, Fàbregas-Molas S, Pascual-Leone A. Transcranial direct current stimulation improves neurorehabilitation of task-specific dystonia: a pilot study. Med Probl Perform Art 2014;29(1):16–18. doi: 10.21091/mppa.2014.1004 [DOI] [PubMed] [Google Scholar]
- 83.Horisawa S, Yamaguchi T, Abe K, et al. A single case of MRI-guided focused ultrasound ventro-oral thalamotomy for musician’s dystonia. J Neurosurg 2018;131(2):384–386. doi: 10.3171/2018.5.Jns173125 [DOI] [PubMed] [Google Scholar]
- 84.Meng Y, Suppiah S, Scantlebury N, Lipsman N, Schwartz ML. Treatment of a patient with task-specific writing tremor using magnetic resonance-guided focused ultrasound. Can J Neurol Sci 2018;45(4):474–477. doi: 10.1017/cjn.2018.19 [DOI] [PubMed] [Google Scholar]
- 85.Kupsch A, Benecke R, Müller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355(19): 1978–1990. doi: 10.1056/NEJMoa063618 [DOI] [PubMed] [Google Scholar]
- 86.Volkmann J, Mueller J, Deuschl G, et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol 2014;13(9):875–884. doi: 10.1016/s1474-4422(14)70143-7 [DOI] [PubMed] [Google Scholar]
- 87.Pauls KAM, Krauss JK, Kämpfer CE, et al. Causes of failure of pallidal deep brain stimulation in cases with pre-operative diagnosis of isolated dystonia. Parkinsonism Relat Disord 2017;43: 38–48. doi: 10.1016/j.parkreldis.2017.06.023 [DOI] [PubMed] [Google Scholar]
- 88.San Luciano M, Robichaux-Viehoever A, Dodenhoff KA, et al. Thalamic deep brain stimulation for acquired dystonia in children and young adults: a phase 1 clinical trial. J Neurosurg Pediatr 2020;27(2):1–10. doi: 10.3171/2020.7.Peds20348 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Reich MM, Horn A, Lange F, et al. Probabilistic mapping of the antidystonic effect of pallidal neurostimulation: a multicentre imaging study. Brain 2019;142(5):1386–1398. doi: 10.1093/brain/awz046 [DOI] [PubMed] [Google Scholar]
- 90.Horisawa S, Kohara K, Nonaka T, et al. Case report: deep cerebellar stimulation for tremor and dystonia. Front Neurol 2021;12:642904. doi: 10.3389/fneur.2021.642904 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Ruiz-Lopez M, Fasano A. Rethinking status dystonicus. Mov Disord 2017;32(12):1667–1676. doi: 10.1002/mds.27207 [DOI] [PubMed] [Google Scholar]
- 92.Fasano A, Ricciardi L, Bentivoglio AR, et al. Status dystonicus: predictors of outcome and progression patterns of underlying disease. Mov Disord 2012;27(6):783–788. doi: 10.1002/mds.24981 [DOI] [PubMed] [Google Scholar]
- 93.Termsarasab P, Frucht SJ. Dystonic storm: a practical clinical and video review. J Clin Mov Disord 2017;4:10. doi: 10.1186/s40734-017-0057-z [DOI] [PMC free article] [PubMed] [Google Scholar]