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REVIEW ARTICLE
Year : 2018 | Volume : 66 | Issue : 7 | Page : 48--58

Dystonia: A review
Amit Batla
Department of Neurology, Luton and Dunstable University Hospital, University College of London Institute of Neurology, Queen Square, London,
UK

Correspondence Address:
Dr. Amit Batla
University College of London Institute of Neurology, 7, Queen Square, London WC1N 3BG
UK

Abstract
Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions that
cause abnormal repetitive movements, abnormal postures, or both. The new consensus classifies dystonia into two
axes to characterize clinical characteristics, and etiology. This system allows correct identification of isolated and
combined forms of dystonia and retains the description of generalized and focal dystonia which is very useful in
planning investigations and management. The characterization of dystonia for its better identification and a brief
overview of its management are discussed in this article. The treatment options for dystonia include drugs,
botulinum toxin and deep brain stimulation surgery.

How to cite this article:

Batla A. Dystonia: A review.Neurol India 2018;66:48-58

How to cite this URL:

Batla A. Dystonia: A review. Neurol India [serial online] 2018 [cited 2020 Feb 9 ];66:48-58
Available from: http://www.neurologyindia.com/text.asp?2018/66/7/48/226439

Full Text

Dystonia is commonly recognized as an abnormal posturing of a part or whole of the body. Among the movement
disorders that are classified based on the paucity of movements (hypokinetic) or the excess of movements
(hyperkinetic), dystonia is a hyperkinetic movement disorder.[1] Clinically, the involuntary movements in dystonia
are sustained or intermittent muscle contractions that cause abnormal repetitive movements, abnormal postures, or
both. With recent advances in the understanding of dystonia, tremor is increasingly being recognized as one of the
presentations of the abnormal repetitive movements that results from underlying dystonia.[2] These movements
are usually patterned and based on body distribution; these may be seen in a single body part (focal), two or more
contiguous body parts (segmental), or two or more non-contiguous body parts (multifocal). Depending on the
spread of these movements, hemi-dystonia (one side) and generalized dystonia (>2 contiguous body parts plus
trunk) can be seen. The commonest clinical presentations of dystonia in adults are cervical dystonia (cervical
torticollis) and focal hand dystonia (writer's cramp); and in children, generalized dystonia (Oppenheim's or torsion
dystonia) is commoner. Wilson's disease and inherited metabolic disorders, including dopamine responsive dystonia,
are common in the clinical practice of movement disorders in India. Due to the multiple underlying aetiologies of
dystonia and a variety of clinical features, it is now recommended to use a classification of dystonia using two axes.
Axis one is for clinical features and phenomenology, and axis two is for aetiology. This classification system
acknowledges the significant overlap that might be seen in the presentation of dystonia due to various underlying
pathologies [Table 1]. This article provides a contemporary review of the clinical approach, aetiological
considerations and management options available for dystonia.{Table 1}

Phenomenological Considerations That Help to Recognise Dystonia

Dystonic movements are caused by co-contraction of agonist and antagonist muscles that can manifest as

Abnormal postures that are typically mobile (not fixed) with or without twisting movementsSlow writhing
movements (athetosis)Dystonic tremor

Although dystonia can involve several body parts and muscles, the nature of the abnormal postures is 'repetitive' or
'patterned'. This implies that it consistently involves the same muscle groups. This consistency and pattern helps to
distinguish dystonia from other hyperkinetic movement disorders, such as chorea, which are non-patterned and
much more variable. While differentiating dystonia from other hyperkinetic movement disorders, it is worth noting
that dystonic movements cannot be suppressed like tics or have urge associated with them. Although hyperkinetic
by definition, dystonia is much slower than chorea and myoclonus. Athetoid movements can occur, where the
dominant muscle activity switches from the agonist to the antagonist group of muscles, and vice versa.

The differentiation of dystonic tremor from essential or other varieties of tremor is much less concrete in clinical
practice and it may be difficult to have a consensus even among movement disorders specialists on this matter.[2]
By definition, dystonic tremor is jerky, irregular and variable in amplitude, and typically worsens in particular
positions of the affected body part. Tremor occurs commonly with dystonia. If the tremor affects the body part
where dystonia is present, it is called a 'dystonic tremor'. If tremor is seen in another body part not directly affected
by dystonia, it is termed as 'tremor associated with dystonia'.

A clinical examination clue that may help in identifying the presence of dystonia is that dystonia is often aggravated
by voluntary movements. Action dystonia is characterized by dystonic movements only with action or voluntary
movements. When dystonia manifests only with specific tasks, it is called 'task-specific dystonia.' These types of
dystonia include specific variants such as the writer's cramp and the musician's dystonia (embouchure). Other
factors that tend to exacerbate dystonia include fatigue and emotional stress, whereas the movements usually
decrease with relaxation or sleep.

Another characteristic of dystonic movements is 'overflow'. This is defined as activation of dystonic movements by
actions in parts of the body remote from the affected area. Examples include the occurrence of leg dystonia while
writing, or of axial dystonia while talking.

Dystonia can often improve by tactile or proprioceptive sensory tricks (geste antagoniste). Often a patient will be
able to improve to some degree, the abnormal posture by touching, or even sometimes, by thinking about touching
the affected body part.[3],[4] The sensory involvement in dystonia is quite unique compared to that of other
movement disorders. Although tics have a sensory phenomenon of 'urge', the role of sensory tricks in dystonia is
quite different. An 'urge' precedes and initiates a movement (tic), and a geste (sensory trick) is used to stop an
involuntary movement or correct an abnormal posture in dystonia.

Despite the 'motor' definition of dystonia, it is increasingly being recognized that non-motor features are seen in
many patients with primary dystonia.[5],[6] These include disease-related pain, mild sensory symptoms, and
depressive disorders.[7],[8],[9],[10] These non-motor symptoms are clinically relevant, and must be recognized
early as they can impair the quality of life almost as much, if not more than the motor symptoms.[11],[12],[13]

An Approach to the Classification of Dystonia

The classification scheme of dystonia has changed several times in the last 20 years. The changes or advances in
classification are useful for clinical practice and help in establishing an accurate diagnosis. It, thereby, has a
significant bearing on management and medical research. Some approaches to classification are discussed here
briefly and the evolution of terminology is summarized in [Table 1].

Dystonia can be young-onset (<20-30 years, 25 years is a rough guideline) and late-onset dystonia (after 26
years). The new scheme of classification uses axis 1 for defining the age of onsetDystonia has been classified based
on the aetiology as primary, secondary, heredo-degenerative dystonia and dystonia plus syndromes. In the new
consensus statement (2013),[1] this has been taken out [Table 1] and replaced with axis 2 (the aetiology of
dystonia)Dystonia can be classified by its distribution as focal, segmental, multifocal, hemi-dystonia and generalized
dystonia. This is retained in the current classification and is very useful from a management perspective [1],[14]

Focal dystonia: The abnormal movements involve a single body part only. The various forms include: Writing
dystonia (Writer's cramp): Hand/finger hyperextension, flexion or any other abnormal posturing of the writing
apparatus that occurs only while writingCervical dystonia (spasmodic torticollis): Rotation, lateral bending, lateral
tilting, flexion or extension abnormality of the neckBlepharospasm: Bilateral eye closure produced by spasmodic
contractions of the orbicularis oculi musclesOromandibular dystonia: Jaw or mouth closure with trismus and
bruxism, or involuntary jaw opening or deviationLingual dystonia, laryngeal dystonia (spasmodic dysphonia) and
geniospasm are other forms of focal dystoniaOthers, such as hemimasticatory spasm, are rare forms of dystonia.
Although commonly seen in botulinum toxin injection clinics, it is worth emphasizing here that hemifacial spasm or
synkinesis is not a form a dystonia but a cranial nerve disorder.Segmental dystonia: The abnormal movements
affect two or more contiguous body parts (for example, the arm and neck) Craniocervical dystonia: A combination
of blepharospasm as well as oromandibular, lingual, facial, laryngeal, and cervical dystoniaBrachial: One or both
arms with or without the involvement of neck or cranial muscles are involvedCrural: One leg plus trunk, or both legs
are involvedAxial: Neck and trunk with or without cranial muscles are involved.Multifocal dystonia: Two or more
noncontiguous body areas are involved (for example, the right arm and the left leg)Hemidystonia: Affects one side
of the bodyGeneralized dystonia: Involves two or more contiguous body parts in addition to the trunk.

A Clinical Approach to Dystonia

It is recommended to use the two axes to approach a patient with dystonia and investigate the aetiology,[14] as
elaborated in [Table 2]. Some specific dystonia syndromes and their clinical features are further elaborated below.
{Table 2}

Childhood-onset isolated dystonia

The commonest genetic cause of young-onset primary dystonia is DYT1 [early-onset torsion dystonia gene] dystonia
(Oppenheim dystonia, dystonia musculorum deformans). It is characterized by early-onset dystonia (with the mean
age being 13 years), affecting a limb initially (leg or arm is affected first in 90% of the cases). It progresses to
generalized/multifocal (65%) involvement while the spread to the cranial structures is less common (15-20%).[15],
[16] However, there is a wide phenotypical and intrafamilial variability, ranging from a severe dystonic storm to a
mild writer's cramp, as well as various atypical phenotypes.[17],[18]DYT-6 dystonia is a common cause of
generalized dystonia but commonly starts with focal, (laryngeal or craniocervical) involvement.

Combined dystonia in the period between childhood to adulthood without nervous system pathology

Dystonia myoclonus

The DYT11 myoclonus-dystonia (MD) is characterized typically by myoclonic jerks and dystonia that usually begins
very early in childhood. Myoclonus is the commonest presenting symptom and most often affects the neck, trunk,
and upper limbs. Unlike myoclonic epilepsies, legs are less prominently affected. The myoclonic jerks typically show
a dramatic response to alcohol.[19],[20] The jerks are not stimulus-sensitive, indicating a subcortical origin. About
two-third of patients with DYT11 show dystonia, mostly cervical or a writer's cramp, which tends to remain mild.
Psychiatric manifestations, including depression, anxiety, panic attacks and obsessive-compulsive disorder (OCD),
have been reported and in particular, OCD has been found in those patients not manifesting with motor signs
suggesting that it is related to the genetic defect.[21],[22],[23]
Dystonia-parkinsonism

DYT3 is the only form of dystonia that is inherited as an X-linked trait. Its onset occurs in the mid-thirties (range
12-52 years) with complete penetrance by the end of the 5th decade. The symptoms start as focal dystonia in
almost any part of the body and progress to multifocal or generalized dystonia in most cases within 5 years.
Parkinsonism evolves later in the disease in about 50% of the patients.[24],[25]

DYT5a was initially described by Segawa in 1976,[26] and later by Nygaard and colleagues, as a dopa-responsive
dystonia (DRD) because of the dramatic and sustained response to low dose of levodopa.[27] The typical phenotype
includes childhood (average 6 years) limb-onset dystonia with a diurnal variation (e.g., worsening of the symptoms
as the day progresses), an improvement after sleep and a dramatic response to levodopa. With the identification of
the implicated gene, the clinical spectrum of DRD has expanded to include oromandibular dystonia, spasticity with
developmental delay mimicking cerebral palsy, psychiatric abnormalities and generalized hypotonia with proximal
weakness.[28],[29]

In a minority of cases, DRD can also be inherited as an autosomal recessive disorder with mutations in the genes
coding for other enzymes involved in dopamine synthesis including tyrosine hydroxylase (TH) [often referred to as
DYT5b],[29],[30] sepiapterin reductase (SR) and aromatic L-amino acid decarboxylase (AADC) deficiency.[31] The
clinical manifestations are often more severe and less responsive to dopamine. The spectrum can include mental
retardation, oculogyric crisis, ptosis, hypotonia, severe bradykinesia, drooling and seizures. The presence of these
features in patients with early-onset dystonia that is responsive to dopamine must prompt cerebrospinal fluid (CSF)
analysis for pterins and products of dopamine pathway.

Another dystonia-parkinsonism syndrome has been designated the DYT12 locus, which was mapped to chromosome
19q13.[32],[33] The disease phenotype is designated as a type rapid-onset dystonia-parkinsonism syndrome
because of its key clinical features including its abrupt onset, within hours to weeks, of dystonia with signs of
parkinsonism, usually triggered by physical or emotional stress (fever, child birth, running or alcohol binges). The
age of onset varies from 4 to 58 years, but typically, it presents in the teens or early twenties and the distribution
follows a rostro-caudal (face>arm>leg) gradient with a prominent bulbar involvement.

An autosomal recessive form of dystonia-parkinsonism, DYT16, was assigned to chromosome 2q31.[34] The
phenotype in these patients is characterized by an early (2-18 years) limb-onset dystonia with progression to
generalized dystonia, including a prominent bulbar involvement with spasmodic dysphonia, dysarthria, and even
dysphagia. Some affected members also had parkinsonism.

It is recommended that in the absence of obvious contraindications, all cases of young-onset generalized dystonia
must be administered levodopa to exclude the presence fo dopa - responsive dystonia (DRD) due to guanosine
triphosphate [GTP] cyclohydroxylase-1 (GCH-1) deficiency. Also called Segawa syndrome, DRD is commoner in
female patients and is associated with a diurnal worsening of walking. The other forms of DRD can be due to defects
in the dopamine synthesis pathway and can manifest with episodes of oculogyric crisis, skeletal abnormalities, and
seizures. Perinatal hypoxic injury often leads to a severe generalized dystonia with or without spasticity. This is
often called the athetoid cerebral palsy and should be differentiated from DRDs.

Combined dystonia in the period between childhood to adulthood with nervous system pathology

Although dystonia is typically non-progressive, if it follows a static brain pathology, such as a perinatal infract or a
brain lesion, there could be an initial worsening of the symptoms after the event for up to some years and then the
condition becomes static. Continuous progression should raise the suspicion of a degenerative cause of dystonia.
[35],[36] The past medical history as well as abnormalities in the neurologic examination, neuroimaging, or
laboratory evaluation; its characteristic distribution (e.g., hemidystonia); and, the age at onset and its distribution
(which are unusual in primary dystonia such as young-onset cranial dystonia or late-onset lower limb dystonia) are
clues to establish the diagnosis of secondary dystonia.

Brain injury or infection (e.g., perinatal injury, stroke, head trauma or peripheral trauma, brain tumor, exposure to
neurotoxic agents, Japanese B encephalitis, encephalitis lethargica, brain abscesses), especially involving the basal
ganglia (mostly putamen), cerebellum, and thalamus may lead to dystonias.[37] Perinatal hypoxic injury often
leading to severe generalized dystonia with or without spasticity, is commonly associated with combined dystonia.
This condition is often called athetoid cerebral palsy and should be differentiated from DRD.[29],[38],[39]

Dystonia due to degenerative nervous system pathology

Inherited degenerative diseases that can cause dystonia include many autosomal-dominant and autosomal-
recessive conditions, X-linked dominant and recessive conditions, and mitochondrial defects. Based on its definition,
additional symptoms and signs and dystonia may be observed as a part of the neurodegenerative process. The most
important conditions, along with the responsible genes, are included in [Table 2].

Wilson's disease is a common cause for dystonia, which can be generalized, segmental, or multifocal, but cranial
involvement is characteristic; other common signs include “sardonic” smile, wing-beating tremor, dysarthria,
dysphagia, drooling, ataxia, and dementia. In addition to brain and liver (cirrhosis, acute hepatitis) involvement,
systemic findings can involve the eye (Keyser-Fleischer rings), heart, kidney, bones, joints, glands, and muscles. As
this condition is potentially treatable, this condition must be kept in mind while observing any patient with
movement disorders.

Late adult-onset isolated dystonia

Focal dystonia is more common in adults, which can become segmental, with spread of symptoms over some years
and then their plateauing over time. Lower limb dystonia is very unusual for isolated dystonia at this age, and
therefore, isolated lower limb dystonia after the age of 30 years should raise the possibility of Parkinson's disease.
Traditionally, adult-onset primary dystonias are thought to be sporadic but recently there is evidence that at least
the tremulous type of cervical dystonia is more likely to be familial.[40]

Cranio-cervical or cervical dystonia is the most common adult-onset primary dystonia. Most commonly, these are
idiopathic, but some genes have been linked to this presentation [Table 2].

Genetic forms of cervical dystonia have been recognized. DYT13 is an autosomal dominant disorder with
adolescence-onset mainly segmental dystonia and prominent cranio-cervical involvement.[41]DYT17 is a rare form
of dystonia with autosomal recessive inheritance, and manifesting as segmental dystonia or generalized dystonia,
sometimes with severe dysphonia and dysarthria.[42]DYT 24 presents with a tremulous cervical dystonia due to
ANO3 mutations.[43]DYT 23 linked to CACNA1B gene [44] and DYT25 due to GNAL mutationsalso present with
focal-onset dystonia.[45],[46]

The typical age at onset for idiopathic cervical dystonia is around 55 years, and women are more often affected than
men. It can start with gradual onset of discomfort or pain in the neck and may often be confused with cervical
spondylosis or degeneration in the earlier stages of the condition. As symptoms progress, involuntary pulling of the
head in any direction can be more visible. Various combinations of neck muscles may be involved to produce
abnormal head positions, including horizontal turning (torticollis), tilting (laterocollis), flexion (anterocollis), or
extension (retrocollis). Jerky tremor, which worsens by turning the head towards the normal position is very
common and can be the predominant feature. Patients may have a geste antagoniste (more common in primary
dystonia), where they can partially relieve their spasm by touching the chin or part of their face. Symptoms usually
progress over 6-12 months and then plateau. Remission can occur in 10-15% of the patients, especially in those
with younger-onset dystonia, and may be sustained.

Idiopathic Focal Dystonia

Blepharospasm causes contraction of the orbicularis oculi muscles; it tends to start later than other cranio-cervical
dystonia, with the mean age at onset being around 63 years. Women are more commonly affected than men (3:1).
An uncomfortable feeling around the eyes, dry eyes and/or photophobia may precede the spasm. Mild cases are
characterized by increased blink rate with flurries of blinking, whereas more severely affected patients have visual
impairment due to sustained forceful eye closure. In some patients, there is an inability to activate the levator
palpebri, so that the eyelid cannot open, and this is called levator inhibition. About two-thirds of the patients are

significantly disabled and 12-36% of them are considered to be functionally blind.[47]

Spasmodic dysphonia (SD) results from dystonia of the vocal cords and has a similar age of onset and sex ratio to
patients with a cervical dystonia. Compared to other forms of cranial dystonia, it occurs less often in conjunction
with other forms of cranial dystonia.[48] It is estimated that the majority of patients have isolated SD; in about 10-
15% of patients, this form of dystonia progresses to other cranial regions; and, in about 5% patients, it spreads to
extracranial sites.[49],[50] In adductor dysphonia (the most common form), which involves the thyroarytenoid
muscles, there is excessive glottal closure in a rigid fashion that prevents air flow and causes a strained, strangled
voice. If associated with generalized dystonia, DYT-6 dystonia must be considered in the differential diagnosis.
Abductor dysphonia (much less common) involves the posterior cricoarytenoid muscles and is characterized by an
open glottal configuration and a paucity of vocal cord vibration so that the voice appears like a whisper associated
with breathy sounds.

In oromandibular dystonia (OMD), there is abnormal activity in lower facial, tongue, jaw, and pharyngeal muscles,
also affecting sometimes the platysma. It has a similar age of onset to patients with a cervical dystonia and women
are more commonly affected than men. Jaw closing dystonia has been considered to be the most common form,
while simultaneous movements of jaw openers (lateral pterygoids, digastric muscles) and closers (medial
pterygoids, masseters and temporalis muscles) may result in jaw tremor.[51] OMD may cause pain and difficulty in
speaking, chewing and swallowing. Sensory tricks like putting a finger in the mouth, chewing gum or placing a
toothpick in the mouth can partially help in reducing the symptoms.[52] An important differential diagnosis is OMD
caused by neuroleptic drugs, since this presents with a similar clinical picture. A combination of blepharospasm and
OMD is called Meige's syndrome.

Primary lingual dystonia is rare and may or may not be associated with OMD. Although severe tongue protrusion
dystonia is more frequently seen in combined dystonia,[53] it has been described also with antipsychotic drugs.[54]
Tongue movements may be repetitive, or protrusion may be sustained. Movements are often action-induced,
commonly with speaking,[55] and the tongue may also curl up instead of protruding out of the mouth.[56]

Task Specific Dystonia

The most common adult-onsetlimb dystonia is the writer's cramp, where the patient shows abnormal postures
affecting the hand when writing, but not while performing other tasks. The age at onset is around 25-35 years and
men are more commonly affected than women. The unaffected hand may show mirror movements when writing
with the affected hand. Other adult-onset limb dystonias include task-specific dystonias like the musician's, typist's,
or golfer's dystonia.

Musician's dystoniais a focal task-specific dystonia (FTSD). A genetic contribution has been suggested in the
musician's dystonia, with phenotypic variability. It may encompass the embouchure dystonia affecting the mouth
and fingers; and, the hand dystonia in pianists or organ players.

Paroxysmal Dystonia

Paroxysmal dystonia represents conditions where dystonia may occur as paroxysms or episodes. Based on the
precipitating event, paroxysmal dystonia is subdivided into the kinesigenic (PKD), non-kinesigenic (PNKD), and
exercise-induced forms (PED).

Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by attacks of dystonia, chorea, ballism, or athetosis.
These are often provoked by alcohol or caffeine but sometimes no triggers are identified. The episodes last from
minutes to hours with a frequency between once per day to one or two per year. The age of onset is typically in the
childhood or during the adolescent period but this dyskinesia may present late enough to be occurring at the age of
50 years.[57] PNKD has one known gene DYT8

(PNKD1)[58],[59],[60] and one locus DYT20 (PNKD2) mutation.[61]

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by short (seconds to minutes) and frequent (up to 100
times per day) attacks of dystonic or choreiform movements precipitated by sudden movements. The age of onset is
usually the childhood or adolescence period, but symptoms can resolve in adulthood. PKD has one known gene
DYT10 (PRRT2; proline-rich transmembrane protein 2) mutation [62],[63] and a second locus for PKD has been
designated DYT19.[64]

Paroxysmal exercise-induced dyskinesia (PED) is characterized by exercise induced attacks of dystonic, choreo-
athetotic, and ballistic movements, affecting the exercised limbs, which last from a few minutes to an hour. The
disease usually has an onset in childhood and can have other disease manifestations including epilepsy, migraine,
developmental delay and hemolytic anemia. It shows an autosomal dominant inheritance pattern with slightly
reduced penetrance. DYT18 is known with mutations in the SLC2A1 gene encoding glucose transporter 1 (GLUT1).
[65]

Drug Induced Dystonia

Exposure to dopamine receptors blocking drugs

(DRB) or other agents (amine depletors, serotonin-reuptake inhibitors, monoamine-oxidase inhibitors, calcium
antagonists, benzodiazepines, general anesthetic agents, carbamazepine, phenytoin, triptans, ranitidine, cocaine or
ecstasy) are common causes of secondary dystonia. Acute dystonic reactions may occur in up to 2% of patients
beginning treatment with DRBs. The time-to-onset of the manifestations is variable but 50% of the patients will
develop dystonia within 1-2 days and 90% within 5 days. The common presentations are OMD, oculogyric crisis,
cervical dystonia and laryngeal dystonic spasm. Tardive dystonia is caused by chronic exposure to DRBs. All
neuroleptic drugs including the atypical ones, with the exception of clozapine, can cause tardive dystonia.[66] In
contrast to the acute dystonic reactions, amine depletors (e.g., tetrabenazine) do not cause tardive syndromes.
Clinically, the dystonia is characterized by axial dystonia with hyper-extension of the spine and retrocollis. The mean
time from exposure to onset of the disease manifestations is around 6 years but the shortest exposure time to
onset of the disease manifestations reported is 4 days. Around 10% of the patients show a spontaneous remission,
while the prognosis in rest of the patients depends on the prompt discontinuation of the DRB and the total duration
of the exposure.[66]

Central nervous system disorders that resemble dystonia

A variety of central and peripheral nervous systems disorders, as well as non-neurologic conditions, can be
associated with abnormal postures that resemble dystonia, such as neuromyotonia, myotonic disorders,
inflammatory myopathies, and glycogen storage diseases. Stiff-person syndrome causes contraction of axial and
proximal limb muscles. Carpopedal spasms of tetany can be the manifestation of hypocalcemia, hypomagnesemia,
or alkalosis. Orthopedic and rheumatologic processes involving bones, ligaments, or joints can result in abnormal
postures. In Sandifer syndrome, patients (typically seen in young boys) with hiatal hernia develop head tilt in
association with gastroesophageal reflux. Psychogenic dystonia can be a part of conversion disorder and is not
classified with dystonia syndromes. It is commonly fixed compared to organic dystonia. Fixed dystonia can manifest
with skin changes and a complex regional pain syndrome. There can be an immediate placebo-like response to
botulinum toxin in fixed dystonia.

Investigative Approach to Dystonia

Basic investigations
Specific blood tests for investigating dystonia include copper and ceruloplasmin levels, and white cell enzymes,
acanthocytes, lactate, pyruvate, creatine kinase and antinuclear antibody screening to look for systemic disorders

causing nervous system pathology. They should be individualized based on the clinical picture and the associated
features seen. Specific clinical findings or laboratory abnormalities may dictate the need for further investigations,
including electrophysiological studies to assess for associated myopathy or neuropathy, as indicated. Lumbar
puncture is useful to study the dopamine pathway metabolites and can serve as a guide for further genetic testing if
a patient is suspected to be having GCH1 negative DRD.

The muscle or skin biopsy, or metabolic studies of blood or urine may be helpful in investigating for rarer causes
such as mitochondrial and metabolic disorders, as well as amino acid and lysosomal storage disorders.

Magnetic resonance imaging (MRI) of the brain is not always necessary, particularly in isolated focal or generalized
dystonia. If metabolic disorders involving iron or copper are suspected, MRI with sequences to detect the iron
deposition may be useful to identify the 'eye of the tiger' sign in pantothenate kinase associated neurodegeneration
or the 'cortical pencil lining' sign seen in neuroferritinopthy.[67] MRI is also useful in other heredodegenerative
cases, particularly Wilson's disease, and may show radiological signs of Wilson's disease.

Dopamine transporter imaging can help in documenting dopaminergic depletion in parkinsonism, when the diagnosis
is in doubt. One should also keep in mind the possibility of psychogenic dystonia if there is variability in the clinical
manifestations, and the clinical and investigation profile do not follow a recognizable pattern. Psychogenic dystonia
can be diagnosed based on the established clinical criteria.[68]

Genetic testing

It is recommended that DYT1 testing should be offered for patients with limb-onset, primary dystonia with the onset
before the age of 30 years, as well as in those with onset after 30 years of age, if they have an affected relative
with early-onset dystonia. Data to guide the protocol for DYT6 testing is insufficient at present. Most patients with
clinically typical DRD will have identified mutations in the GTPCH1 gene if a comprehensive analysis is performed,
including testing for deletions. There is genetic testing available for the myoclonus-dystonia DYT11 gene, although
many sporadic cases do not harbour the SGCE mutations. Evaluation of secondary/ heredo-degenerative dystonia is
dictated by clues provided by the history and examination of the patients.

Approach to Treatment for Dystonia

Treatment of dystonia is possible with drugs, botulinum toxin injections and deep brain stimulation surgery.

Treatment with oral medication Trihexiphenidyl is an anticholinergic drug that is useful in generalized and focal
dystonias.[69] The usual starting dose is 1 mg daily and the drug is increased by 1mg every 4-7 days to reach 1mg
tds. Then it is increased by 1mg every 4-7 days to reach 2-4 mg tds. In case side effects develop, dose titration
must be stopped and reattempted after 1-2 weeks. The maximum dose is 50-100mg/day. The common side effects
are mouth and eye dryness, nausea, confusion, memory loss, hallucinations, constipation, and urinary retention.
Anticholinergics are contraindicated in the presence of closed angle glaucoma and known urinary retention.

Tetrabenazine is a dopamine-depleting drug, an inhibitor of vesicular monoamine transporter 2. At present, there is

insufficient evidence to support the use of tetrabenazine for focal dystonia, but it is still commonly used for
generalized dystonia. The usual starting dose is 12.5 mg once daily, that is increased 12.5 mg every week to reach
12.5 mg three times a day. The average dose is 25-50 mg three times a day and the maximum dose is 200 mg per
day. This drug should be avoided in depression as it is known to increase the chances of suicide. Tetrabenazine
should not be used in dystonia with parkinsonism.

Clonazepam is a benzodiazepine, which acts as a muscle relaxant and is commonly used for its benefit in
generalized dystonia. The starting dose is 250µg once daily, that is increased by 250µg every week to reach 500 µg
to 1mg bd or tds, and the maximum dose is 4-6 mg/day. As this can cause sleepiness, there is a risk of an accident
occurring in professions that involve the operation of machines and prolonged driving. Thus, carrying out these
activities are relative contraindications while this medication is being given.

Treatment with botulinum toxins

There are 7 serotypes of botulinum toxins labelled as A-G.[69] The type A and B are available for clinical use in
dystonia. Each serotype binds to a serotype-specific acceptor site on the presynaptic nerve terminals, and each
selectively cleaves a specific protein involved in vesicle fusion and neurotransmitter release. The doses and site of
injections vary based on the clinical phenotype. Caution is advised when injecting this medication in the presence of
pre-existing muscle or neuromuscular weakness due to disorders such as amyotrophic lateral sclerosis, myopathies,
motor polyneuropathies, and myasthenia gravis or Lambert-Eaton syndrome; and, when the patients is on the
concurrent use of aminoglycoside antibiotics or other neuromuscular blocking agents. Patients with known bleeding
disorders or on a regular use of anticoagulants such as warfarin will need to have an international normalized ratio
(INR) monitoring done before injecting the medication as there is a significant chance of haematoma formation.
Patients on newer anticoagulants such as apixaban will need to miss a couple of doses of the medicine around the
time of the injections. Advice must be taken from the haematology department regarding this before injecting
botulinum toxin. The safety and efficacy of botulinum toxin injections are not established in patients less than 16
years age for the treatment of cervical dystonia, and in patients less than 12 years age for the treatment of
blepharospasm and strabismus. There is insufficient data to allow the use of botulinum toxin in pregnancy and
lactation. The main side effects of botulinum toxin are the development of excessive weakness of the muscles
injected, and the spread of the medication to the adjacent muscles causing their weakness also. Other side effects
include fatigue, flu-like symptoms, a dry mouth as well as dizziness. The development of a skin rash as well as local
pain or bruising at the injection site are common side effects, irrespective of the site of focal dystonia.

Treatment with DBS

DBS is a useful option for the treatment of primary generalized and segmental dystonia.[68] Bilateral globus
pallidus interna (GPi) is the preferred site for the electrode placement if DBS is considered, and the complication
rates are similar to that of DBS procedures done for other conditions. The DBS device consists of three components:
a lead with four electrodes (contacts) [which is implanted within the deep brain target, usually the GPi in this case],
and a programmable pulse generator [which is used to deliver the therapeutic current]. This is usually implanted in
the chest wall. After the lead implantation, the pulse generator can be programmed transcutaneously from the chest
wall. The currently accepted target of DBS for dystonia is the globus pallidus internus (GPi). Usually the site of the
electrode is localized using microelectrode recording, with or without an intraoperative MRI guidance. The device is
activated 7 to 14 days after the implantation. The amplitude, pulse width, frequency, and choice of the active
contacts can be regulated. There is no consensus regarding the optimal settings required for the treatment of
dystonia. Wide pulses (210–400 µsec) and high frequencies (130 Hz or higher) are preferred. Using lower settings
prolongs the battery life, and therefore, the device requires fewer battery replacement surgeries. With the
availability of batteries with longer lives or the options of recharge, this may not be a problem. The duration of
effect of the procedure varies in different studies.[69] There is an immediate lesioning effect and cervical dystonia
improves but returns in a week. The contraindications for DBS include the presence of a psychiatric disease,
cognitive impairment, swallowing difficulty or possible non-compliance with the required close follow-up for
programming and maintenance of the device after the surgery. Psychiatric side effects may limit the success of
surgery. The patients with a poor performance on neuropsychological testing, especially in the frontal lobe and
memory domains, may not be suitable candidates and may be at risk of worsening with DBS. The known
complications of the procedure include an intraoperative haemorrhage or ischemia, a perioperative infection, and a
displacement or fracture of the extension cable.[70],[71]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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