Dystonia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Dystonia
ICD-10	G24.9
ICD-9	333
DiseasesDB	17912
MeSH	D004421

Overview

Dystonia is a hyperkinetic movement disorder identified by involuntary sustained or intermittent contraction of a single or group of muscles that leads to repetitive movements or abnormal posture. The typical dystonic movements are usually rhythmic or patterned contractions that may be accompanied by tremor.

Historical Perspective

• The term Dystonia was first introduced by Hermann Oppenheim, a German Neurologist , in 1911 following delineating abnormal posturing (dystonia muscularum deformans) in 4 unrelated Jewish children.
• The association between hereditary factors and dystonia was made in 1959 during reporting families with similar symptoms .
• The association between genes and dystonia was made in 1989 during introducing DYT1 or TOR1A gene as a major cause of young-onset generalized dystonia .
• In 1989, Ozelius .et.al were the first to discover the association between ITD1 gene ( further known as DYT1 gene ) and the development of dystonia.
• The variant "Focal Dystonia" was first introduced by Charles David Marsden, an English Neurologist, in 1976, following reporting different cases of adult-onset blepharospasm and/or oromandibular dystonia,, torticollis, spasmodic dysphonia, and writer’s cramp without any hereditary background or known cause.
  

Classification

Dystonia may be classified into several subtypes based on age of onset, topographic distribution, temporal aspects, associated clinical features and etiology .

• Dystonia may be classified into five subtypes based on the age of onset; infancy (up to two years), childhood (3-12 years), adolescence (13-20 years), early adulthood (21-40 years) and late adulthood (>40 years)
• Dystonia may be classified into five subtypes based on the topographic distribution : focal, segmental, multifocal, generalized or hemidystonia

- Focal : if only one body part of the body is involved. The examples include writing dystonia, cervical dystonia, blepharospasm, Oromandibular dystonia and laryngeal or lingual dystonia

- Segmental : if two or more contiguous parts are involved. The examples include bi-brachial and cranial dystonia.

- Multifocal : if two or more noncontiguous parts are involved. The examples include dystonia of the right arm and the left leg

- Hemidystonia : if half of the body is involved.

- Dystonia is classified as generalized if trunk and two or more other parts are involved.

• Dystonia may be classified into eight subtypes based on the temporal aspects of the disease : manner of onset (acute versus insidious), symptoms variability (diurnal, intermittent, or action induced), and overall progression (static versus progressive).
• Dystonia may be classified into five subtypes based on associated clinical features:

• Dystonia is classified into four subtypes based on the etiology: Known Pathology of the nervous system, inherited, acquired or idiopathic

- Nervous system pathology : if there are any structural lesion or confirmed degeneration

- Inherited: if there is autosomal dominant, autosomal recessive , X-linked recessive or mitochondrial pattern of inheritance

- Acquired : if there is any history of brain injury, infection, toxic or drug consumption, vascular event, neoplasm or psychogenic cause

- Idiopathic

Pathophysiology

Th exact pathogenesis of dystonia is not fully understood. However, the main mechanism has been attributed to the impaired central inhibitory circuits. It is thought that dystonia is the result of changes in synaptic pathways, reduced brain inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and decreased inhibition at the level of spinal, brain stem and especially cortex of the brain. It is also thought that dystonia may be associated with microscopic changes in brain stem nuclei, loss of Purkinje cells and axonal swelling in the cerebellum, changes in basal ganglia-cerebello-thalamo-cortical pathway and cerebellar and basal ganglia structures.

Causes

Common known causes of dystonia include:

• Genetic mutations in TOR1A, THAP1, GCH1 and KMT2B

Symptoms vary according to the kind of dystonia involved. In most cases, dystonia tends to lead to abnormal posturing, particularly on movement. Many sufferers have continuous pain, cramping and relentless muscle spasms due to involuntary muscle movements.

Early symptoms may include loss of precision muscle coordination (sometimes first manifested in declining penmanship, frequent small injuries to the hands, dropped items and a noticeable increase in dropped or chipped dishes), cramping pain with sustained use and trembling. Significant muscle pain and cramping may result from very minor exertions like holding a book and turning pages. It may become difficult to find a comfortable position for arms and legs with even the minor exertions associated with holding arms crossed causing significant pain similar to restless leg syndrome. Affected persons may notice trembling in the diaphragm while breathing, the need to place hands in pockets, under legs while sitting or under pillows while sleeping to keep them still and to reduce pain. Trembling in the jaw may be felt and heard while lying down and the constant movement to avoid pain may result in TMJ-like symptoms and the grinding and wearing down of teeth. The voice may crack frequently or become harsh triggering frequent throat clearing and swallowing can become difficult and accompanied by painful cramping.

Electrical sensors (EMG) inserted into affected muscle groups, while painful, can provide a definitive diagnosis by showing pulsating nerve signals being transmitted to the muscles even when they are at rest. The brain appears to signal portions of fibers within the affected muscle groups at a firing speed of about 10 Hz causing them to pulsate, tremble and contort. When called upon to perform an intentional activity, the muscles fatigue very quickly and some portions of the muscle groups do not respond (causing weakness) while other portions over-respond or become rigid (causing micro-tears under load). The symptoms worsen significantly with use, especially in the case of focal dystonia, and a "mirror effect" is often observed in other body parts: use of the right hand may cause pain and cramping in that hand as well as in the other hand and legs that were not being used. Stress, anxiety, lack of sleep, sustained use and cold temperatures can worsen symptoms.

Direct symptoms may be accompanied by secondary effects of the continuous muscle and brain activity including disturbed sleep patterns, exhaustion, mood swings, mental stress, difficulty concentrating, blurred vision, digestive problems and short temper. People with dystonia may also become depressed and find great difficulty adapting their activities and livelihood to a progressing disability. Side affects from treatment and medications can also present challenges in normal activities.

In some cases, symptoms may progress and then plateau for years or stop progressing entirely and the progression may be delayed by treatment or adaptive lifestyle changes while forced continued use may make symptoms progress more rapidly. In others, the symptoms may progress to total disability making some of the more risky forms of treatment worth considering.

An accurate diagnosis may be difficult because of the way the disorder manifests itself. Sufferers may be diagnosed as having similar and perhaps related disorders including Parkinson's Disease, Essential Tremor (ET), Carpel Tunnel Syndrome, TMJ, Tourette's Syndrome or other neuromuscular movement disorders.

Differential diagnosis

Dystonia must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
	Spasticity	Hypotonia	Ataxia	Dystonia
Leigh syndrome	-	-	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	-	-	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	-	+	+	-	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	--
Adrenoleukodystrophy	+	-	-	-	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	--
Zellweger syndrome	-	+	-	-	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	--
Pyruvate dehydrogenase deficiency	+	+	+	-	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	--
Arginase deficiency	+	-	-	-	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	--
Holocarboxylase synthetase deficiency	-	+	-	-	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	--
Glutaric aciduria type 1	-	-	-	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	-	-	+	-	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	--
Pontocerebellar hypoplasias	-	+	-	-	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	-	+	+	-	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	--
Pelizaeus-Merzbacher	+	-	+	-	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	-	-	+	-	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	--
Rett syndrome	+	-	-	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	--
Lesch-Nyhan syndrome	+	-	-	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	--
Miller-Dieker lissencephaly	+	+	-	-	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	--
Dopa-responsive dystonia	+	-	-	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	--

Treatment

Treatment has been limited to minimizing the symptoms of the disorder as there is yet no successful treatment for its cause. Reducing the types of movements that trigger or worsen dystonic symptoms provides some relief as does reducing stress, getting plenty of rest, moderate exercise and relaxation techniques. Various treatments focus on sedating brain functions or blocking nerve communications with the muscles via drugs, neuro-suppression or denervation. All current treatments have negative side affects and risks.

Physicians may prescribe a series of different medications on a trial-and-error basis in an effort to find a combination that is effective for a specific patient. Not all patients will respond well to the same medications. Drugs that have had positive results in some patients include anti-Parkinsons agents (Trihexyphenidyl), muscle relaxers (Valium), keppra, and beta-blockers including "off-label" uses for some blood pressure medications.

Drugs, such as anticholinergics which act as an inhibitor of the neurotransmitter acetylcholine, may provide some relief. Clonazepam, an anti-seizure medicine, is also sometimes prescribed. However, for most sufferers their effects are limited and side affects like mental confusion, sedation, mood swings and short term memory loss occur.

Botulinum toxin injections into affected muscles have proved quite successful in providing some relief for around 3-6 months, depending on the kind of dystonia. Bo-Tox injections have the advantage of ready avalibility (the same form is used for cosmetic surgery) and the affects are not permanent. There is a risk of temporary paralysis of the muscles being injected or the leaking of the toxin into adjacent muscle groups causing weakness or paralysis in them. The injections have to be repeated as the effects wear off and around 15% of recipients will develop immunity to the toxin. There is a Type A and Type B toxin approved for treatment of dystonia; often those that develop resistance to Type A may be able to use Type B.

Surgery, such as the denervation of selected muscles, may also provide some relief, however, the destruction of nerves in the limbs or brain is not reversable and should only be considered in the most extreme cases. Recently, the procedure of deep brain stimulation (DBS) has proved successful in a number of cases of severe generalised dystonia.

One type of dystonia, dopa-responsive dystonia can be completely treated with regular doses of L-dopa in a form such as Sinemet (carbidopa/levodopa). Although this doesn't remove the condition, it does alleviate the symptoms most of the time.

A baclofen pump has been used to treat patients of all ages exhibiting muscle spasticity along with dystonia. The pump delivers baclofen via a catheter to the thecal space surrounding the spinal chord. The pump itself is placed in the abdomen. It can be refilled periodically by access through the skin.

Physical therapy can sometimes help with focal dystonia. A structured set of exercises are tailored to help the affected area.

See also

• Tardive Dyskinesia
• Edward Flatau
• Geste antagoniste

Template:Diseases of the nervous system