Dystonia

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

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.[1] The typical dystonic movements are usually rhythmic or patterned contractions that may be accompanied by tremor.[2][3]

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.[4]
  • The association between hereditary factors and dystonia was made in 1959 during reporting families with similar symptoms . [5]
  • 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 .[6][7]
  • 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. [7]
  • 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. [8]

Classification

Dystonia may be classified into several subtypes based on age of onset, topographic distribution, temporal aspects, associated clinical features and etiology .[1][9][10]

  • 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. [11][12][13][14][15] 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.[16][17][18][19][20][3]

Causes

Common known causes of dystonia include:[10][21][22][19][23]

  • Genetic mutations in TOR1A, THAP1, GCH1 and KMT2B
  • Brain injury or infections including perinatal hopoxic injury, encephalitis, brain abscess or neoplasms, stroke and neurotoxic agents that affect basal ganglia (especially putamen), cerebellum, thalamus regions
  • Diseases contributing to degenerative changes in central nervous system including Wilson's disease, GM1 and GM2 gangliosidosis, homocyctinuria, Lesch Nyhan syndrome and ataxia-telangiectasia
  • Drugs including dopamin receptor blocking agents, amine depletors, serotonin-reuptake inhibitors, monoamine-oxidase inhibitors, calcium antagonists, benzodiazepines, general anesthetic agents, carbamazepine, phenytoin, triptans, ranitidine, cocaine or ecstasy



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 - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
--
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
--
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
--
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
--
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • 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 + - - + --
Miller-Dieker lissencephaly + + - -
  • 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.[24]

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.[25]

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.[26]

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

References

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  2. Louis ED (August 2019). "Tremor". Continuum (Minneap Minn). 25 (4): 959–975. doi:10.1212/CON.0000000000000748. PMID 31356289.
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  4. Newby RE, Thorpe DE, Kempster PA, Alty JE (2017). "A History of Dystonia: Ancient to Modern". Mov Disord Clin Pract. 4 (4): 478–485. doi:10.1002/mdc3.12493. PMC 5573933. PMID 28920067.
  5. ZEMAN W, KAELBLING R, PASAMANICK B, JENKINS JT (June 1959). "Idiopathic dystonia musculorum deformans. I. The hereditary pattern". Am. J. Hum. Genet. 11 (2 Part 1): 188–202. PMC 1931983. PMID 13661153.
  6. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO (September 1997). "The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein". Nat. Genet. 17 (1): 40–8. doi:10.1038/ng0997-40. PMID 9288096.
  7. 7.0 7.1 Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, Schuback DE, Falk CT, Risch N, de Leon D (May 1989). "Human gene for torsion dystonia located on chromosome 9q32-q34". Neuron. 2 (5): 1427–34. doi:10.1016/0896-6273(89)90188-8. PMID 2576373.
  8. Marsden CD (December 1976). "Blepharospasm-oromandibular dystonia syndrome (Brueghel's syndrome). A variant of adult-onset torsion dystonia?". J. Neurol. Neurosurg. Psychiatry. 39 (12): 1204–9. doi:10.1136/jnnp.39.12.1204. PMC 492566. PMID 1011031.
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  21. Furukawa Y, Graf WD, Wong H, Shimadzu M, Kish SJ (January 2001). "Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations". Neurology. 56 (2): 260–3. doi:10.1212/wnl.56.2.260. PMID 11160968.
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  24. Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O'Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M (1999). "Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia". Neurology. 53 (7): 1431–8. PMID 10534247.
  25. Bittar RG, Yianni J, Wang S, Liu X, Nandi D, Joint C, Scott R, Bain PG, Gregory R, Stein J, Aziz TZ (2005). "Deep brain stimulation for generalised dystonia and spasmodic torticollis". J Clin Neurosci. 12 (1): 12–6. PMID 15639404.
  26. Jankovic, Dr. Joseph (2007). Parkinson's Disease & Movement Disorders (fifth edition ed.). Philadelphia, Penn.: Lippincott Williams & Wilkins. pp. pp. 349-350. ISBN 0-7817-7881-6. Unknown parameter |coauthors= ignored (help)

See also


ca:Distonia de:Dystonie nl:Dystonie fi:Dystonia