case files neurology
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case files neurology

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Dystonia is classified according to etiology, as idiopathic or symptomatic.
Primary dystonia is defined as a condition with no etiology that can be iden-
tified, and dystonia is the sole or major symptom. Primary dystonias are further
subdivided by criteria such as age of onset, distribution of affected body parts,
presence of diurnal variation of symptoms, responsiveness to drugs, and genetic
markers. Secondary dystonia refers to dystonia in the context of a neurologic
disease in which dystonia is only one of several symptoms or in which dysto-
nia is the result of an environmental insult. There are at least 15 genetic causes
of dystonia. Generalized dystonia tends to have its onset in childhood. A three\u2013-
base-pair guanine\u2013adenine\u2013guanine (GAG) deletion in exon 5 of DYT1
(TOR1A) is the most frequent cause of early onset, generalized dystonia starting
in a limb and is known as DYT-1 dystonia. However, there is a large phenotypic
variability even within families with an identical mutation. Primary generalized
torsion dystonia is a progressive, disabling disorder that usually begins in child-
hood and is linked to several genetic loci. Many cases are inherited as autosomal
Table 3\u20131
Secondary dystonias
Drug-induced tardive dystonias
Antipsychotic drugs: dopamine receptor\u2013blocking older typical and newer atypical
Anxiolytic drug: buspirone
Antidepressant agents: selective serotonin-reuptake inhibitors
Dopaminergic drugs: levodopa and dopamine agonists
Antiemetic drugs: metoclopramide
Antiseizure drugs: phenytoin, carbamazepine, gabapentin
Cerebral palsy
Wilson disease
Mitochondrial encephalopathies
Pantothenate kinase\u2013associated neurodegeneration (Hallervorden\u2013Spatz disease)
Fahr disease
dominant traits caused by a deletion in the torsin A gene (DYT1 locus), result-
ing in the deletion of glutamate in torsin A, a brain protein of unknown func-
tion with highest concentrations in the substantia nigra.
Penetrance is 30\u201340%, and clinical expression varies from generalized dysto-
nia to occasional adult-onset focal dystonias. It begins as a focal action dystonia
before the middle of the third decade of life with most cases beginning in child-
hood. Because of its rarity and unfamiliar features, it is sometimes misdiagnosed
a psychogenic disorder. Approximately 65% of cases progress to a generalized or
multifocal distribution, 10% become segmental, and 25% remain focal.
Childhood-onset cases commonly evolve to generalized dystonia, which pro-
duces severe disability owing to serious gait and posture abnormalities (Fig. 3\u20131).
This can result in a life-threatening condition called status dystonicus. The
diagnosis of DYT-1 can be made by commercially available testing.
Most primary dystonias have normal routine neuroimaging studies. [18F]-
fluorodeoxyglucose and positron emission tomography (PET) has been used
with a novel regional network analytical approach to identify a reproducible
pattern of abnormal regional glucose metabolism in primary torsion dystonia.
This pattern is not specific for the DYT1 genotype, can be present in other pri-
mary dystonia genotypes, and is not routinely available.
Figure 3\u20131. Incapacitating postural deformity in a young man with dystonia.
(With permission from Ropper AH, Brown RH. Adams and Victor\u2019s principles
of neurology, 8th ed. New York: McGraw-Hill; 2005: Fig. 4\u20135c.)
In any given case, the first consideration is whether this represents a sec-
ondary dystonia, particularly one which is amenable to effective treatment,
including discontinuation of offending agents. Some clues that dystonia is sec-
ondary include:
\u2022 History of trauma or exposure to drugs, infections, cerebral anoxia
\u2022 Dystonia at rest, rather than with action, at its onset
\u2022 Atypical site for age of onset\u2014for example, leg onset in an adult, cranial
onset in a child
\u2022 Early onset of speech abnormality
\u2022 Hemidystonia
\u2022 Presence of abnormalities other than dystonia on neurologic examination
or general medical examination
\u2022 Nonphysiologic findings suggesting a psychogenic basis
\u2022 Abnormal brain imaging
\u2022 Abnormal laboratory tests
Table 3\u20132 summarizes common etiologies of secondary dystonia. The current
functional model of basal ganglia suggests that dystonia results from abnormally
low or generally abnormal pattern of activity of basal ganglia output structures:
the internal segment of globus pallidus (GPi) and substantia nigra pars reticulata.
Table 3\u20132
Hereditary disorders associated with
Neurodegeneration (Huntington disease, juvenile Parkinson disease (parkin),
Wilson disease, lysosomal storage disorders, Rett syndrome)
Dystonia-plus syndromes (dopa-responsive dystonia, myoclonus-dystonia, rapid-
onset dystonia-parkinsonism)
Acquired/exogenous causes (Medication: dopamine receptor-blocking agents,
Antiepileptic agents, levodopa, dopamine agonists, calcium-channel blockers;
Toxins: manganese, carbon monoxide, carbon disulphide, methanol, wasp sting;
Perinatal cerebral injuries: cerebral palsy, kernicterus; Vascular lesions: stroke,
arteriovenous malformation, antiphospholipid syndrome ; Infection: encephalitis,
subacute sclerosing panencephalitis, HIV/AIDS, abscess; Brain tumors; paraneo-
plastic syndromes; demyelination: multiple sclerosis, pontine myelinolysis;
Trauma: head trauma, cervical cord injury; Structural: atlanto-axial subluxation,
Klippel-Feil syndrome, Arnold-Chiari malformation)
Parkinson disease and other parkinsonian disorders (progressive supranuclear
palsy, corticobasal degeneration, multiple system atrophy)
Other movement disorders (tic disorders, familial paroxysmal kinesigenic dyski-
nesias, familial paroxysmal non-kinesigenic dyskinesias, episodic ataxia syndromes)
This low activity consequently disinhibits the motor thalamus and cortex, giv-
ing rise to abnormal movements. In addition, drugs that inhibit the action of
dopamine (through type 2 dopamine [D2] receptors) can cause acute or chronic
dystonia. This seems to be mediated by disinhibition of cholinergic neurons.
Symptomatic treatment of dystonia in the past has employed primarily phar-
macologic agents. These include systemic agents such as levodopa, blockers of
central muscarinic cholinergic receptors, benzodiazepines, and baclofen.
Anatomically targeted administration of agents is also feasible including botu-
linum toxin and intrathecal administration of baclofen. There is mounting evi-
dence that the most effective treatment for generalized dystonia is high-frequency
stimulation of the GPi, through the surgical placement of a deep brain stimulator.
Comprehension Questions
[3.1] The drug most likely to help dystonic symptoms in a patient with DYT-1
dystonia is:
A. Haloperidol
B. Trihexyphenidyl (Artane)
C. Phenytoin
D. Chlorpromazine
[3.2] A 12-year-old boy has the acute onset of sustained contractions of the
left leg and right arm as well as loss of sensation above the neck. The
severity of the symptoms is highly variable. The most likely diagnosis is:
A. DYT-1 dystonia
B. Acute dystonia from a medication
C. Bilateral ischemic infarction of the globus pallidi
D. Psychogenic disorder
E. A right spinal cord hemisection syndrome
[3.3] A 32-year-old woman is seen in the emergency department. She has no
medical problems nor allergies to medications. She receives a medica-
tion intravenously and has an acute dystonic reaction with muscle
spasm of the neck. Which of the following drugs is most likely respon-
sible for this reaction?
A. Haloperidol
B. Trihexyphenidyl (Artane)
C. Phenytoin
D. Levodopa
[3.1] B. Trihexyphenidyl (Artane) is an antimuscarinics anticholinergic.
[3.2] D. This is likely psychogenic because