Download Movement Disorders Caused by Medical Disease

Movement Disorders Caused by Medical
Disease
Brandon Barton, M.D.,1 S. Elizabeth Zauber, M.D.,1 and Christopher G. Goetz, M.D.1
ABSTRACT
Movement disorders often occur in the context of medical illness, whether as the
presenting sign of the illness, as a related feature of the underlying disease process, or as a
complication of treatment. Early recognition of an underlying medical cause for movement
disorders is essential because the treatment and prognosis differ significantly depending on
the underlying pathophysiology. Parkinsonism, nonparkinsonian tremor, dystonia, and
chorea have a wide variety of etiologies, requiring a careful medical history in the evaluation
of new-onset movement disorders. The spectrum of medical diseases associated with these
four syndromes is reviewed in this article.
KEYWORDS: Systemic disease, parkinsonism, dystonia, chorea, tremor
M
ovement disorders occur in a variety of
medical illnesses and can be a complication of medications used to treat medical illnesses. In some cases,
the movement disorder can be the presenting sign of a
general medical condition, and accurate recognition of
the movements is helpful in establishing the medical
diagnosis. In other cases, the general medical diagnosis will suggest the risk for either a single type of
disorder or a mixed form of several movement disorders, so that the clinician can be vigilant to look for
their appearance. Drug-related movement disorders
are especially important to recognize because often
the disorder will clear completely with medication
adjustment. Of the many movement disorders, the
four prototypic conditions are parkinsonism, nonparkinsonian tremor, dystonia, and chorea. An understanding of the common systemic diseases associated
with these disorders and the common drugs used in
internal medicine that can precipitate these four
syndromes will facilitate rapid diagnosis and intervention strategies.
PARKINSONISM
The term parkinsonism describes a clinical syndrome
with the cardinal motor features of rest tremor, rigidity,
bradykinesia, and postural instability. Parkinsonism
occurs due to disruption of the structure, physiology,
or neurochemical function of the dopaminergic pathway traveling from the substantia nigra to the subcortical nuclei, including the putamen and caudate nucleus
(striatum), thalami, and cortical circuits. This primary
cell system can be influenced by involvement of the
brainstem or other basal ganglia nuclei. Although the
most common cause of parkinsonism is Parkinson’s
disease, a wide range of medical conditions and treatments may be associated with parkinsonian signs.
Given that these secondary causes of parkinsonism
may involve a different prognosis or treatment than
Parkinson’s disease, an individual patient presenting
with parkinsonism requires a thorough medical history.
In general, presentations of parkinsonism with rapid or
subacute onset, mild or absent rest tremor, symmetric
akinesia and rigidity, and early-onset gait disorder
1
The Neurological Complications of Medical Disease; Guest Editor,
Steven L. Lewis, M.D.
Semin Neurol 2009;29:97–110. Copyright # 2009 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-0029-1213731. ISSN 0271-8235.
Department of Neurological Sciences, Movement Disorders Section,
Rush University Medical Center, Chicago, Illinois.
Address for correspondence and reprint requests: Christopher G.
Goetz, M.D., Department of Neurological Sciences, Movement Disorders Section, Rush University Medical Center, 1725 West Harrison
Street, Suite 755, Chicago, IL 60612 (e-mail: [email protected]).
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2009
with postural instability suggest secondary causes of
parkinsonism.
hyperkinetic movements including chorea, tremor, and
dystonia.10
IRON METABOLISM
Disorders of Metabolism
Many kinds of metabolic disorders may cause parkinsonism.
THYROID DISEASE
Hypothyroidism shares many features in common with
parkinsonism—including rigidity, fatigue, masked facial
expression, constipation, depression, and slowed movements, speech, and gait—but can be distinguished from
Parkinson’s disease by other medical features and diagnostic studies of endocrine dysfunction. The development of hypothyroidism in the setting of Parkinson’s
disease may be mistaken for worsening parkinsonism,
but the symptoms can improve with thyroid hormone
replacement.1 Conversely, hyperthyroidism may mimic
the weight loss or increased sweating seen with
Parkinson’s disease or may exaggerate parkinsonian
tremor, and improvement occurs with antithyroid
treatment.2
RENAL FAILURE
Parkinsonism has been reported in patients with uremia
due to end-stage renal disease, particularly in patients
with concomitant diabetes.3 Typical features include
acute or subacute onset of parkinsonian symptoms and
additional clinical features of altered consciousness,
myoclonus, dysarthria, and ataxia. Neuroimaging findings include bilateral, symmetric, and reversible basal
ganglia lesions with evidence of vasogenic edema.4
CALCIUM DISORDERS
Disorders of calcium metabolism may occur in association with parkinsonism. Hypoparathyroidism has been
reported to cause parkinsonism both in the presence and
absence of basal ganglia calcifications. It may occur as a
late complication after thyroidectomy5 and may be
responsive to levodopa in some cases.6 Pseudohypoparathyroidism, characterized by end-organ resistance to
normal endogenous parathyroid hormone, may be associated with parkinsonism in up to 4 to 12% of patients,
either with or without evidence of basal ganglia calcifications,7 and may respond partly to normalization of
serum calcium.8 Hyperparathyroidism due to parathyroid adenomas can rarely cause parkinsonism, which is
reversible after surgical removal of the tumor.9 Bilateral
subcortical calcification involving the basal ganglia and
cerebellum, often labeled as Fahr’s disease, represents a
heterogeneous collection of disorders that are not
associated with a known disorder of calcium metabolism. Movement disorders in Fahr’s disease most commonly present as parkinsonism (55%), often in
association with dementia, cerebellar signs, or other
Hereditary hemochromatosis is an autosomal-recessive
disorder characterized by abnormal iron accumulation
in several organs, including the heart, liver, pituitary
gland, and pancreas. Concurrent movement disorders
in patients with hereditary hemochromatosis have
rarely been reported, including eight cases of parkinsonism,11 as well as other movement disorders such as
dystonia and tremor. There is debate, however, as to
whether hereditary hemochromatosis is a cause of
movement disorders or whether the association is only
coincidental.12
LIVER FAILURE
Non-Wilsonian liver disease may be associated with
parkinsonian syndromes. Acquired hepatocerebral degeneration is a syndrome of neuropsychiatric and motor
abnormalities associated with chronic liver failure. Multiple clinical phenotypes have been described, including
isolated parkinsonism, cognitive impairment with psychiatric features, and gait ataxia associated with cognitive
impairment and other motor signs, such as tremor and
dystonia. Magnetic resonance imaging (MRI) demonstrates T1 basal ganglia hyperintensities, which are
believed to correlate with brain manganese deposition
(Fig. 1).13 A prospective evaluation of 51 liver transplant
candidates documented 11 patients with parkinsonism
who had postural tremor, lack of rest tremor, rapid
progression, symmetric bradykinesia and rigidity, and
early gait and postural impairment. These patients had
T1 hyperintensities in the substantia nigra and globus
pallidus, elevated serum and cerebrospinal fluid manganese levels, and variable response to levodopa therapy.14
Although ideal treatment of this disorder is unclear, the
parkinsonism has been reported to improve after liver
transplantation.15
ELECTROLYTE DISTURBANCE
Extrapontine and central pontine myelinolysis syndromes can occur in the setting of chronic alcohol use,
liver disease, rapid correction of sodium electrolyte
imbalance, or malnutrition. Rarely, these syndromes
may be associated with a subacute course of parkinsonism, often with neuropsychiatric symptoms and dystonia, which may respond to levodopa treatment.16
MITOCHONDRIAL DISEASE
Parkinsonism may be observed in up to 12% of adult
patients with respiratory chain disorders associated with
mitochondrial dysfunction, including Leber hereditary
optic neuropathy. Additional features usually include
myopathy, polyneuropathy, progressive external ophthalmoplegia, and premature menopause. In this context,
MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL
Figure 1 T1-weighted magnetic resonance imaging of the brain in a patient with chronic liver disease (cirrhosis) and
parkinsonism. Bilateral, symmetric hyperintensities of the globus pallidus are demonstrated on sagittal (A) and axial (B) images.
Hyperintensity of the substantia nigra and hypothalamus are also noted (C).
levodopa may improve parkinsonism and cause druginduced dyskinesias.17
INBORN ERRORS OF METABOLISM
Gaucher’s disease is caused by an autosomal recessively
inherited deficiency of glucocerebrosidase (GBA) secondary to a mutation in the GBA gene, leading to
accumulation of intracellular glucosylceramide. The disease manifests itself in a wide range of organ systems,
with signs of hepatosplenomegaly, osteopenia, anemia,
cardiopulmonary disease, or neurodegenerative syndromes. Neurological signs include ataxia, pyramidal
signs, myoclonic epilepsy, or supranuclear ophthalmoplegia. A syndrome resembling Parkinson’s disease occurs in patients with Gaucher’s disease or carriers of
GBA mutations, with relatively mild Gaucher’s symp-
toms. Unlike typical Parkinson’s disease, these patients
have an earlier onset and more aggressive disease course,
with more prominent cognitive decline and less responsiveness to anti-Parkinson’s medications, although classic levodopa response has been described.18 Mutations in
the GBA gene have been shown to increase the risk for
developing Parkinson’s disease up to 13-fold compared
with controls.19
Phenylketonuria, an autosomal-recessive disorder
caused by deficiency of enzymatic conversion of phenylalanine to tyrosine, may result in severe neurological
disability with seizures, mental retardation, and microcephaly unless treated by a strict diet in early infancy.
Parkinsonism may occur in adult phenylketonuria patients
after relaxation of dietary restrictions, and can be responsive to reinstitution of dietary therapy and levodopa.20
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Infectious Disease
Multiple types of movement disorders, including parkinsonism, may occur as a consequence of central nervous system infections, either as an acute or chronic
manifestation.21 Infectious diseases with parkinsonism
as their most frequent manifestation include Japanese
encephalitis, encephalitis lethargica, influenza A encephalitis (as a long-term complication), and neurocysticercosis; the last disease is related to both focal basal
ganglia lesions and secondary hydrocephalus. Other
infections associated with parkinsonism include other
forms of viral encephalitis (arbovirus, enterovirus,
varicella-zoster virus, measles virus/subacute sclerosing
panencephalitis), Mycobacterium tuberculosis meningitis
or tuberculomas, Mycoplasma pneumoniae, Salmonella
typhi, Plasmodium falciparum, prion disease, and African
trypanosomiasis.
As a special case, a variety of movement disorders
may occur in the context of infection with HIV through
several proposed mechanisms, including drug-induced
parkinsonism, focal lesions of the basal ganglia from
opportunistic infections or other secondary etiologies,
or pathological changes related to HIV-associated
dementia (HAD). In comparison with Parkinson’s
disease, parkinsonism with HAD presents with more
symmetric symptoms, less frequent occurrence of rest
tremor, and earlier presentation of postural instability
and gait disorders. Parkinsonism is a common feature
of HAD, supported by documented pathological and
radiological abnormalities of the basal ganglia in patients with this disorder.22 Parkinsonism may, although
rarely, be the presenting feature of HIV infection and
can respond to therapy with levodopa and highly active
antiretroviral therapy (HAART).23 In addition, HIVinfected patients are more susceptible to the extrapyramidal side effects of dopamine receptor-blocking
medications than HIV-negative patients, and drug
interactions between HIV medications and other
classes of medications may also predispose these patients to parkinsonism.22
Autoimmune Disease
SJÖGREN’S SYNDROME
Sjögren’s syndrome is an autoimmune disorder associated with exocrine gland dysfunction, with symptoms of
dry eyes or dry mouth and evidence of lymphocytic
infiltration of the salivary and lacrimal glands. Sjögren’s
syndrome can be associated with a wide variety of central
and peripheral neurological symptoms. Parkinsonism
has been reported in eight patients with Sjögren’s
syndrome, some with abnormal white matter lesions
on neuroimaging, all lacking significant response to
levodopa, and with variable improvement with immunosuppressive therapy.24
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is associated with neuropsychiatric symptoms, which occur in 30 to 60% of
patients. Movement disorders are rarely reported, and
chorea is seen more often than parkinsonism or myoclonus.25 Recent literature reviews and case reports
identify 29 cases of systemic lupus erythematosusassociated parkinsonism,26 10 with juvenile onset.27
Most cases were young women under 30 years of age.
Rigidity and akinesia were more common signs than
tremor, and one third of the cases had hyperreflexia
and Babinski signs. Additional associated features included mutism, anorexia, seizures, psychiatric symptoms, and altered consciousness, suggesting more
widespread brain involvement. All patients who were
treated with immunomodulatory therapy and/or antiparkinsonian medications improved. The mechanisms
of extrapyramidal symptoms in systemic lupus erythematosus are unclear, with possible direct or indirect
contributions from the disease: only a minority of
patients had focal basal ganglia lesions on neuroimaging, one case demonstrated serum antidopaminergic
antibodies,28 and neuroimaging in one case noted basal
ganglia hyperperfusion.29
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Antiphospholipid antibody syndrome is rarely associated
with parkinsonism, with a probable main mechanism of
thrombo-occlusive vasculopathy, and is associated with
periventricular white matter changes on MRI, cerebral
infarctions, and poor response to levodopa treatment.30
NEURO-BECHET’S DISEASE
Behçet’s disease may cause parkinsonism in the setting of
oral ulcerations, recurrent monoarthritis, and skin papules and pustules, with abnormal MRI findings in the
basal ganglia.31
NONVASCULITIC AUTOIMMUNE INFLAMMATORY
MENINGOENCEPHALITIS
Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) is a syndrome involving encephalopathy, evidence of inflammatory disease on tissue biopsy,
and responsiveness to steroids. It may present in a similar
manner to prion disease, with rapidly progressive parkinsonism, dementia, and myoclonus associated with
periodic sharp wave complexes on electroencephalogram
(EEG), but responds dramatically to high-dose corticosteroids.32
Paraneoplastic
Paraneoplastic parkinsonism is rare. Two cases were
associated with breast cancer, one described as a syndrome
of parkinsonism and painful dystonia, with progression to
death 5 months after onset. On autopsy, there was
MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL
degeneration of the substantia nigra without Lewy bodies
or inflammation.33 Another case described a patient with
multiple myeloma and rapidly progressive parkinsonism
with incontinence, impotence, and levodopa-induced
moaning. Pathological findings included loss of pigmented neurons from the substantia nigra without Lewy
bodies. In addition, there are two reports of progressive
supranuclear palsy-like syndromes in association with
B-cell lymphoma and bronchial carcinoma.34 No immunological markers had been discovered for the above cases.
More recent reports have documented associations with
specific antibodies. The collapsin response-mediator
protein (CRMP)-5 antibody has been reported with a
few cases of parkinsonism,35 and antineuronal nuclear
antibody type 2/Anti-Ri has been reported with two
cases of parkinsonism and breast cancer.36 Anti-Ma2associated encephalitis has been associated with atypical
parkinsonism in three patients, with a syndrome of
severe hypokinesia and rigidity associated with dystonia, hyperreflexia, excessive sleepiness, hypophonia, and
poor verbal output.37 Parkinsonism was reported in
11% of a series of 72 patients with voltage-gated
potassium channel autoimmunity, in addition to tremor
(7%) and chorea (3%).38
Toxins
Exposure to a variety of exogenous environmental toxins
may play a role in the development of parkinsonism, and
may be risk factors for Parkinson’s disease based on
current models of the molecular pathogenesis of the
disease.39 Reported agents include organophosphates,
methanol, cyanide, mercury, carbon disulphide, aliphatic
hydrocarbons, manganese, and addictive drugs (MPTP
[1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]), heroin
pyrolysate, inhaled solvents such as toluene, and
ecstasy).40 Exposure history, improvement after removal
from the putative toxic environmental source, and, in
some cases, biochemical assays may help solidify the
diagnosis.
drugs are not effective, but spontaneous recovery occurs
in the majority of patients after 6 months.
TOTAL PARENTERAL NUTRITION
Patients on long-term total parenteral nutrition (TPN)
may have high-signal abnormalities in the basal ganglia,
but the relationship of these imaging abnormalities,
presumably due to manganese deposition, to neurological symptoms is unclear, because they may occur in
asymptomatic patients.43
Drugs
A variety of drugs commonly used in the treatment of
medical disease may cause drug-induced parkinsonism,
and may account for up to 20% of cases of parkinsonism
in a community setting.44 In contrast to Parkinson’s
disease, women are affected more commonly than
men.
DOPAMINE RECEPTOR-BLOCKING MEDICATIONS
Drug-induced parkinsonism can occur in patients
treated with dopamine receptor blockers, such as antipsychotics (haloperidol, risperidone, perphenazine),
antiemetic agents (prochlorperazine, promethazine),
and prokinetic agents (metoclopramide). A history of
dopamine receptor-blocking medication use may not be
offered up front, requiring specific questioning about
their use in the evaluation of new-onset parkinsonism.
Metoclopramide, a frequently used drug in the treatment
of gastroparesis, esophagitis, nausea, and vomiting, may
account for up to 29% of drug-induced parkinsonism in
the elderly (with average age of 69), second only to
antipsychotics.45 Although drug-induced parkinsonism
may be less prevalent in patients treated with atypical,
newer generation antipsychotics compared with traditional neuroleptics, the risk is still clinically pertinent.
Discontinuation of the offending agent usually leads to
recovery in several weeks or months.
OTHER MEDICATIONS
EPHEDRONIC ENCEPHALOPATHY
A distinct syndrome of parkinsonism, severe hypophonia, and gait abnormality in association with manganese-related hyperintense signal on T1-weighted MRI
in the globus pallidus and substantia nigra has recently
been reported in Eastern European methcathinone
users; these patients also had hepatitis C and/or
HIV.41
CARBON MONOXIDE POISONING
Carbon monoxide poisoning may lead to delayed-onset
postanoxic parkinsonism in up to 10% of patients,
typically within 4 weeks but occurring up to 6 months
after initial encephalopathy, associated with changes in
the pallidum on neuroimaging.42 Antiparkinsonian
Among the other medications used to treat medical
diseases that are reported to cause reversible parkinsonism
or exacerbate Parkinson’s disease in small series or single
case histories are calcium channel blockers (diltiazem,
nifedipine, verapamil), monoamine depleters (reserpine,
tetrabenazine), antiarrhythmic drugs (amiodarone), anticonvulsants (phenytoin, sodium valproate), immunosuppressants or chemotherapeutic agents (cyclosporine,
vincristine, busulfan, cytosine arabinoside, doxorubicin), lithium, procaine, a-methyldopa, chloroquine,
buspirone, and high doses of diazepam.40 When the
drug is stopped, parkinsonism improves; in those cases
where parkinsonism persists, it is probable that the
patient had early Parkinson’s disease unmasked by the
drug.
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NONPARKINSONIAN TREMOR
As opposed to parkinsonian tremor, which most often
occurs at rest, tremor induced by drugs and metabolic
disorders typically causes postural and/or action tremor.
Most postural tremor is due to enhanced physiological
tremor.
Disorders of Metabolism
Conditions associated with increased catecholamine levels are common causes of enhanced physiological tremor,
such as pheochromocytoma, stress, anxiety, fever, and
amphetamine use. Metabolic derangements such as
hypoglycemia, hyperthyroidism, and renal and hepatic
dysfunction also cause tremor.
Of special note, Wilson’s disease is an autosomalrecessive disorder caused by a mutation in the ATP7B
gene, which encodes a copper transport protein.
Although the gene is known and genetic testing can be
used to identify affected family members, gene testing is
not useful as a screening test for the disease because the
gene is large and there are many different diseasecausing mutations. Expression of the defective ATP7B
protein results in the failure of the biliary excretion of
excess copper, leading to progressive accumulation of
copper in liver hepatocytes and other organs and tissues.
Symptoms usually appear in the second or third decade
of life and may include hepatic, neurological, and psychiatric symptoms. Patients who present with neurological symptoms tend to be older than those presenting
with hepatic symptoms.46
Neurological features can be the presenting signs of
Wilson’s disease in 40 to 60% of patients, with tremor
being the most frequent initial finding; the proximal
‘‘wing-beating’’ tremor is common, but other types of
tremor may also occur, including rest, posture, and action
tremor.47 A wide variety of other neurological symptoms
may occur, including dystonia, gait abnormalities, dysarthria, ataxia, and parkinsonism as well as cognitive or
behavioral changes such as depression, anxiety, and psychosis. Dystonia can occur in 40% of cases and can be
generalized, segmental, or multifocal, but the ‘‘sardonic
smile’’ is most characteristic of the disorder.48 Other
systemic findings include renal dysfunction, cardiac involvement, pancreatic disease, hemolytic anemia, hypoparathyroidism, osteoporosis, and skin abnormalities.
Workup for Wilson’s disease should be considered in any patient with a new-onset movement disorder
and liver abnormalities of uncertain cause. Patients
with Wilson’s disease have low serum ceruloplasmin,
although this finding is not sensitive or specific enough
to be used alone as a screening tool. Additional workup
should include measurement of 24-hour urine copper,
which is increased (> 100 mg) in Wilson’s disease, and
slit-lamp examination to look for Kaiser-Fleischer rings
because these are present in the majority of patients with
neurological symptoms. Liver biopsy is usually not
required but can be diagnostic. Brain MRI shows increased T2 and decreased T1 signal in the basal ganglia.
Treatment consists of either copper chelation to promote
copper excretion or treatment with zinc to reduce copper
absorption. Trientine is recommended as first-line treatment because of its effectiveness and fewer side effects
than penicillamine.46
Drugs
Drugs are a common cause of acquired tremor. In
general, patients with advanced age, impaired renal
and hepatic function, or underlying medical or neurological disease are more susceptible to drug-induced
tremor.
Amiodarone causes tremor in one third of exposed patients. The tremor is usually postural and
increases with intention, closely resembling essential
tremor. Dose reduction usually leads to improvement in
2 weeks. Cyclosporin frequently causes a postural
tremor with rates as high as 40% reported, but the
tremor is usually mild and does not require dose
reduction.49 Tacrolimus causes a more disabling
tremor: most frequent reports are in liver transplant
patients, although it has also been described in patients
with rheumatoid arthritis.50
Antidepressants are a common cause of tremor,
which occurs in 20% of patients treated with selective
serotonin reuptake inhibitors (SSRIs), and even more
frequently in patients treated with tricyclic antidepressants. Tremor usually develops 1 to 2 months after
starting therapy and resolves 1 month after discontinuation. Lithium causes tremor frequently: at least 30% of
patients develop tremor at therapeutic levels, and at toxic
levels nearly all patients have tremor. Concomitant
treatment with SSRIs increases the likelihood of developing tremor with lithium use. Valproic acid is the most
common antiepileptic drug to cause tremor: tremor
occurs in 25% of patients, usually after 3 months of
treatment. Tremor severity does not necessarily correlate
with serum level, although dose reduction and longacting preparations may reduce the tremor.50
Other types of drugs used to treat medical diseases
that can cause tremor are antiviral agents (acyclovir,
vidarabine) and chemotherapy drugs (thalidomide,
cytarabine).
In general, the approach to treating drug-induced
tremor is to taper the drug or substitute another drug
with a lower risk of tremor. Propranolol can be added if
tapering or changing the medicine is not feasible.
DYSTONIA
Dystonia is a movement disorder characterized by involuntary, sustained, patterned, and repetitive muscle
MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL
contractions leading to twisting movements or abnormal
postures.51 Dystonic movements may be classified by
their anatomical distribution or by their clinical characteristics, and can be further categorized as primary
(idiopathic) or secondary (symptomatic) in regard to
etiology. Primary dystonia, by definition, is unaccompanied by other neurological deficits, and may be associated
with several known genetic mutations.52 Secondary
dystonia should be suspected when dystonia occurs in
association with the following:
Other neurological abnormalities, other movement
disorders, or other abnormalities on general medical
examination
Rapid presentation
Presentation in a location or pattern atypical for
demographics
Medical history that includes a known medical condition or treatment associated with dystonia
In all instances, dystonia is thought to involve the
neuroanatomic circuitry that includes the basal ganglia
nuclei, sensorimotor system, brainstem, and cerebellum.53 Secondary dystonia is associated with a very
wide range of etiologies, each of which has a different
prognosis and some of which are treatable; therefore,
every effort should be made to identify secondary causes
by obtaining a careful medical history.
Heredodegenerative Diseases
A large number of heredodegenerative diseases can cause
secondary dystonia, often in the setting of other multisystemic abnormalities and other movement disorders.54
Most of these disorders are rare and inherited as autosomal-recessive diseases; present at a younger age; are
associated with abnormal neuroimaging; and may have
other features more prominent than the dystonia, such as
mental retardation, seizures, peripheral neuropathy,
and ophthalmological abnormalities.48 However, some
disorders are autosomal-dominant, X-linked, or mitochondrially inherited, and they may present in adolescence or adulthood. A specific diagnosis should be
sought because some conditions have therapeutic interventions. Clues to diagnosis can include concomitant
involvement of other organ systems. Table 1 summarizes
those disorders that may present in adulthood. Some of
the diseases seen in the table are discussed in the text that
follows.
ACERULOPLASMINEMIA
Aceruloplasminemia is an autosomal-recessive disorder
of iron metabolism caused by mutations in the CP gene,
which encodes ceruloplasmin. This mutation results in
iron accumulation in the brain and viscera and may be
associated with anemia, diabetes mellitus, and retinal
Table 1 Heredodegenerative Dystonias Associated
with Medical Disease
Autosomal-Recessive
X-linked Recessive
Wilson’s disease
Lesch-Nyhan syndrome
Aceruloplasminemia
Neuroacanthocytosis
Hartnup disease
Mitochondrial
GMI/GM2 gangliosidosis
Leigh’s disease
Niemann-Pick Type C
Homocystinuria
Leber’s disease
MELAS
Ataxia-telangiectasia
Kearns-Sayre syndrome
Cockayne’s syndrome
Gaucher’s disease
MELAS: mitochondrial encephalomyopathy, lactic acidosis, and
stroke-like episodes.
degeneration. Neurological symptoms may start in the
fifth decade and include dystonia (60%, particularly
craniocervical), parkinsonism (41%), ataxia, dysarthria,
and progressive dementia. Brain MRI may be abnormal,
with low intensities on T1- and T2-weighted images of
the striatum, thalamus, and dentate nuclei representative
of iron deposition.55
NEUROACANTHOCYTOSIS
Neuroacanthocytosis is a heterogeneous group of disorders in which abnormally spiculated red blood cells are
found in association with a neurological syndrome.
Chorea-acanthocytosis is an autosomal-recessive disorder caused by a mutation in the VPS13A gene, which
encodes the protein chorein. Patients most characteristically present with involuntary movements of the face,
mouth, and tongue, which may have a choreic or
dystonic component, most dramatically with a tongue
protrusion dystonia that interferes with eating. Dystonia
occurs in 50% of patients and parkinsonism in one
third.56 Dystonia and chorea may also be prominent
features in McLeod’s syndrome, an X-linked mutation
of the XK gene.57
NIEMANN-PICK DISEASE
Niemann-Pick Type C is an autosomal-recessive lipid
storage disease caused by a mutation in the NPC1 or
NPC2 gene. Patients can present over a wide age range,
with the classic presentation in middle-to-late childhood
with dementia, vertical supranuclear gaze palsy, and
ataxia. Dystonia is common and can start in one limb,
gradually involving all limbs as well as axial muscles;
patients may also have myoclonus, chorea, or parkinsonism. Speech is affected with findings of dysphonia,
dysarthria, and eventual dysphagia. Clues to NiemannPick C include hepatosplenomegaly, particularly in early
childhood. Bone marrow, spleen, and liver contain
characteristic foamy cells.58
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HOMOCYSTINURIA
Homocystinuria is an autosomal-recessive inherited disease caused by cystathionine-b-synthase deficiency, with
multiple systemic, ophthalmological, and neuropsychiatric manifestations. Dystonia, chorea, tremor, and
(rarely) parkinsonism have been reported in association
with the disorder.59
Disorders of Metabolism
MITOCHONDRIAL DISEASE
Mitochondrial/respiratory chain disorders may cause
dystonia, typically presenting in childhood and associated with bilateral basal ganglia lesions on brain imaging.
Dystonia may occur with Leigh syndrome, a heterogeneous disorder associated with multiple respiratory chain
defects and pyruvate dehydrogenase deficiency. Dystonia
is also reported in association with Leber hereditary
optic neuropathy; mitochondrial encephalomyopathy,
lactic acidosis, and stroke-like episodes (MELAS); and
Kearns-Sayre syndrome.17
HYPOXIA
Hypoxic brain injury, particularly in the perinatal period,
may cause any pattern of dystonia, typically more generalized, in 1% of survivors of perinatal asphyxia,
starting even up to 32 years after the initial insult.60 In
a review of 12 patients recovering from hypoxic injury
due to various causes, dystonia developed between
1 week and 36 months after the injury, was gradually
progressive, and was most often associated with evidence
of putamenal damage on neuroimaging. An older age at
time of insult and lesions involving the globus pallidum
predicted the development of an akinetic-rigid motor
syndrome, which frequently later developed dystonic
features.61
CALCIUM METABOLISM
Hypocalcemia from idiopathic hypoparathyroidism may
cause paroxysmal dystonia and choreoathetosis, which,
rarely, may be kinesigenic. It is associated with basal
ganglia calcification on neuroimaging.62
THYROID DISEASE
Hyperthyroidism has been associated with the onset of
segmental and task-specific dystonia that improved
after treatment with antithyroid medications, with
postulated alteration of the dopaminergic system by
elevated thyroid hormone.63 Pseudohypoparathyroidism was discovered in one case of an 11-year-old girl
presenting with paroxysmal, exercise-induced facial and
upper extremity dystonic movements in association
with hypocalcemia, which ceased with normalization
of calcium levels.64
Infectious Disease
Infectious agents associated with dystonia are numerous.21 Dystonia as a prominent symptom has been
reported with viral encephalitis (Japanese encephalitis,
influenza A, cytomegalovirus), tuberculous meningitis,
cerebral malaria, and M. pneumoniae infection. Although
reported less frequently in HIV infection, dystonia can
occur in patients with HAD treated with dopamine
receptor antagonists, who may have increased susceptibility due to underlying basal ganglia dysfunction.22
Dystonia may also occur in association with opportunistic
infections related to HIV (particularly toxoplasmosis).
Autoimmune Disease
The relationship of dystonia to autoimmune disease has
been demonstrated in a small number of case reports and
case series. In a series of 100 patients with blepharospasm
and orofacial-cervical dystonia (Meige syndrome), a high
antinuclear antibody (ANA) titer (> 1:80) was found in
26%, and specific autoimmune disease was diagnosed in
7%.65 Antibasal ganglia antibodies were found in 63% of
a series of 46 patients with atypical dystonia (adult onset
generalized dystonia or fixed limb dystonia), suggesting
an underlying autoimmune pathophysiology.66 A group
of patients with dystonia and antibasal ganglia antibodies
responded favorably to immunomodulatory therapy.67
SYSTEMIC LUPUS ERYTHEMATOSUS
Individual cases of blepharospasm and torticollis have
been reported in the setting of systemic lupus erythematosus or myasthenia gravis. The dystonic movements in
these cases responded to immunomodulatory therapies
and, in the case of systemic lupus erythematosus, correlated in severity with autoimmune titers.68
NEURO-BEHÇET’S DISEASE
One case of Neuro-Behçet’s disease presented as a jawopening dystonia in association with chorea as part of
generalized cerebral, meningeal, and brainstem involvement, with good response to immunomodulatory
treatment.69
CELIAC DISEASE
Celiac disease, a gluten-sensitive enteropathy associated
with malabsorption and development of autoantibodies,
may be associated with neurological syndromes, including ataxia, myoclonus, and dementia. Unilateral dystonic
limb posturing, in association with cortical tremor, has
been reported as the presenting neurological sign in a
case of untreated celiac disease.70
Paraneoplastic
Case reports of paraneoplastic dystonia are rare, with
dystonia occurring mostly in association with other
MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL
movement disorders, as referenced in the section on
parkinsonism. Two additional cases with dystonia
predominance were reported in association with nonHodgkin’s lymphoma—one case of camptocormia that
began 3 years before the development of the malignancy,71 and another case associated with the CRMP5 antibody manifesting as cervical dystonia, blepharospasm, dysphonia, bradykinesia, and choreodystonic
limb movements. Anti-Ri (ANNA-2) antibodies were
identified in four patients with laryngospasm and four
patients with jaw opening dystonia (two of the latter
with additional cervical dystonia and one with parkinsonism) in association with breast, cervix, and lung
malignancies.36
Toxins
Many of the same toxins predisposing to parkinsonism
may cause dystonia due to injury to the basal ganglia.
Methanol, cyanide, carbon monoxide, manganese, mercury, carbon disulfide, and mycotoxin are examples.72 As
discussed earlier, treatment involves removal of the
offending agent in addition to the use of dopaminergic
drugs or anticholinergic agents in cases of residual
dystonia.
Drugs
Drug-induced dystonia may appear otherwise similar to
primary dystonia because it most commonly manifests
only as dystonic movements. Therefore, careful questioning for the typically implicated medications during
the medical history is crucial.48 Many of the drugs
previously mentioned as causing drug-induced parkinsonism are also implicated in drug-induced dystonia,
but, unlike parkinsonism, dystonia usually occurs either
acutely or late in treatment.
Drugs can be grouped by their tendency to cause
acute or late (tardive) dystonic syndromes, although
many cause both. Classes of drugs that may cause acute
dystonia include dopaminergic agents, antidepressants,
neuroleptics, anxiolytics, antiepileptic drugs, and antihistamines. Acute dystonic reactions usually occur in
axial, cranial, cervical, or pharyngeal muscles, but can be
variable in location. Effective treatment of acute dystonic reactions includes discontinuation of the causative
agent and intravenous diphenhydramine or anticholinergic medications.73 Tardive dystonia is most often
associated with dopamine receptor-blocking antipsychotic drugs such as neuroleptics, antiemetics, and
prokinetic gastrointestinal agents.51,72 Next to haloperidol, metoclopramide is the second most common
drug reported to cause tardive dystonia and tardive
dyskinesia.74 Patients with HIV-associated dementia
are particularly sensitive to dopamine receptor-blocking
medications.22
Pseudodystonia
Some medical conditions can themselves mimic dystonia, and may be termed ‘‘pseudodystonia.’’ Examples
include tetany-related carpopedal spasm due to alkalosis,
hypocalcemia, or hypermagnesemia; abnormal postures
secondary to bone, joint, or ligamental pathology from
orthopedic or rheumatologic conditions; torticollis associated with retropharyngeal abscess; or the head tilt
associated with hiatal hernia and gastroesophageal reflux
with Sandifer’s syndrome.48
CHOREA
Chorea is associated with a large number of hereditary or
systemic diseases. This discussion focuses on chorea that
arises secondary to medical diseases. Chorea consists of
involuntary, irregular movements that may either take on
a ‘‘worm-like’’ appearance called athetosis or a more
proximal flinging movement called ballismus.
Vascular
STROKE
Chorea is the most common movement disorder to occur
as a result of stroke. In a series of 1500 patients with
stroke, 4% developed movement disorders; of that 4%,
chorea accounted for a third. There are several interesting features of the patients who developed chorea
following stroke: compared with patients who developed
other movement disorders, patients with stroke-induced
chorea were older and had the shortest time interval
between stroke and development of the movement disorder. Chorea caused by stroke is usually unilateral,
called hemichorea, and occurs contralateral to the side
of the stroke. Thalamic lesions are the most common
localization of stroke-induced chorea. The majority of
patients (75%) improve partially or fully by 1 year.75
POSTPUMP CHOREA
Chorea can occur in children after cardiac surgery, often
called postpump chorea. Most cases are mild and resolve;
however, more severe forms can be life-threatening.
These severe cases are associated with older age and
preoperative cyanosis. It is not known whether chorea
results from hypoxia, hypothermia, or the combination
of both factors.76
POLYCYTHEMIA VERA
Polycythemia vera is often categorized as a vascular cause
of chorea, although the exact mechanism of action is not
known. Chorea usually occurs acutely or subacutely and
may often precede the hematologic changes.77 It is most
common in elderly females, even though polycythemia
vera is more common in men. This discrepancy suggests
that multiple factors underlie the pathophysiology of
105
106
SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2
2009
chorea in these patients. Chorea occurs in only 1 to 5% of
patients with polycythemia vera and improves with
phlebotomy.78
Autoimmune
Autoimmune mechanisms account for several types of
acquired chorea.
estrogen enhances central dopaminergic sensitivity.
However, it is not known whether OCPs alone are
sufficient to cause chorea because many patients with
chorea on OCPs had coexisting antiphospholipid antibody syndrome, lupus, or prior rheumatic fever.85 Positron emission tomography (PET) imaging of a patient
with OCP-associated chorea showed contralateral caudate hypermetabolism, suggesting that in this condition
chorea is not due to a lesional effect.86
SYDENHAM’S CHOREA
Sydenham’s chorea occurs in 25% of cases of acute
rheumatic fever. Chorea develops weeks to months after
infection with group A b-hemolytic streptococcus. The
onset of chorea can be delayed by up to 6 months after
infection. Chorea can be accompanied by facial grimacing, dysarthria, gait disturbance, and hypometric saccades. The average age of onset is 9 years. Girls are
more often affected than boys. Remission occurs in half
the patients by 6 months, but mild chorea may persist
for years.79 It has also been suggested that changes in
attention and behavior such as learning disabilities,
obsessive compulsive disorder, and tics are more common
in patients with a history of Sydenham’s disease, although
this is controversial.80
The mechanism of action of chorea in Sydenham’s chorea is thought to be cross-reactivity between
antibodies to group A b-hemolytic streptococcus and the
basal ganglia. In fact, antibasal ganglia antibodies have
been identified as sensitive and specific markers of
Sydenham’s chorea.81 Volumetric MRI shows enlargement of the basal ganglia in affected patients without
other abnormalities. Pathology shows inflammation and
neuronal loss in the basal ganglia.80
Patients with Sydenham’s chorea and rheumatic
fever require treatment with penicillin for acute pharyngitis followed by chronic penicillin prophylaxis for
10 years. A randomized controlled trial of prednisone
2 mg/kg/d for 4 weeks followed by a taper showed that
treatment with steroids improved chorea and shortened
the time to remission.82 If symptomatic, chorea can be
treated with valproic acid, carbamazepine, or haloperidol; however, some suggest that patients with Sydenham’s chorea may be more susceptible to drug-induced
parkinsonism.83
SYSTEMIC LUPUS ERYTHEMATOSUS
Other systemic autoimmune diseases are rare causes of
chorea. Chorea occurs in 1% of patients with systemic lupus erythematosus and usually is associated
with the antiphospholipid antibody syndrome.84 Antibody-related pathophysiology may underlie these
conditions.
CHOREA GRAVIDARUM
Chorea gravidarum may share a similar mechanism of
action to that of OCP-associated chorea. It usually
begins in the first trimester of pregnancy and improves
later in pregnancy or after delivery.87
Paraneoplastic
Paraneoplastic chorea is most often associated with antiCRMP-5 antibodies in small-cell lung cancer. The
majority of these patients have other paraneoplastic
neurological signs, including vision loss, neuropathy,
ataxia, limbic encephalitis, elevated cells and protein
concentration in cerebrospinal fluid (CSF), and T2 and
fluid-attenuated inversion recovery (FLAIR) lesions on
MRI. Chorea improves with cancer treatment and
steroids.88 Paraneoplastic chorea has been reported in
several other malignancies and in some cases can be
refractory to medical treatment.89
Disorders of Metabolism
GLUCOSE METABOLISM
Nonketotic hyperglycemia-induced chorea has several
interesting features. It occurs more often in women and
usually is associated with very high blood glucose (average 481 mg/dL).90 Nearly all patients recover fully by
6 months. All cases have MRI changes in the putamen
with high signal intensity on T1-weighted imaging
(Fig. 2). The etiology of the MRI changes is not fully
understood, but most resolve on follow-up, suggesting a
reversible process such as petechial hemorrhage (not
calcification); however, rare pathological reports show
gliosis without hemorrhage. A study evaluating singlephoton emission computed tomography (SPECT) scans
in patients with nonketotic hyperglycemia-induced
chorea documented striatal hypometabolism compared
with patients without chorea who had the same level of
hyperglycemia.91 Hypoglycemia-induced chorea has also
been reported.92
THYROID DISEASE
ORAL CONTRACEPTIVES
Chorea has been attributed to use of oral contraceptive
pills (OCPs). Several lines of evidence suggest that
Hyperthyroidism is a rare metabolic cause of chorea. It is
thought to result from enhanced catecholamine effects in
the striatum,93 and can occur with thyroid replacement
MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL
clopramide, a dopamine antagonist, can cause tardive
syndromes.
OTHER DRUGS
A variety of drugs have been reported to cause chorea.
Those of special importance in internal medicine include
cimetidine, digoxin, isoniazid, verapamil, and theophylline. Others include baclofen, tricyclic antidepressants,
steroids, and antiepileptics.100 Chorea can also develop
from abuse of cocaine and amphetamines.
Figure 2 T1-weighted magnetic resonance imaging of the
brain in a patient with left-sided hemichorea and nonketotic
hyperglycemia demonstrates right putaminal hyperintensity.
therapy. When chorea occurs with Hashimoto’s thyroiditis, it is usually in the setting of Hashimoto’s encephalopathy.94 Chorea due to hyperthyroidism improves with
treatment of hyperthyroidism, although it may persist for
weeks after thyroid levels are normalized.95 Symptomatic
treatment with propranolol is also effective.93
RENAL FAILURE
Uremia has been associated with the sudden onset of
chorea. Patients with diabetes and end-stage renal disease
who develop chorea have MRI changes in basal ganglia
consistent with vasogenic edema.96 Treatment with more
frequent dialysis leads to resolution of the chorea.97
CALCIUM METABOLISM
Hypocalcemia, most frequently in the setting of hypoparathyroidism, can cause chorea, which improves when
calcium is corrected.98,99
INBORN ERRORS OF METABOLISM
Several inborn errors of metabolism can cause chorea but
usually include a mix of different movement disorders.17
Drugs
DOPAMINE RECEPTOR ANTAGONISTS
Tardive dyskinesia occurs after exposure to dopamine
receptor antagonists.74 Most characteristically, patients
develop oral-lingual-buccal movements, although chorea
may affect the limbs and the trunk as well. Of particular
relevance to medical conditions is the fact that meto-
FUTURE PERSPECTIVES
Movement disorders occur in medical illness, and appreciation of their phenomenology and etiologies will help
to direct clinicians to appropriate diagnostic tests and
treatments. Although the movement disorders have been
presented here in four categories, patients will often have
multiple movement disorders simultaneously. Combinations of movement disorders can cloud understanding
because of the phenomenological presentation, but recognition of the most frequent patterns of movement can
be useful in directing astute diagnosticians to the likely
diagnosis.
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