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Handbook of Clinical Neurology, Vol. 100 (3rd series)

Hyperkinetic Movement Disorders
W.J. Weiner and E. Tolosa, Editors
# 2011 Elsevier B.V. All rights reserved

Chapter 25

Hyperkinetic movement disorders associated with

HIV and other viral infections

ELIZABETH CARROLL AND JUAN SANCHEZ-RAMOS *

Department of Neurology, University of South Florida, Tampa, FL, USA

INTRODUCTION The acute viremia is accompanied by a marked decrease

Neurologic manifestations of human immunodefi-
ciency virus (HIV) and other viral infections may
involve all levels of the central and peripheral nervous
system. Direct infection of the basal ganglia by the
virus or complications from opportunistic infections
result in a range of movement disorders, with tremor
and parkinsonism occurring more frequently than
hyperkinetic movement disorders such as hemichorea-
hemiballismus, generalized chorea, and dystonia. In
this chapter, the clinical features, etiology, and treat-
ment of acquired immunodeficiency syndrome
(AIDS)-related (and other viral encephalopathy-related)
hyperkinetic movement disorders will be discussed.
Prion diseases that result in hyperkinetic movement
disorders will also be reviewed.
HIVAND AIDS
Infection with HIV, a retrovirus, gradually destroys
the immune system and results in AIDS, a progressive
disease with a variable latency between initial viral
infection and the development of opportunistic infec-
tions, malignant tumors, wasting, and central nervous
system (CNS) degeneration. The HIV virus, identified
in 1983–1984 by two separate teams of researchers in
France and the USA as the cause of AIDS (Barre-
Sinoussi et al., 1983; Gallo et al., 1984; Popovic et al.,
1984; Schupbach et al., 1984), is transmitted by direct
contact of a mucous membrane or the blood stream
with a bodily fluid containing HIV, such as blood,
semen, vaginal fluid, preseminal fluid, and breast milk
(Royce et al., 1997). The first stage of infection is a
period of rapid viral replication leading to an abundance
of virus in the peripheral blood (Piatak et al., 1993).
in numbers of circulating CD4þ T cells and activation
of CD8þ T cells which kill HIV-infected cells. The
CD8þ T-cell response is important for controlling virus
levels, which peak and then decline, as the CD4þ T cells
rebound to around 800 cells/mL. During this period
(2–4 weeks postexposure) most individuals develop an
influenza or mononucleosis-like illness (acute HIV infec-
tion) which may include fever, lymphadenopathy, phar-
yngitis, rash, myalgia, malaise, mouth and esophagal
sores, and may also include, but less commonly, head-
ache, nausea and vomiting, enlarged liver/spleen, weight
loss, thrush, and neurological symptoms such as forget-
fulness associated with slowed mental and motor abilities
(Simpson and Tagliati, 1994).
A strong immune defense reduces the number of
viral particles in the blood stream, marking the start
of the infection’s clinical latency stage. Clinical latency
can vary between 2 weeks and 20 years. During this
early phase of infection, HIV is active within lymphoid
organs, where large amounts of virus become trapped
in the follicular dendritic cells network (Burton et al.,
2002). The surrounding tissues that are rich in CD4þ
T cells may also become infected, and viral particles
accumulate both in infected cells and as free virus.
Individuals who are in this phase are still infectious.
The clinical diagnosis of AIDS is made when CD4þ
T cell numbers decline below a critical level, cell-
mediated immunity is lost, and the patient becomes
susceptible to infections with a variety of opportunistic
microbes or develops malignant tumors. In this setting,
the clinical diagnosis can be confirmed with laboratory
evidence such as a positive antibody test or detectable
HIV RNA or DNA. From the epidemiological perspec-
tive of the Centers for Disease Control (CDC), a case

*Correspondence to: Juan Sanchez-Ramos, PhD, MD, Ellis Professor of Neurology, Dept of Neurology (MDC 55), 12901 Bruce B.
Downs Blvd, Tampa, FL 33612, USA. Tel: 813-974-6022, Fax: 813-974-7200, E-mail: jsramos@health.usf.edu
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324 E. CARROLL AND J. SANCHEZ-RAMOS

definition for diagnosis of HIV infection and AIDS
must include these confirmatory laboratory tests
(CDC, 1999).
HYPERKINETIC MOVEMENT
DISORDERS IN HIV-INFECTED
PATIENTS
Neurologic abnormalities are common in HIV-infected
patients. The prevalence of neurologic deficits in HIV-
infected patients based on retrospective chart review
has been reported to range from 21.3% to 60% (Nath
et al., 1987; Brew, 2001; Mattos et al., 2002). At the
height of the AIDS epidemic, movement disorders
reflecting dysfunction of the extrapyramidal system
were recognized in 2–3% of AIDS patients (Brew,
2001). More recent reviews and prospective studies
suggest a higher prevalence of movement disorders
(4.4–50%), especially of tremor and parkinsonism
(Tse et al., 2004). Hyperkinetic movement disorders
seen in the context of HIV infections include
generalized chorea, hemichorea-hemiballismus, dysto-
nia, isolated tremors, myoclonus, and paroxysmal
dyskinesias (Table 25.1).
Hyperkinetic movement disorders can be observed
either as an initial clinical manifestation of the viral

Table 25.1
Hyperkinetic movements in patients infected with human immunodeficiency virus (HIV)

Hyperkinetic movements Neuropathology-pathogenesis Comments

Hemichorea-hemiballismus Toxoplasmosis lesions in STN or its Most common cause of hemichorea-

connections in the basal ganglia hemiballismus in AIDS
Cryptococcal granuloma in STN Discovered because of failure to respond to
treatment for toxoplasmosis
Generalized chorea HIV encephalitis Acute encephalopathy with generalized chorea
is an infrequent consequence of HIV
encephalitis
HAD Generalized chorea is a rare clinical
manifestation of HAD
PML Generalized chorea is uncommon in PML
Facial dyskinesia Drug-induced chorea Unusual complication in HIV-infected patients
Paroxysmal dyskinesia HAD complex Associated with kinesiogenic and
Involvement of left frontal cortex, nonkinesiogenic dyskinesias
unknown etiology
Dystonia Cerebral toxoplasmosis Hemidystonia on side contralateral to lesion
Dopamine receptor antagonists Patients with HAD have increased
susceptibility to developing dystonia with
neuroleptics
Bilateral putaminal lesions of May be related to direct effects of the virus on
unclear etiology striatal neurons
Tremor HIV infection of basal ganglia Tremor may be isolated or part of a parkinson
syndrome
HAD complex Tremor may be seen at all stages of disease
Tuberculoma in midbrain “Rubral tremor”
Drug-induced Rest, postural and kinetic tremors may be
observed
Myoclonus HIV infection of basal ganglia Associated with generalized myoclonus
HAD complex
Cerebral toxoplasmosis
Mycobacterium tuberculosis Associated with spinal myoclonus
PML Myoclonic ataxia
Herpes zoster radiculitis Segmental myoclonus
Involvement of left frontal cortex,
unknown etiology

STN, subthalamic nucleus; AIDS, acquired immunodeficiency syndrome; HAD, HIV-associated dementia; PML, progressive multifocal
leukoencephalopath.
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TS1 HYPERKINETIC MOVEMENT DISORDERS
infection or as a later complication of opportunistic
infections, primarily toxoplasmosis (Tse et al., 2004).
Motor dysfunction, when it occurs in the setting of
cognitive and behavioral deficits, is catagorized as the
AIDS–dementia complex. The cognitive deficits have
characteristics of a subcortical dementia and typically
antedate extrapyramidal motor manifestations includ-
ing tremor, slowness, chorea, and ballismus. The syn-
drome of motor and cognitive abnormalities in the
setting of HIV infection has also been termed HIV-
associated dementia (HAD), HIV encephalopathy, and
HIV-associated minor cognitive/motor disorder. For
the purposes of the present chapter, the term HAD will
be used to cover the syndrome of motor and cognitive
disorders in HIV-infected patients.
CHOREA AND HEMICHOREA-
HEMIBALLISM
Generalized chorea has been described as a state of
excessive spontaneous movements, irregularly timed,
nonrepetitive, randomly distributed, and abrupt in
character (Weiner and Lang, 1989). Chorea that
involves only the limbs on one side of the body is
termed hemichorea and it often overlaps clinically with
hemiballismus, defined as uncontrollable, rapid, large-
amplitude proximal movements of the upper and lower
limbs limited to one side of the body. Ballismus has
also been described as wild, flinging, violent move-
ments of the limbs (Weiner and Lang, 1989; Grandas,
2002). Isolated hemiballism is extremely rare, and
more typically there are components of the slower
hemichorea associated with the ballistic movements
(Grandas, 2002). Hemichorea and hemiballism are part
of the spectrum of hyperkinetic movements associated
with a common underlying pathophysiology that
involves the subthalamic nucleus and/or its connections
(Weiner and Lang, 1989). In a review of 62 cases of
movement disorders arising from focal lesions of the
thalamus and subthalamus, it was concluded that bal-
lism or chorea results from damage to the subthalamic
nucleus or its efferent pathways, which removes exci-
tation of the globus pallidus, thus disinhibiting the ven-
trolateral and ventroanterior thalamic nuclei receiving
pallidal projections (Lee and Marsden, 1994).
The incidence and prevalence of hemichorea-
hemiballismus in the population of HIV-infected patients
are not established but it is clearly much more prevalent
than in the noninfected population. A retrospective
review of all sporadic cases of chorea admitted to general
neurology departments in two Italian hospitals over a
period of 3 years revealed an incidence of 0.294%
(a total of 2.94 cases of chorea per 1000 admissions per
year) (Piccolo et al., 1999b). In contrast, a retrospective
325
review of 51 sporadic cases of chorea revealed that
9.8% (5 of 51) were cases of AIDS: 2 of them with
generalized chorea, 1 with hemichorea, and 2 with focal
chorea (Piccolo et al., 1999a). In a series of 253 patients
with AIDS seen over 5 years in an academic neurology
department, 54 (21.3%) exhibited neurologic problems
and 6 of these (11%) had movement disorders. Of these
6 patients, 3 (50%) exhibited hemichorea-hemiballismus
(Nath et al., 1987). An early clinical-pathological study
of AIDS patients harboring cerebral toxoplasmosis
reported that 7.4% of them (2/27 cases) exhibited
hemichorea-hemiballismus or generalized chorea (Navia
et al., 1986c).
The pathogenesis of chorea-ballism in HIV-related
opportunistic lesions appears to be due to the same
mechanism of chorea generation that results from
destructive lesions of the subthalamus and its efferent
pathways (Lee and Marsden, 1994). The most common
lesion associated with hemichorea-hemiballism in
AIDS patients is localized to the subthalamic nucleus
(Nath et al., 1993; Maggi et al., 1996; Piccolo et al.,
1999a). However the majority of cases of hemichorea-
hemiballism involve multiple cerebral lesions. In addi-
tion to the subthalamic nucleus, lesions may be found
in thalamus, head of the caudate, putamen, globus
pallidus, midbrain, and internal capsule (Sanchez-
Ramos et al., 1989; Maggi et al., 1996; Krauss et al.,
1999). Cases of generalized chorea or bilateral chorea
are rare: a single case of HIV encephalitis presented
with rapidly progressive encephalopathy and bilateral
choreic and ballistic movements (Gallo et al., 1996).
Other cases of generalized chorea were observed in
patients with HIV encephalitis and neuropsychological
symptoms consistent with HAD (Pardo et al., 1998;
Sporer et al., 2005). Facial chorea is extremely uncom-
mon in AIDS patients. A single case of involuntary
facial movements preceding the appearance of hemi-
chorea-hemiballism secondary to cerebral toxoplasmo-
sis has been reported (Nath et al., 1993). Another
AIDS patient presented with buccolingual and mastica-
tory dyskinesias, in which the facial movements were
assumed to be iatrogenic due to norepinephrine and
dopamine used for the treatment of hypovolemic shock
(Sporer et al., 2005).
Rare cases have been reported of paroxysmal dyski-
nesias, which differ from generalized chorea cases
by the sudden onset of choreoathetotic or dystonic
movements of transient duration (Nath et al., 1987;
Mirsattari et al., 1999). In kinesigenic dyskinesias,
normal movements may trigger the dyskinesias. From
a series of 6 AIDS patients with paroxysmal dyskine-
sias, a single postmortem examination revealed severe
HIV encephalitis, intense astrogliosis, and loss of
calbindin-expressing neurons in the subcortical gray
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326 E. CARROLL AND J. SANCHEZ-RAMOS
matter (Mirsattari et al., 1999). In another case of
nonkinesigenic paroxysmal dyskinesias, a lesion was
visualized by magnetic resonance imaging in the left
frontal cortex (Nath et al., 1987). Patients with kinesi-
genic dyskinesias were more likely to respond to
benzodiazepine treatment than those with nonkinesi-
genic dyskinesias.
Treatment of hemichorea-hemiballism in these
patients should address the causative opportunistic
infections, the HIV infection itself, and symptomatic
control of hyperkinetic movements. In cases of cere-
bral toxoplasmosis, prompt administration of sulfadia-
zine and pyrimethamine is often followed by rapid
improvement and occasional resolution of the move-
ment disorder (Navia et al., 1986c; Sanchez-Ramos
et al., 1989; Noel et al., 1992; Garretto et al., 1995). In
some cases the response to antitoxoplasmosis therapy
is not optimal, suggesting to some researchers that
the underlying HIV infection contributes to the move-
ment disorder even after resolution of the Toxoplasma
abscesses (Nath et al., 1993). To provide relief for
incessant involuntary movements, especially in the case
of ballistic movements that may cause self-injury,
dopamine receptor antagonists or presynaptic dopa-
mine depletors (tetrabenazine) are often effective,
though some cases may be resistant even to these
agents (Nath et al., 1993). In a case of generalized
chorea associated with HIV encephalitis, treatment
with antiretroviral and antidopaminergic drugs was
not effective in controlling chorea (Gallo et al., 1996).
However, other reports of generalized chorea or bilat-
eral chorea associated with HIV encephalitis have
found antiretroviral therapy to be very effective in
resolving the movements (Pardo et al., 1998; Trocello
et al., 2006).
DYSTONIA
Generalized, segmental, and focal dystonias have been
described in AIDS patients. Hemidystonia is extremely
rare, with only 1 case out of 2460 HIV patients exhibit-
ing this movement disorder (Mattos et al., 2002). In a
small series of 7 cases with AIDS or HAD, one patient
exhibited paroxysmal dystonia and a second patient
manifested postural tremor associated with dystonia
(Nath et al., 1987). While rare cases of generalized or
focal dystonia in the setting of HIV infection have
been reported (Abbruzzese et al., 1990; Tolge and
Factor, 1991), treatment with dopamine receptor
antagonists is liable to trigger acute-onset medication-
induced dystonia (and/or parkinsonism) (Hollander
et al., 1985; van Der Kleij et al., 2002). HAD has been
shown to be associated with neuronal loss in the palli-
dum, as well as reduced levels of dopamine and
homovanillic acid in the cerebrospinal fluid (CSF),
providing a neurochemical/neuroanatomical substrate
for these patients to develop movement disorders when
exposed to dopamine receptor antagonists (Factor
et al., 1994; Lopez et al., 1999).
As with all movement disorders associated with
HIV infection, treatment of dystonia is directed
towards eradicating underlying opportunistic infec-
tions, antiretroviral therapy, and symptomatic thera-
pies. Results in general are very poor. In a single
case of hemidystonia caused by cerebral toxoplas-
mosis, treatment with sulfadiazine and pyimethamine
did not change the dystonic symptoms but did improve
the lesions viewed by neuroimaging (Mattos et al.,
2002). Modulation of complex neurotransmitter
systems of the basal ganglia also has little impact on
dystonia. A patient with HAD complex and persistent
neuroleptic-induced dystonia was treated unsuccess-
fully with a combination of trihexyphenidyl, diphenhy-
dramine, and carbidopa/levodopa (Factor et al., 1994).
Minimal improvement of generalized dystonia was
reported after a course of high-dose anticholinergic
medication (Abbruzzese et al., 1990). Perhaps the best
approach is to prevent dystonia from developing by
whenever possible avoiding the use of neuroleptic
drugs or antiemetic drugs that block central dopamine
receptors.
TREMOR
Tremor is typically a component of the hypokinetic
syndrome of parkinsonism and is considered to be
the most common movement disorder observed in
HIV patients, with an incidence ranging from 5.5 to
44% of patients with HAD (Navia et al., 1986b;
Cardoso, 2002). The tremor observed in AIDS patients
may also occur as an isolated phenomenon. Tremor
can be observed in both early and late stages of HAD.
In some cases tremor may antedate the appearance of
dementia and other neurologic deficits. Tremor in AIDS
is typically a mild bilateral postural tremor but may also
occur at rest. Occasionally the tremor is present with
action (kinetic tremor). In some cases, the tremor has
components of rest, postural and kinetic tremors and
can be classed as a “rubral” or Holmes tremor (Deuschl
et al., 1996; Cardoso, 2002). A rubral tremor is typically
associated with a lesion in the vicinity of the red nucleus
of the midbrain caused by an opportunistic infection
with Toxoplasma or tuberculosis. Rubral tremors can
present with accompanying focal signs pointing to
a midbrain localization such as ophthalmoplegia and
contralateral hemiparesis.
Tremors can also develop in AIDS patients treated
with various drugs and may be observed as part of a
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HYPERKINETIC MOVEMENT DISORDERS 327

parkinsonian syndrome, especially in those treated with
neuroleptics or antiemetics that block dopamine recep-
tors. In addition, patients treated with trimethoprim-
sufamethoxazole for Pneumocystis carinii pneumonia
can develop tremor that can present as a rest tremor or
a bilateral high-frequency postural tremor with a kinetic
component (Borucki et al., 1988; Van Gerpen, 1997).
Treatment of isolated tremor associated with HIV
infections requires recognition of opportunistic infec-
tions and review of medications that might elicit tremors.
When rubral tremor was found to be a consequence of a
midbrain tuberculoma, treatment with the appropriate
antituberculosis drugs was reported to resolve the tremor
(Mattos et al., 2002).
MYOCLONUS
Segmental and generalized myoclonus has been
reported in HIV-infected patients, but it is also rare.
In over 2000 hospitalized HIV patients, only 4 exhib-
ited myoclonus: 2 with spinal myoclonus and 2 with
generalized myoclonus (Mattos et al., 2002). However,
smaller case report series tend to report a relatively
higher frequency of segmental myoclonus (2 out of
7 patients with movement disorders in the setting
of HAD) (Nath et al., 1987). From another center,
3 patients with generalized myoclonus and HAD were
reported in which the myoclonus persisted until death,
invariably after a course of a few months. In 2 of the
patients, myoclonus was elicited by sudden auditory
stimuli and resembled a startle response (Maher
et al., 1997). A single patient with HIV exhibited myoc-
lonus restricted to the axial muscles resulting in flexion
of the neck trunk and lower extremities but with no
structural lesions evident by neuroimaging (Lubetzki
et al., 1994).
Treatment of opportunistic infections with appro-
priate medications and with antiretroviral drugs
resulted in variable relief of myoclonus. In a series of
3 cases of generalized myoclonus and HAD complex,
all patients failed therapy and died within months of
onset of myoclonus (Maher et al., 1997). A single
patient with segmental myoclonus that preceded herpes
zoster radiculitis experienced complete remission after
treatment with the antiviral drug acyclovir. Another
case with HAD complex and generalized myoclonus
experienced a remarkable improvement following
aggressive treatment with zidovudine. Administration
of a regimen of antituberculosis medications to a
patient exhibiting spinal myoclonus secondary to tuber-
culous radiculomyelopathy resulted in mild improve-
ment of the myoclonus. In terms of symptomatic
relief, occasional patients may derive slight benefit
from clonazepam treatment (Maher et al., 1997).
NEUROIMAGING
Structural neuroimaging with magnetic resonance imag-
ing (MRI) or computed tomography (CT) is useful in
visualizing mass lesions caused by opportunistic infec-
tions in AIDS cases. Toxoplasma encephalitis may
appear on CT or MRI as a focal or multiple rings and/or
nodular enhancing lesions surrounded by variable
degrees of vasogenic edema. The lesions tend to be
located in the deep gray matter (basal ganglia, thalamus)
or at the corticomedullary junction (Sakaie and
Gonzalez, 1999). Rarely, lesions can be found in the
brainstem and cerebellum (Sakaie and Gonzalez, 1999).
Primary CNS lymphoma is the second most common
cause of a focal CNS mass lesion after Toxoplasma
encephalitis. Clinically, it is difficult to distinguish
primary brain lymphoma from other intracranial
masses, particularly Toxoplasma encephalitis. On CT and
MRI, lymphoma may appear as a focal ring and/or
nodular enhancing mass lesion(s) with surrounding
edema. The lesions may be single or multiple, superficial
(corticomedullary junction), and/or deep (basal ganglia,
thalamus, corpus callosum). The posterior fossa may
also be involved (cerebellum, pons, midbrain).
Functional neuroimaging with MRI and positron
emission tomography (PET) have been useful in detect-
ing early stages of HIV infection (Sakaie and Gonza-
lez, 1999). A comparison of MR proton spectroscopy,
perfusion-weighted (PR) MR, diffusion-weighted
(DW) MR, and conventional MRI was performed in
32 HIV-positive patients with various degrees of
HAD complex (Wenserski et al., 2003). No patients
exhibited abnormalities with conventional and DW
MR images, but quantitative PR MR imaging and
proton MR spectroscopy depicted pathologic changes
in patients with HAD complex.
PATHOGENETIC MECHANISMS
Most hyperkinetic movement disorders are a conse-
quence of dysfunction of the basal ganglia. The HIV
virus has a predilection for the basal ganglia, as evi-
denced by neuropathological and neuroimaging studies
(Navia et al., 1986a; Dal Pan et al., 1992; Aylward et al.,
1993). Microglial nodules with multinucleated giant
cells are especially abundant in the caudate and puta-
men (Navia et al., 1986a). PET studies of HIV-infected
patients reveal a relative hypermetabolism in early
stages of HIV dementia and global cerebral hypometa-
bolism in more advanced stages (Rottenberg et al.,
1987). In cases of HAD complex, progressive atrophy
of the caudate has been reported (Dal Pan et al.,
1992). Dopaminergic neuronal function is impacted
by HIV, as reflected by decreased dopamine levels in
CSF and in caudate nucleus (Berger et al., 1994; Sardar
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328 E. CARROLL AND J. SANCHEZ-RAMOS

et al., 1996). Moreover, loss of neurons in substantia Table 25.2
nigra has been reported, though the pattern of loss in Hyperkinetic movements associated with other viral
the pars compacta is different than that seen in normal infections and prion diseases
aging and in Parkinson’s disease. Neuropathologic
studies revealed the effects of the virus in basal gang- Hyperkinetic Virus Comments
lia and other subcortical areas (Reyes et al., 1991). The movements
sensitivity of HIV patients to dopamine receptor
antagonists may be a result of the deficiency in dopa- Tremor WNV Static, kinetic (common)
mine neurotransmission. Moreover, opportunistic Kuru Cerebellar type (common)
infections by Toxoplasma, cryptoccocus, and condi- JEV Postural, intermittent, or
CJD resting (common)
tions such as lymphoma have a predilection for the
Postural, kinetic (rare)
basal ganglia. Damage to the basal ganglia results in Chorea Variant CJD Included in diagnostic
derangement in the normal execution of movement. WNV criteria
Kuru –
OTHER VIRAL INFECTIONS HSV In later stages
ASSOCIATED WITH HYPERKINETIC JEV In pediatric relapse cases
MOVEMENT DISORDERS Postural, kinetic (rare)
Dystonia WNV –
Similar to the HIV virus, many other viral infections of JEV Axial and fixed with
the CNS have an affinity for the basal ganglia and Variant CJD associated thalamic
result in a variety of movement disorders, either as Familial, or lesions
part of the acute encephalitis or as a delayed effect sporadic CJD Focal, typically progressing
of the infection. The viral agents implicated include to generalized with
the influenza viruses (avian influenza A), flaviviruses associated myoclonus
(arthropod-borne viruses), herpesvirus, and others or choreathetosis
(Table 25.2). (Rare)
Myoclonus Familial, Jerks that are diffuse or
sporadic, focal, typically provoked,
ENCEPHALATIS LETHARGICA
variant CJD can occur during sleep;
Encephalitis lethargica (von Economo’s encephalitis) WNV concominant with
was a mysterious epidemic that swept the world from Kuru dystonia or
1917 to 1928 (Vilensky et al., 2006). The epidemic paral- JEV choreoathetosis
leled the 1918 Spanish influenza pandemic and some (common)
Seen in late stages
experts believed both were caused by an influenza virus
(ARNM, 1921). The frequency of encephalitis lethargica
WNV, West Nile virus; JEV, Japanese encephalitis virus; CJD,
has declined dramatically since the late 1920s, but
Creutzfeldt–Jakob disease; HSV, herpes simplex virus.
sporadic cases that clinically resemble encephalitis
lethargica have continued to appear. In the acute phase
of the illness, patients exhibited fever, somnolence, and common subtype (after the most frequent “somnolent-
ophthalmoplegia. Examination of the CSF typically ophthalmoplegic” type), a “hyperkinetic” syndrome was
revealed mild elevation of protein levels and a pleocy- ranked as the sixth most common clinical phenotype.
tosis (50–100 lymphocytes) (ARNM, 1921). Nearly half The hyperkinetic movements observed in this sub-
of the patients affected did not survive the initial phase; type included generalized chorea, choreathetosis, and
postmortem examination of the brain showed periven- dystonia. Unlike the common dyskinesias triggered by
tricular and midbrain inflammation (Tilney and Howe, dopamine replacement in Parkinson’s disease, the hyper-
1920; ARNM, 1921). Of those who survived the acute kinetic movement disorders observed in encephalitis
encephalitic stage, a significant proportion developed lethargica occurred spontaneously in the pre-levodopa
a syndrome of parkinsonism which differed from era. A myoclonic syndrome was extremely rare (Tilney
Parkinson’s disease by the presence of abnormal move- and Howe, 1920; Vilensky et al., 2006).
ments such as dystonia, blepharospasm, and oculogyric The neuropathological findings in postencephalitic
crises (Vilensky et al., 2006). Based on variations in movement disorders included marked loss of dopamine
clinical presentation and outcome, encephalitis lethar- neurons in substantia nigra, but, unlike Parkinson’s
gica was classified into multiple clinical subtypes (Tilney disease, neurofibrillary tangles were found distributed
and Howe, 1920; Vilensky et al., 2006). Whereas a Par- throughout the brain. In this feature, the neuropathology
kinson’s syndrome was ranked the second most resembles cases of progressive supranuclear palsy and
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HYPERKINETIC MOVEMENT DISORDERS
the Guam Parkinson–dementia complex (Forno, 1996;
Lowe et al., 1997).
The etiological association of influenza virus with
encephalitis lethargica has been controversial for
decades. However, analysis of RNA extracted from
29 tissue samples from archived postencephalitic cases
failed to show influenza viral genes in all the samples
(McCall et al., 2001). Nevertheless, some experts still
suspect a mutation of the influenza H1N1 virus (an
avian influenza strain) might have been the etiological
agent (Vilensky et al., 2006). According to these
experts, a mutation in the avian influenza A virus (sub-
type H5N1) that would facilitate contagion from bird
to human might result in reappearance of an epidemic
of encephalitis lethargica.
Another concept regarding the pathogenesis of
abnormal movements suggests that postencephalitic
dyskinesias are a consequence of an autoimmune pro-
cess. This hypothesis is based on the findings of oligo-
clonal bands in the CSF of contemporary encephalitis
lethargica-like cases and the beneficial effects of
steroid therapy (Dale et al., 2004). In support of this
hypothesis, 95% of 20 recent cases were found to have
autoantibodies against human basal ganglia antigens
(Dale et al., 2004).
FLAVIVIRUS INFECTIONS
Of the small RNA virus genus Flavivirus, Japanese
encephalitis virus (JEV) is the most significant with
regard to incident cases as well as mortality worldwide
(Solomon, 2008). The closely related West Nile virus
(WNV) was responsible for the greatest outbreak of
encephalitis recorded in 2002 (Solomon et al., 2003a).
Most flaviviruses cause a febrile illness with associated
myalgias, rash (WNV), arththralgias, headache, and
nucchal rigidity. Encephalitis can accompany meningi-
tis or occur in isolation. Other viruses of this genus
that cause encephalitis are St. Louis encephalitis virus,
endemic to the Americas, Murray valley encephalitis
(Australia and Papa New Guinea), rocio virus (Brazil),
and kunjin virus (Australia), now considered a subtype
of WNV (Solomon, 2004).
WNV and JEV are responsible for the greatest num-
ber of reported cases exhibiting hyperkinetic move-
ment disorders. Members of the Flavivirus genus are
mostly arboviruses (arthropod-borne), primarily trans-
mitted via mosquito and tick vectors, and the human
is traditionally considered a dead-end host. However,
transmission via transplanted organs, blood products,
and even transplacental transmission has been reported
(Solomon, 2004). WNV and JEV infect the Culex
species of mosquitoes and are transmitted by this insect
vector primarily to birds. Extrapyramidal syndromes,
329
typified by a syndrome of parkinsonism, predominate
the movement disorders observed following CNS
infection with JEV, western equine encephalitis, and
encephalitis lethargica.
WEST NILE VIRUS
The emergence of WNV within the west, specifically
the USA, occurred in 1999 with a case clustering in
the New York city area, with 719 cases of suspected
disease reported to the New York health department
(Nash et al., 2001). A multistate epidemic followed in
2002 with 1157 cases (out of 4156 internationally)
reported to the CDC via Arbonet, a national surveil-
lence system used to follow WNV trends in the USA.
Fifty-four percent of these cases were confirmed cases
of WNV infection (O’Leary et al., 2006). By 2005,
WNV had made its appearance in California with
880 case reports, 305 of them exhibiting neuroinvasive
disease (Jean et al., 2007).
Tremor, myoclonus, and parkinsonism occurred at a
much higher prevalence than previously thought with
WNV infection. Prior to the 2002 epidemic, the typical
neurologic illness reported was either West Nile menin-
gitis or West Nile encephalitis. In a series of 59 hospi-
talized patients in the New York city area during the
1999 WNV epidemic, 63% of patients had encephalitis,
29% had meningitis without encephalitis, and 8% had
illness typified by fever and headache (Nash et al.,
2001). Although previous studies made mention of
West Nile-associated “Guillain–Barré-type” weakness,
it wasn’t until 2002 that the distinctive syndrome of
acute flaccid paralysis, as well as a high incidence of
movement disorders, was defined (Nash et al., 2001;
Tyler, 2004). In another series of patients from
St. Tammany parish, Louisiana, in 2002, 16 of 39
patients were seropositive for WNV infection. Of these
16 seropostiive patients, all (100%) exhibited tremors,
38% exhibited myoclonus, and 5% showed features
of Parkinson’s syndrome (bradykinesia, postural insta-
bility, rigidity) (Sejvar et al., 2003). Tremors were
described as “static” or kinetic, asymmetric involving
the upper extremities. No rest tremor was reported,
even in parkinsonism. A single patient with opsoclo-
nus-myoclonus and cerebellar ataxia as the presenting
symptoms was also reported (Khosla et al., 2005).
Neuroimaging correlates to movement disorders
seen with WNV infections are scant. CT scans of the
brain have not revealed abnormalities (Nash et al.,
2001; Sejvar et al., 2003). MRI of the brain occasion-
ally reveals nonacute abnormalities of the bilateral
basal ganglia, thalamus, and pons on T2 and diffusion-
weighted sequences (Jeha et al., 2003; Sejvar et al.,
2003). In a small percentage of those patients with severe
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330 E. CARROLL AND J. SANCHEZ-RAMOS
parkinsonism these imaging changes were still present at
8-month follow-up (Sejvar et al., 2003). Other case stud-
ies have shown involvement of the substantia nigra, spe-
cifically the pars compacta (Bosanko et al., 2003), similar
to other viral encephalitides such as St. Louis and Japa-
nese encephalitis.
Electroencephalograms (EEGs) in encephalitis can
show abnormalities such as focal sharp waves or diffuse
irregular slowing; however, there is no association
between EEG findings and myoclonus or tremor (Sejvar
et al., 2003).
Limited neuropathologic studies of encephalitis
show perivascular and meningeal inflammation with
neuronal loss, neuronophagia, microglial nodules, and
astrocyte proliferations, with the most severe pathol-
ogy within the basal ganglia, thalamus, and brainstem,
inclusive of the substantia nigra (Bosanko et al., 2003;
Jeha et al., 2003; Solomon et al., 2003b; Tyler, 2004).
Autopsy reports on 4 patients from the New York city
epidemic suggest WNV is more likely to affect the
brainstem (Nash et al., 2001).
The diagnosis of WNV is most sensitively assessed
by the presence of immunoglobulin M (IgM) antibody
in the CSF. More than 90% of patients will have anti-
bodies by day 8 of illness with false-negative results
within the first 72 hours (Tyler, 2004). Polymerase
chain reaction (PCR) is not as sensitive, with only
70% of IgM-positive patients with positive PCR
results. CSF findings are typical for aseptic meningitis
with elevated protein, normal glucose levels, and a
lymphocytic-predominant cell population, although
polymorphonuclear predominance can occur, especially
throughout the first week (Tyler, 2004).
Age remains an established predictor of mortality.
An age of 75 years or older was most strongly asso-
ciated with death (Nash et al., 2001). Of the 2942
neuroinvasive cases, 9% were fatal, with a clear
increase in mortality with an age > 70 years: 21% for
those patients > 70 years, 4% for 20–69 years and
1% for patients < 19 years (O’Leary et al., 2004).
Diabetes mellitus was also a risk factor in mortality
(Nash et al., 2001), with male sex and hypertension
possible risk factors for more severe disease (Jean
et al., 2007).
JAPANESE ENCEPHALITIS VIRUS
Endemic to Southeast Asia, India, and China, JEV
most commonly presents in the pediatric population
after mosquito inoculation. Emergence of JVE within
the western hemisphere became most apparent in
returning veterans from World War II who displayed
a high incidence of parkinsonism as a result of JEV
infection (Solomon and Vaughn, 2002). Hyperkinetic
movement disorders are uncommon (Solomon, 2004).
A series of 17 patients from India with a diagnosis of
JEV revealed 14 of the 17 patients with movement dis-
orders described as masking of the face, hypophonia,
and profound bradykinesia. Dystonia was seen in
8 patients, typically axial and fixed, in association with
bilateral lesions of the thalamus on CT imaging. MRI
in 3 of the patients showed lentiform nucleus involve-
ment bilaterally. These movement disorders were most
often seen in patients emerging from coma and tended
to regress with time (Misra and Kalita, 1997).
A 3-year prospective study evaluated 555 patients
with suspected JVE presenting to Hin Yu hospital in
Southern Vietnam; there were 296 pediatric (45%)
and 10 adult (4%) cases of JVE (Solomon et al.,
2002). Typical clinical features upon presentation were
fever, headache, and vomiting, followed by confusion,
coma, and seizure. Of the movement disorders
described, 27 patients had intermittent resting tremor,
12 had orofacial dyskinesias, 4 had choreoathetosis,
2 had mandibular dystonia, 1 had hiccups, and 1 had
opsoclonus myoclonus (Solomon et al., 2002).
Typical MRI findings may include abnormalities of
the bilateral thalamus showing a propensity for pete-
chial hemorrhages (Kumar et al., 1997). Involvement
of the midbrain, substantia nigra and, less commonly,
cerebellum and cortical areas have been reported
(Kumar et al., 1997; Kalita and Misra, 2000).
HERPES SIMPLEX ENCEPHALITIS
Herpes simplex is a member of the Herpesviridae, a
double-stranded DNA virus group. CNS infection with
herpes simplex virus (HSV) typically produces a
meningoencephalitis with notable predilection for tem-
poral and frontal lobes. Movement disorders are not a
typical feature of initial HSV infection but are present
frequently within clinical “relapses” of HSV. Post-HSV
“relapse” cases occur more often in pediatrics from
weeks to years after initial infection and completed
antiviral treatment. Movement disorders alone have
been reported in 25% of pediatric HSV relapses, with
choreoathetosis as the most common type of move-
ment disorder (Kullnat and Morse, 2008). In a series
of 42 HSV-infected pediatric patients, 6 experienced
relapses accompanied by varying degrees of neurologic
symptoms and signs after having completed a full
course of acyclovir. Within these 6 relapsed cases,
2 patients presented with bilateral choreoathetoid
movements within the first month after having com-
pleted acyclovir. Eventual clinical improvement was
noted (De Tiege et al., 2003, 2005). A recently reported
single case described a young child who had HSV
encephalitis followed by a relapse 2–3 weeks later,
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HYPERKINETIC MOVEMENT DISORDERS 331

presenting with severe generalized choreiform move- KURU
ments (Marschitz et al., 2007).
Kuru, a rare disease among the Fore people in Papa
Neuroimaging, specifically MRI and CT, studies
New Guinea, remains a scarce clinical entity since the
have failed to show abnormalities of the basal ganglia
decline in the ritual practice of cannabalism. A prion
during these relapses (De Tiege et al., 2003; Martino
disease acquired through consumption of deceased
and Giovannoni, 2004; Kullnat and Morse, 2008).
tribe members’ brain tissue, it affects less than 1%
A single case report described an 8-month-old infant
of the current population (Kompoliti et al., 1999). The
with relapse after HSV encephalitis presenting with
disease typically progresses through three stages with
four-extremity ballism and choreathetosis (Kullnat
progressive loss of ambulation and worsening of cere-
and Morse, 2008). Repeat CSF studies were negative.
bellar signs. The first stage is the ambulant phase typi-
However, MRI revealed signal abnormality in the
fied by an action/intention tremor which is the most
medial thalamus. This case report is one of the first
common manifestation; the name “kuru” is the Fore
to reveal abnormalities on MRI in a relapse HSV case
word for “shivering.” Other cerebellar symptoms of
(Kullnat and Morse, 2008).
ataxic gait, truncal instability, and titubations predomi-
Whether or not patients presenting with the above
nate early phases. Patients progress to the second stage
syndromes constitute reinfection/reactivation versus
once they are unable to walk. Severe tremor, as well as
autoimmune continues to be debated. In the case pre-
other movement disorders, predominates. Dystonia of
sented above of an 18-month-old infant who presented
the limbs, especially with superimposed athetosis of
with choreiform movements 2–3 weeks after infection,
distal extremities, can be seen. Myoclonic jerks, in
CSF analysis was repeated at clinical relapse . CSF
addition to myoclonic-type movements of the eyelids
fluid samples were HSV PCR/IgM-negative through-
with exaggerated startle responses, have also been
out the patient’s hospital course. In this case the inves-
documented. Personality changes with emotional labil-
tigators also tested the CSF for antibasal ganglia
ity and cognitive slowing emerge.
antibodies (ABGA). These antibodies have been found
Eventually patients enter the terminal stage where
to be specific and sensitive for postinfectious states,
they are unable to sit up without support and ataxia,
typically in cases of Syndenham’s chorea or postence-
dysarthria, and tremors have become severe. Extrapy-
phalitis lethargica syndromes (Martino and Giovan-
ramidal symptoms may be present as well. Choreiform
noni, 2004). Immunoblotting with ABGA was found
jerks are seen predominantly later, occasionally early
to be positive and steroids and plasmapharesis were
(Kompoliti et al., 1999). Kuru remains indistinguish-
initiated since acyclovir, neuroleptics, and antiepileptic
able from Creutzfeldt–Jakob disease (CJD) from the
drugs had been ineffective in stopping clinical progres-
molecular and cellular perspective and resembles idio-
sion. Retesting CSF after clinical improvement failed
pathic cases of CJD from human growth hormone
to demonstrate further positivity for ABGA, support-
(Kompoliti et al., 1999).
ing antigenic mimicry/autoimmune etiology (Marschitz
et al., 2007).
CREUTZFELDT^JAKOB DISEASE
In the prion disease of Creutzfeldt–Jakob, movement
PRION DISEASES
disorders remain a typical clinical feature (90%) and
Prion diseases, also known as transmissible spongiform part of the diagnostic criteria for all three types of
encephalopathies (TSE), are a family of rare progres- CJD (familial, sporadic, and variant), with a propensity
sive neurodegenerative diseases that affect both for the development of these disorders as the disease
humans and animals. Pathophysiological characteristics progresses (Maltete et al., 2006). Both pyramidal and
of these diseases include long incubation periods extrapyramidal-type movement disorders have been
between infection and disease manifestations, vacuolar reported with all types of CJD. Types of movement
“spongiform” changes associated with neuronal loss, disorders include myoclonus, dystonia, choreoatheto-
and failure to elicit an inflammatory response (CDC, sis, tremor, hemiballism, and parkinsonism syndromes.
2008). The causative agent of TSE is an abnormal A higher frequency of hyperkinetic movement disor-
prion, a nonnucleic acid-containing, transmissible ders are present in variant CJD, and were seen with
agent that induces abnormal folding of normal cellular the emergence of variant CJD as a separate entity. In
prion proteins in the brain, leading to brain damage 2002, the World Health Organization (WHO) added
and characteristic signs and symptoms of the disease. choreathetosis and dystonia to the revised case criteria
Prion diseases are typically rapidly progressive once for variant CJD (WHO, 2002). These two movement
the neurologic manifestations appear and are always disorders occur more often together as well as later
fatal. in disease progression (Maltete et al., 2006).
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332 E. CARROLL AND J. SANCHEZ-RAMOS
The typical clinical features of familial and sporadic
CJD include progressive dementia, startle myoclonus,
ataxia, visual disturbances, extrapyramidal and pyrami-
dal disturbances, as well as dyskinetic mutism (Maltete
et al., 2006). Myoclonus, the most frequent hyperki-
netic movement disorder, is present in 82–100% of
patients with CJD, regardless of the subtype. Jerks
can be focal or generalized but are typically diffuse,
rhythmic, and provoked by stimulation (such as noise
and touch). They can occur during sleep and have asso-
ciated period sharp-wave EEG activity. They also may
be associated with athetoid movements of the fingers
(Maltete et al., 2006).
Dystonia and choreoathetosis occur with increasing
frequency with disease progression (Will et al., 2000).
Dystonia otherwise has rarely been reported in late
cases of familial and sporadic CJD. The dystonia can
be focal, segmental, or generalized, with the latter typ-
ically an evolution of previous focal dystonia that has
worsened. It is also more common for the dystonia to
be present concomitantly with focal jerk myoclonus,
choreotathetoid movements, postural tremor, alien
limb, or bradykinesia (Maltete et al., 2006).
Extrapyramidal syndromes typify terminal stages of
sporadic CJD or variant CJD; however atypical parkin-
sonian symptoms may be an early presentation.
Autopsy cases have reported CJD pathology in patients
with clinical histories of Parkinson’s disease, corticoba-
sal degeneration with alien limb syndrome, as well as
in supranuclear palsy (Maltete et al., 2006).
Seizures are a rare manifestation of CJD (0.4% at
presentation, 8–25% prevalence) and can be partial or
generalized. If present, seizures will manifest late in
disease course. They remain difficult to treat with resis-
tance to antiepileptic drug therapy (Maltete et al., 2006).
Neuroimaging abnormalities within the basal ganglia
occur commonly across variant, familial, and sporadic
CJD. Familial CJD shows fluid-attenuated inversion
recovery (FLAIR) MRI changes in the caudate and
putamen with an 87% sensitivity and 91% specificity.
DWI abnormalities in the caudate nucleus showed a
sensitivity of 73% and a specificity of 100% (Fulbright
et al., 2008). Variant CJD has classic hyperintensity
involving the pulvinar nucleus, especially when com-
pared to the anterior putamen. The classic “pulvinar
sign” can be seen on MRI T2/FLAIR imaging as hyper-
intensity of the pulvinar nucleus, specifically when
compared to the anterior putamen. Changes of the dor-
somedial nucleus of the thalamus are also considered
highly sensitive (Will et al., 1996; Collie et al., 2003).
MRI is considered by some experts to be more specific
and sensitive for clinical diagnosis of variant CJD than
CSF and EEG findings. FLAIR MRI and DW MRI
may also reveal high-intensity signals in the cortical
mantle in cases of sporadic CJD (“cortical ribbon” sign)
(Zeidler and Green, 2004; Nitrini et al., 2005).
ACKNOWLEDGMENT
This study was supported by the Helen Ellis Endow-
ment to JSR.
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ABSTRACT
Viral infections of the central nervous system often result in a spectrum of movement disorders, ranging from
slowness and rigidity to hyperkinetic movements such as chorea, ballism, dystonia, and myoclonus. The basal gang-
lia are especially susceptible to some viruses, because of their intrinsic neurotropism, a predilection of opportunis-
tic infections for the deep gray matter of the brain, and possibly the mounting of an autoimmune response against
basal ganglia antigens. Viral encephalitides reviewed here include those caused by the human immunodeficiency
virus, influenza A virus, the Flavivirus family (such as West Nile virus, Japanese encephalitis virus), and herpes
simplex. Hyperkinetic movement disorders associated with prion diseases will also be discussed. The clinical
features, etiology, pathogenesis, diagnosis, and treatment of the underlying infections and ensuing movement
disorders will be reviewed.
Comp. by: GVasenthan Stage: Proof Chapter No.: 25 Title Name: HCN_Weiner_Tolosa
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