Movement Disorders and AIDS: a Review

Home , Chorea, Movement disorder, Paraplegia

Parkinsonism and Related Disorders 10 (2004) 323–334 www.elsevier.com/locate/parkreldis Review Movement disorders and AIDS: a review

Winona Tsea,*, Maria G. Cersosimob, Jean-Michel Graciesa, Susan Morgelloc, C. Warren Olanowa, William Kollera

aDepartment of Neurology, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1052, New York, NY 10029, USA bDepartment of Neurology, University of Buenos Aires, Buenos Aires, Argentina cDepartment of Pathology, Mount Sinai Medical Center, New York, NY, USA

Abstract Movement disorders are a potential neurologic complication of acquired immune deﬁciency syndrome (AIDS), and may sometimes represent the initial manifestation of HIV infection. Dopaminergic dysfunction and the predilection of HIV infection to affect subcortical structures are thought to underlie the development of movement disorders such as parkinsonism in AIDS patients. In this review, we will discuss the clinical presentations, etiology and treatment of the various AIDS-related hypokinetic and hyperkinetic movement disorders, such as parkinsonism, chorea, myoclonus and dystonia. This review will also summarize current concepts regarding the pathophysiology of parkinsonism in HIV infection. q 2004 Elsevier Ltd. All rights reserved.

Keywords: Parkinsonism; AIDS; Human immunodeﬁciency virus; Movement disorders; Dopamine; Chorea

Contents 1. Introduction...... 324 2. Tremor ...... 324 2.1. Epidemiology of tremor...... 324 2.2. Clinical features and etiology of tremor ...... 324 2.3. Treatment of tremor ...... 326 3. Parkinsonism ...... 326 3.1. Epidemiology of parkinsonism...... 326 3.2. Clinical features of parkinsonism ...... 326 3.3. Parkinsonism and HIV infection...... 326 3.4. Parkinsonism and HIV-associated dementia ...... 326 3.5. Parkinsonism in AIDS patients with opportunistic infections ...... 327 3.6. Drug-induced parkinsonism and AIDS ...... 327 3.7. Pathophysiology and neuropathology of parkinsonism...... 327 3.8. Treatment of parkinsonism...... 328 4. Chorea and ballism ...... 328 4.1. Epidemiology of chorea/ballism ...... 328 4.2. Clinical features of chorea/ballism ...... 329 4.3. Etiology of chorea/ballism ...... 329 4.4. Pathophysiology of chorea/ballism ...... 329 4.5. Treatment of chorea/ballism...... 329 5. Myoclonus...... 330 5.1. Epidemiology of myoclonus...... 330 5.2. Clinical features and etiology of myoclonus ...... 330 5.3. Pathophysiology of myoclonus...... 330 5.4. Treatment of myoclonus ...... 331 6. Dystonia ...... 331 6.1. Epidemiology of dystonia ...... 331

* Corresponding author. Tel.: þ1-212-241-6960; fax: þ1-212-987-7363. E-mail address: [email protected] (W. Tse).

6.2. Clinical features and etiology of dystonia ...... 331 6.3. Pathophysiology of dystonia ...... 331 6.4. Treatment of dystonia ...... 331 6.5. Paroxysmal dyskinesias ...... 332 7. Conclusion ...... 332 References ...... 332

1. Introduction 2. Tremor

Neurologic disorders are a well-known complication of 2.1. Epidemiology of tremor human immunodeficiency virus (HIV) infection [1]. Movement disorders are increasingly recognized as a The reported incidence of tremor in AIDS patients has potential complication of acquired immune deficiency ranged from 5.5 to 44% of patients with HAD [9]. As HAD syndrome (AIDS) and may sometimes represent the initial is a late-stage manifestation of HIV infection, this may manifestation of HIV infection [2]. A 2–3% incidence of suggest an increased incidence of tremor with increasing movement disorders has been reported in various HIV- immunosuppression [13]. infected populations studied retrospectively at tertiary referral centers [3]. However, when carefully evaluated in 2.2. Clinical features and etiology of tremor prospective studies, the incidence of movement disorders, and particularly parkinsonism, in AIDS patients appears to Tremor in AIDS patients may be seen as part of a be higher than previously appreciated. Prospective studies parkinsonian (Table 1) syndrome or may occur as an have shown evidence of basal ganglia dysfunction, isolated phenomena. The tremor is often symmetrical and particularly tremor and parkinsonism, in 5–44% of may occur at rest, but more typically occurs as a mild patients [4]. bilateral postural tremor. Rarely patients may also display In this review, we will discuss the different an additional kinetic component [14]. hyperkinetic and hypokinetic movement disorders seen Tremor is often seen as one of the neurologic in the setting of HIV infection, including hemichorea– manifestations of HAD in both early and late stages of the hemiballism [5], myoclonus [6], dystonia [7], parkinson- illness. In the early stages of HIV infection, tremor may ism [8], tremor [9], and paroxysmal dyskinesias [10]. occur in the absence of clinically detectable central nervous We will also review movement disorders seen in system (CNS) deficit, and may precede the appearance of association with HIV-associated dementia (HAD), dementia by weeks to months [15]. AIDS-related opportunistic infections or due to Holmes tremor (also known as rubral or midbrain tremor) medications. has been reported in AIDS patients, comprising a tremor Motor dysfunction in the form of generalized slowness with rest, postural and kinetic components [14]. Holmes of movements seen in the setting of global cognitive and tremor may occur as a result of opportunistic lesions in the behavioral abnormalities has been termed the AIDS midbrain such as tuberculosis or toxoplasmosis, and may dementia complex (ADC) [11]. In this syndrome, also present with other focal neurologic signs suggesting a cognitive symptoms mimicking a subcortical dementia midbrain localization, such as opthalmoplegia and contral- usually precede motor symptoms, which most often ateral hemiparesis [3,16]. include a slowing of rapid movements of the eyes and Drug-induced tremor may be observed as part of an limbs. Other terms have been used to refer to this extrapyramidal syndrome seen in AIDS patients exposed constellation of motor and cognitive abnormalities, to dopamine receptor antagonists such as neuroleptics or including HAD, HIV encephalopathy and in milder anti-emetics. An unusual complication of trimethoprim- forms, HIV associated minor cognitive/motor disorder sulfamethoxazole (TMP/SMX) therapy in AIDS patients [11]. For the purposes of this review, we will heretofore for pneumocystis carinii pneumonia (PCP) is tremor, refer to this complex of dementia and motor dysfunction manifesting either as a rest tremor, or as a bilateral, high- in HIV patients as HAD. It should be noted that HAD is frequency, low amplitude postural tremor with a kinetic distinct from HIV encephalitis, which is a neuropatholo- component [17]. The postulated mechanism of tremor gic diagnosis rendered when there is histologic evidence production with TMP/SMX treatment is reduction of of HIV-induced inflammatory lesions in the brain. catecholamine neurotransmission through inhibition of the Approximately 50% of those individuals dying from enzyme dihydrofolate reductase (DHFR), which catalyzes HAD will have HIV encephalitis [12]. the production of tetrahydrobiopterin [18]. It has been Table 1 Hyperkinetic movement disorders in AIDS

Hyperkinetic movement disorders Common? Etiology Comments

Tremor Yes (1) HIV infection Tremor in AIDS patients may be seen as part of a parkinsonian syndrome or (2) HAD may occur as an isolated phenomena. Tremor is often symmetrical and (3) Tuberculosis—One patient with Holmes’ tremor (also called rubral or typically occurs as a mild bilateral postural tremor. Rarely patients may midbrain tremor) was described in association with tuberculosis lesions in display an additional kinetic component. Tremor in patients with HAD may the midbrain and cerebellum be seen in all stages of the illness (4) Drug-induced—A rest, postural or kinetic tremor may be seen in patients taking trimethoprim/sulfamethoxazole (TMP/SMX) or as part of an extrapyramidal syndrome seen in AIDS patients exposed to dopamine

receptor antagonists 323–334 (2004) 10 Disorders Related and Parkinsonism / al. et Tse W.

Chorea–Ballism Yes (1) Subthalamic toxoplasmosis abscess Subthalamic toxoplasmosis abscess is the most common cause of (2) HIV encephalitis hemichorea-hemiballism in AIDS patients. Some authors suggest that (3) HAD—has been described in association with generalized chorea hemichorea-hemiballism in AIDS patients is virtually pathognomonic of (4) Cryptococcus cerebral toxoplasmosis (5) Progressive multifocal leukoencephalopathy (PML)—has been reported in association with focal chorea in one patient (6) Drug-induced—one case of focal chorea described after treatment with dopamine and noradrenaline for hypovolemic shock

Dystonia No (1) Basal ganglia toxoplasmosis–hemidystonia has been reported in Patients with HAD appear to have an increased susceptibility to developing association with contralateral toxoplamosis lesions dystonia when treated with dopamine receptor antagonists (2) HAD (3) Drug-induced—due to dopamine receptor antagonists (4) Bilateral putaminal lesions of unclear etiology—has been described in one patient with generalized dystonia, and left frontal lobe lesion of unclear etiology—has been described in one patient with acute paroxysmal dystonia

Myoclonus No (1) HIV infection Spinal myoclonus has been described as an unusual and early manifestation (2) HAD—has been described in association with generalized myoclonus of HIV infection (3) Toxoplasmosis—has been described in association with generalized myoclonus (4) Mycobacterium tuberculosis—has been described in association with spinal myoclonus (5) Herpes zoster radiculitis—has been described in association with segmental myoclonus (6) Progressive multifocal leukoencephalopathy—has been reported in one patient with diffuse cortical and subcortical lesions presenting with progressive myoclonic ataxia

Paroxysmal dyskinesias No (1) Lesion in left frontal region of unknown etiology—has been reported in Patients with both paroxysmal kinesigenic and nonkinesigenic dyskinesias association with paroxysmal non-kinesigenic dystonia have been reported. Patients with paroxysmal kinesigenic dyskinesias (2) HAD improved with benzodiazepines while only one patient with paroxysmal nonkinesigenic dyskinesias improved with benzodiazepines 325 326 W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 suggested that TMP/SMX-induced tremor may be respon- Parkinsonian features may develop due to HIV infection, sive to a reduction in dosage [19,20]. HAD, or due to underlying opportunistic infections such as Finally, in a study done prior to the use of highly active cerebral toxoplasmosis (Table 2). A drug-induced extra- antiretroviral therapy (HAART), abnormal motor function pyramidal syndrome has also been reported. Further clinical in AIDS patients, including the presence of tremor, was an features will be described under specific etiologies below. indicator of underlying prognosis. Patients with HAD and early detectable motor impairment died within a 2-year 3.3. Parkinsonism and HIV infection period of cerebral AIDS manifestations, including HIV encephalitis and other opportunistic infections. In contrast, Isolated parkinsonian features are common in HIV- patients with normal motor performance only showed a infected patients. Mirsattari described five HIV-infected slight deterioration over a 2-year period accompanied by patients who developed parkinsonism in the absence of decreasing T-helper cell counts. It was hypothesized that opportunistic infections, thus implicating HIV infection as sensitive motor tests could serve as predictors for cerebral the cause of parkinsonism [4]. Hersh et al. describe one disease progression [15]. HIV-infected patient who presented initially with atypical parkinsonism with lack of rest tremor, early bilateral signs 2.3. Treatment of tremor on exam as well as early balance impairment. The parkinsonism improved initially with carbidopa/levodopa Treatment of isolated tremor accompanying HIV infec- treatment and finally resolved on HAART [22]. tion has not been well studied. Evaluation of tremor should involve recognition of possible opportunistic infections and 3.4. Parkinsonism and HIV-associated dementia treatment of any underlying conditions. Drugs which may cause tremor should also be evaluated. De Mattos et al. HAD consists of a constellation of impairment in described one patient with Holmes’ tremor associated with cognitive, motor and behavioral functions. AIDS patients tuberculomas in the midbrain and cerebellum in which the who develop parkinsonism in the absence of opportunistic mass lesions and tremor resolved with treatment of the infections often suffer from HAD [23,24]. Navia et al. noted tuberculosis [21]. that motor symptoms are present early in nearly one-half of patients with HAD, and deterioration in handwriting, reflecting either a loss of motor coordination or tremor, was 3. Parkinsonism seen in six of 44 patients. Tremor may be seen throughout all stages of illness [13]. Parkinsonian features are common 3.1. Epidemiology of parkinsonism manifestations of HAD, including bradykinesia, rigidity, hypomimetic facies, postural instability and hypophonia Mirsattari et al. found a 5% incidence of parkinsonism in [25,26,27]. In Navia et al.’s series of 70 patients with HAD, a 115 HIV-infected patients who fulfilled United Kingdom rapid postural tremor was prominent in seven patients [13]. Parkinson’s Disease Brain Bank (UKPDBB) criteria for the The cognitive disturbances characteristic of HAD are diagnosis of parkinsonism, as well as an additional 10 consistent with a subcortical dementia, which may also be patients with parkinsonian features who did not meet the seen in advanced Parkinson’s disease. This may include a UKPDBB criteria [4]. One prospective study found that slowing of thought, forgetfulness, apathy and poor sequen- 50% of HIV inpatients with movement disorders had tial processing [28,29]. features of parkinsonism. The same study found a similar Even in the early stages of HIV infection in which there mean time of five months between HIV diagnosis and the is no clinically evident CNS deficit, sensitive motor tests onset of parkinsonism, and between parkinsonism and may detect subtle impairments of motor function, i.e. death, suggesting that parkinsonism represents a poor slowing of rapid alternating finger movements, and presence prognostic sign in AIDS patients [15]. Mirsattari et al. of postural tremor, which precede structural alterations seen found that all HIV positive patients who presented with on neuroimaging [26]. Motor performance deficits in early parkinsonism had severe immunosuppression as evidenced HIV disease as detected by electrophysiologic testing by a mean CD4 cell count of 14 cells/mm3 (range 0–40) at undergo rapid deterioration in the presence of HAD [30]. the time of diagnosis [4]. These deficits may precede dementia and radiological abnormalities up to several years [15]. 3.2. Clinical features of parkinsonism With progression of HAD, there is also a progression of the motor and behavioral symptomatology. Early in the The parkinsonism seen in AIDS patients is often illness, forgetfulness, loss of concentration and behavioral atypical in presentation, with symmetrical signs of changes are common, and motor symptoms include bradykinesia and rigidity, frequent lack of rest tremor, progressive loss of balance and deterioration in handwriting. and early presentation of postural instability and gait In late stages, many patients develop global cognitive difficulty [2]. dysfunction accompanied by psychomotor retardation, and W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 327

may exhibit ataxia, hypertonus, weakness and spontaneous tremor or myoclonus [13].

3.5. Parkinsonism in AIDS patients with opportunistic infections

Parkinsonism in AIDS patients has been well described as a rare presentation of an underlying opportunistic infection. Patients with bilateral basal ganglia toxoplasmosis lesions have been reported as presenting with parkinsonian features. Sometimes these patients will manifest with other focal neurologic features which reflect the underlying lesions, or may exhibit other neurologic findings reflecting concomitant HIV-related involvement of other parts of the CNS [8,31]. Parkinsonism has also been reported in small case reports in association with progressive multifocal leukoencephalopathy [32], CNS tuberculosis [33],and Whipple’s disease [2].

3.6. Drug-induced parkinsonism and AIDS

with symmetric bradykinesia and rigidity, frequentearly lack of presentation a of rest postural tremor and instability and gait difﬁculty Exposure to dopamine receptor antagonist medications, such as neuroleptics and anti-emetics is a common cause of drug-induced parkinsonism in AIDS patients. In fact, AIDS patients are particularly susceptible to developing extrapyramidal side effects from these medications. Hriso et al. reported that AIDS patients treated with neuroleptics were 2.4 times as likely to develop an extrapyramidal syndrome as psychotic patients without AIDS, and were 3.4 times as likely to develop an extrapyramidal syndrome when treated with haloperidol [34]. Severe drug-induced parkinsonism has been described in AIDS patients even when given low- potency neuroleptics such as prochlorperazine and low doses of anti-emetics such as metoclopramide [35,36]. Some authors hypothesize that this increased susceptibility is due to direct infection of the basal ganglia by HIV [37,38] or may be the result of an underlying preexistent subclinical nigral degeneration [4]. Potential drug interactions involving anti-HIV medications may also predispose patients to develop parkinsonism. Protease inhibitor medications have been reported to produce parkinsonian symptoms in one patient through an (2) HAD—many of the motor(3) features Due resemble to parkinsonian underlying signs opportunisticCNS infections—i.e. toxoplasmosis, in PML, association CNS with tuberculosis,(4) Whipple’s Drug-induced—AIDS disease patients may bedeveloping particularly extrapyramidal susceptible side to effects frommedications dopamine receptor antagonist interaction of ritonavir and buspirone [39]. Indinavir has also been reported to potentiate the effect of levodopa in a patient with parkinsonism [40]. Antiprotease medications are known to inhibit the hepatic metabolism of several drugs by inhibition of cytochrome P450, which catalyzes oxidative reactions produced by monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). It was hypothesized that the enhanced effect of levodopa in this patient may be secondary to this effect.

3.7. Pathophysiology and neuropathology of parkinsonism

There is substantial evidence from neuroradiologic and

Table 2 Hypokinetic movement disorders in AIDS Hypokinetic movement disorders Common?Parkinsonism Etiology Yes (1) HIV infectionpathological studies Comments supporting dysfunction The parkinsonism seen in AIDS patients is often atypical in presentation, of the basal 328 W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 ganglia in HIV infection. Neuroimaging studies have neurons to the gp120 protein reduced the ability of the demonstrated selective basal ganglia atrophy in patients neurons to transport dopamine [50] and this effect was who develop HAD [41]. Progressive caudate atrophy has blocked by NMDA receptor antagonists (MK-801) [51]. been significantly correlated with the presence of HAD [42]. Functional imaging studies have demonstrated dysfunc- 3.8. Treatment of parkinsonism tion of basal ganglia metabolism in HIV-infected patients. Positron emission tomography (PET) studies have shown In patients with parkinsonism, management should focus relative hypermetabolism in the basal ganglia and thalamus on evaluation for potential underlying opportunistic infec- in the early stages of HIV dementia, with global cerebral tions and a careful review of the patient’s medications for hypometabolism noted in more advanced stages [43]. potential extrapyramidal side effects. Treatment of any Cerebrospinal fluid (CSF) neurotransmitter studies have underlying infection is essential to controlling the move- shown evidence of dopaminergic dysfunction in HIV ment disorder. There are no reported series of adult patients infection. Dopaminergic neuron dysfunction appears to treated with levodopa to draw any firm conclusions occur early in the course of HIV infection, with an apparent regarding its efficacy in the treatment of parkinsonism in correlation between low CSF dopamine levels and declining HIV, although one case report describes an adult patient immune function as reflected by CD4 lymphocyte counts. It having a good response [40]. Levodopa has been reported to was suggested that reduction of CSF dopamine levels may be effective in improving motor function in a series of five antecede CNS dysfunction, with a greater reduction of CSF HIV-infected pediatric patients with parkinsonian symp- dopamine levels seen in AIDS patients with symptomatic toms secondary to HAD [52]. However, there has been neurologic disease compared to asymptomatic patients [44]. concern raised about the potential of dopamine to accelerate Reduced caudate nucleus concentrations of dopamine and HIV infection and induce brain pathology in AIDS patients. homovanillic acid (HVA) in AIDS patients compared to Administration of selegiline and levodopa to monkeys with controls have been demonstrated [45]. early simian immunodeficiency virus infection (SIV, a Neuropathologic studies have shown preferential invol- monkey model of HIV infection) accelerated the onset of vement of subcortical areas in HIV infection and involve- neuropathologic changes, including CNS vacuolization and ment of the basal ganglia is well documented. SIV encephalitic lesions [53]. Dopamine has also been Approximately 50% of patients with HAD demonstrate a found to activate HIV protein expression in HIV-treated microglial nodule encephalitis with multinucleated giant T lymphoblasts [54]. cells, with prominent involvement of the putamen and HAART has been shown to be effective in the reduction caudate nuclei [12]. Other opportunistic disorders in HIV of neurologic complications of HIV infection [55], and may also demonstrate a predilection for the basal ganglia, shows potential as a treatment for parkinsonism in the such as toxoplasmosis, lymphoma and cryptococcus. The setting of HAD. HAART has been shown to improve the substantia nigra may also be affected in HIV. Reyes et al. electrophysiological parameters of motor impairment in showed nigral degeneration with neuronal loss, extracellular HIV infection, as demonstrated by significantly longer melanin and reactive astrocytosis in clinically asympto- latencies to the development of pathologically prolonged matic AIDS patients [46]. Morphometric analysis of contraction times [15,28,56]. One AIDS patient has been neurons in the substantia nigra pars compacta showed a reported in which parkinsonism resolved on HAART alone significant reduction in numerical density of total neurons as with normalization of CD4 count [22]. well as of pigmented neurons, although the pattern of Clozapine has been studied in six patients in an open, neuronal loss was different from that of both PD and normal rising dose study as a treatment for HIV patients with aging in that the density of non-pigmented small neurons psychosis and neuroleptic-induced parkinsonism. Patients was reduced in HIV patients. It has been suggested that the were withdrawn from their neuroleptic medications at least nigral degeneration seen in AIDS patients may explain the seven days prior to being placed on clozapine. A significant increased susceptibility to drug-induced parkinsonism [47]. reduction in psychosis as well as parkinsonism (as measured Several mechanisms have been proposed to explain the by the UPDRS motor subsection) was noted, although it was genesis of neurologic abnormalities in HIV infection. One unclear whether parkinsonian signs were decreased by the hypothesis is that infection of monocytoid cells (macro- action of clozapine, withdrawal of neuroleptic drugs or both phages, microglia or monocytes) by HIV stimulates the actions [57]. production of potential neurotoxins. These toxins include HIV proteins (i.e. gp120, tat) [27,48], and other substances produced by macrophages, including but not limited to 4. Chorea and ballism glutamate, cytokines, nitric oxide, and quinolinic acid [45]. The HIV-1 envelope glycoprotein gp120 and the HIV-1 4.1. Epidemiology of chorea/ballism nuclear protein tat have been shown to be associated with neuronal injury in tissue culture experiments [49].In Choreoathetosis in AIDS was first reported by Navia and animals infected with HIV, exposure of dopaminergic coworkers in 1986 [58], the same year Martinez-Martin et al. W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 329 described another HIV patient who presented with hemi- hemichorea–hemiballism in AIDS patients is virtually chorea–hemiballism [59]. One year later Nath and cow- pathognomonic of cerebral toxoplasmosis [58]. However, orkers described three other cases [2]. Since then, a growing the presence of hemichorea–hemiballism in patients with number of patients with HIV-related choreoathetosis and cerebral toxoplasmosis is not common, occurring in only ballism have been reported. 7.4% of cases, which is surprisingly low considering that The exact frequency of these disorders is not clearly pathological studies have shown that in 50% of cases established. While some studies have reported hemichorea– toxoplasma abscesses occur in the basal ganglia. The reason hemiballism as the most common movement disorder in for this large discrepancy remains unclear [58,64,70]. HIV positive patients [60–62], other reports describe them Interestingly, movement disorders have not been described as the second most frequent movement disorder after in patients with cerebral toxoplasmosis without HIV parkinsonism [3,21]. Interestingly, hemichorea–hemibal- infection [67]. However, it should be emphasized that lismus is one of the rarest of all movement disorders in acquired cerebral toxoplasmosis was exceptional before the patients without HIV infection [63]. AIDS era. Cases of AIDS-related toxoplasmosis are now relatively numerous and the probability of observing move- 4.2. Clinical features of chorea/ballism ment disorders has considerably increased [73]. Generalized chorea may be the result of bilateral The clinical picture of AIDS related hemichorea– toxoplasmosis abscesses but may also be associated with hemiballismus does not differ from that in patients without HAD [65,68,69]. More rarely, other etiologies have been HIV infection. The hyperkinetic movements may affect described, including cryptococcus [61], progressive multi- proximal and/or distal muscles of the extremities and range focal leukoencephalopathy and iatrogenic [62]. from ballistic to choreic or choreoathetotic movements. In Piccolo et al.’s series of 51 sporadic cases of chorea, Hemichorea-hemiballism and even generalized chorea may 5/51 patients had chorea in association with AIDS. Two be the initial presenting symptom of AIDS. [64–66]. patients had chorea secondary to toxoplasmosis, with one The involuntary movements typically compromise only having a toxoplasma abscess in the contralateral STN and one side of the body and the clinical onset is usually acute or one having basal ganglia toxoplasmosis. One patient had subacute [21,59,64,67]. In contrast, generalized chorea is generalized chorea and HIV encephalitis, one had focal rare in AIDS patients. Gallo et al. reported one case of chorea after dopamine treatment for meningoencephalitis bilateral choreic and ballistic movements associated with and one patient had focal chorea secondary to PML. Piccolo HIV encephalitis [68]. Pardo and coworkers reported a et al. concluded that AIDS-related disease should be second case of generalized chorea in a patient with HIV considered in young patients presenting with chorea without encephalitis and neuropsychological symptoms consistent a family history of movement disorders [74]. with HAD [65]. Bilateral chorea has also been reported in one patient with bilateral toxoplasma abscesses who was not 4.4. Pathophysiology of chorea/ballism examined with neuroimaging or autopsy [69]. Facial chorea is extremely uncommon in AIDS patients. Lee and Marsden in a review of movement disorders Nath et al. published a case with involuntary facial arising from lesions of the thalamus and subthalamus movements preceding the appearance of hemichorea– conclude that ballism or chorea were convincingly associ- hemiballism secondary to cerebral toxoplasmosis [67]. ated with damage to the subthalamic nucleus or its efferent Another AIDS patient presented with bucco-lingual and pathways, which removes excitation of the globus pallidus, masticatory dyskinesias, in which the facial movements thus disinhibiting the ventrolateral and ventroanterior were assumed to be iatrogenic due to noradrenaline and thalamic nuclei receiving pallidal projections [75]. The dopamine used for the treatment of hypovolemic shock [62]. pathogenesis of chorea–ballism in HIV-related opportunistic lesions appears to be due to the same mechanisms of 4.3. Etiology of chorea/ballism chorea generation due to other destructive lesions of the subthalamus. Most cases of AIDS-related hemichorea–hemiballismus are associated with lesions affecting the contralateral 4.5. Treatment of chorea/ballism subthalamic nucleus or striatum [2,62,67,70] (Table 1). The majority of cases of chorea-ballism in AIDS reported The management of patients with HIV-related hemi- multiple cerebral lesions rather than a single one. The chorea–hemiballism includes the diagnosis and treatment cerebral structures more commonly affected are the sub- of opportunistic infections, the symptomatic treatment of thalamic nucleus, thalamus, head of the caudate, putamen, the movement disorder and the use of HAART [14].In globus pallidus, midbrain and internal capsule [64,71,72]. some cases, antitoxoplasmosis therapy consisting of A subthalamic toxoplasmic abscess is the most sulfadiazine and pyrimethamine was followed by a marked common cause of hemichorea-hemiballism in AIDS patients improvement or even resolution of the involuntary move- [2,58,70]. Some authors suggest that the appearance of ments [62,64,70], although other authors found that clinical 330 W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 response to antitoxoplasmosis therapy was poor, with little thought that the myoclonus was likely due to dorsal herpes or no improvement of the movement disorder [58,72]. Nath zoster. Two cases of generalized myoclonus were also and coworkers suggested that the underlying HIV infection reported, one due to toxoplasmosis and one due to HAD may play a role in the persistence of the movement [21]. In another series of 1086 AIDS patients, de Mattos disorder despite abscess resolution after antitoxoplasmosis et al. described one patient who presented with a progressive therapy [67]. tuberculous radiculomyelopathy and myoclonic jerks in the Symptomatic control of the hyperkinetic movements is lower limbs, which were presumed to be spinal in origin sometimes necessary. Chorea may respond to antidopami- since it was seen only in the lower limbs and EEG was nergic agents such as dopamine receptor blockers, and normal [3]. presynaptic dopamine depletors like tetrabenazine [68,76] One patient presented with arm and shoulder segmental Occasional cases may be resistant to pharmacological myoclonus preceding the onset of herpes zoster radiculitis, treatments [67]. In generalized chorea associated with which remitted promptly with antiviral treatment [78]. HIV encephalitis, treatment with antiretroviral and anti- Thomas and Borg reported a patient with segmental dopaminergic drugs has been reported by Gallo et al. as myoclonus associated with triphasic waves on EEG, both unsuccessful in controlling the movements [68]. However, of which resolved with zidovudine therapy [79]. Pardo et al. have reported one patient with bilateral chorea Progressive myoclonic ataxia has been described as the associated with HIV dementia complex who had an presenting symptom in an AIDS patient. MRI showed excellent response to antiretroviral therapy [65]. bilateral, symmetrical lesions in the red nucleus, subthalamus, thalamus, lenticular nuclei, and primary motor cortex which were confirmed neuropathologically to be those of 5. Myoclonus progressive multifocal leukoencephalopathy [80].

5.1. Epidemiology of myoclonus 5.3. Pathophysiology of myoclonus

Myoclonus is a rarely reported movement disorder in In a series of cases of generalized myoclonus seen with AIDS patients (Table 1). Both segmental and generalized HAD, the myoclonus was physiologically associated with myoclonus have been described in AIDS patients. In de predominantly subcortical mechanisms. All patients had Mattos et al.’s series of 2460 HIV positive inpatients, four prominent subcortical symptoms, and one patient had patients had myoclonus, two with spinal myoclonus and two pathological confirmation of brainstem and bilateral nucleus with generalized myoclonus [21]. reticularis gigantocellularis and nucleus reticularis pontis caudalis involvement [81]. However, inferences about 5.2. Clinical features and etiology of myoclonus anatomical localization were limited by the diffuse nature of the pathologic condition. EEG showed inconsistent Nath et al. described two patients with segmental evoked response or absent cortical paroxysmal activity. myoclonus associated with a variety of other movement Maher et al. suggest that the generalized myoclonus seen in disorders and neurologic abnormalities [2].Noclear their series of three patients may have been subcortical in correlation was observed between the clinical signs and origin, as a sudden auditory stimulus evoked generalized lesions observed on brain imaging studies. Myoclonus was myoclonus in two patients, suggesting a brainstem origin the first manifestation of HIV infection in one patient and involving the auditory-induced startle response pathway [6, occurred 17 months before AIDS was documented. Lubetzki 82]. The possibility of cortically induced myoclonus is not et al. described a single case of axial myoclonus causing excluded, as patients with HIV infection and myoclonic flexion of the neck, trunk and lower extremities, in which no epilepsy have been reported [79]. structural lesions were found. In this patient, the myoclonus The mechanism of spinal myoclonus is unknown. was an early manifestation of CNS HIV infection [77]. Experimental, clinical and pathologic evidence support Three cases of generalized myoclonus reported by Maher Bradshaw’s theory of intercalated neurons within the et al. were associated with HAD. One patient had a cerebral posterior horn. Increased gamma motor neuron activity toxoplasmosis abscess. The myoclonus was elicited by has also been proposed but anterior horn cells are unlikely to sudden auditory stimuli, resembling a startle response, and be involved in isolation, since some patients have was a late feature of the disease, occurring and persisting myoclonus without paralysis and others have myoclonus several months before death. The appearance of myoclonic affected by sensory stimuli [83,84]. Koppel and Daras dementia had a poor prognosis, leading to death within three hypothesize in their patient with segmental myoclonus months after the onset of myoclonus [6]. preceding herpes zoster radiculitis a localized viral myelitis In their series of 2460 HIV positive inpatients de involved intercalated neurons and sensory pathways con- Mattos et al. reported two cases of spinal myoclonus. tralateral to the skin eruption [78]. One patient had radiculomyelopathy most likely due to Myoclonic ataxia as a presentation of PML lesions in Mycobacterium tuberculosis and in the second case it was bilateral red nuclei, subthalami, thalami, lenticular nuclei W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334 331 and primary motor cortices suggests a role of the dentate- thrombosis rather than the CMV infection, due to rapid rubral-thalamo-cortical tract in the pathogenesis of pro- resolution of the torticollis with anticoagulation treatment. gressive myoclonic ataxia [80]. The patient’s other extrapyramidal signs resolved with anti- CMV medications [86]. 5.4. Treatment of myoclonus AIDS patients treated with dopamine receptor antagonists appear to be particularly susceptible to developing an In a series of three patients with generalized myoclonus acute onset medication-induced dystonia (and/or parkin- and HAD, Maher et al. noted only one patient with sonism) [36,87]. Factor et al. reported the first pathological Toxoplasma gondii abscess, whose myoclonus did not description of a patient with ADC who developed an acute respond to antimicrobial treatment, although it partially onset dystonia and rigidity after a brief trial of low dose responded to treatment with clonazepam [6]. In one patient neuroleptic therapy, which was persistent. Pathological with tuberculous radiculomyelopathy associated with spinal examination revealed a generalized encephalitis with myoclonus, treatment with anti-tuberculosis medications substantial neuronal loss in the medial and lateral globus resulted in mild improvement of the paraplegia and pallidus [38]. myoclonus [3]. Myoclonus remitted promptly with antiviral treatment with acyclovir in a patient with segmental myoclonus preceding herpes zoster radiculitis [78]. In one 6.3. Pathophysiology of dystonia patient with myoclonic encephalopathy associated with HAD and sharp wave activity on EEG, dramatic neurologic It has been hypothesized that the increased susceptibility improvement as well as EEG normalization occurred upon of AIDS patients to develop acute dystonia to low doses of treatment with intravenous and then oral zidovudine [79]. dopamine receptor antagonist medications is probably related to direct invasion of the basal ganglia by the HIV virus and a secondary alteration in dopaminergic mechan- 6. Dystonia isms [36]. Factor et al. suggest in their case report of one HAD patient who developed persistent neuroleptic-induced 6.1. Epidemiology of dystonia dystonia that the severe neuronal loss seen in his globus pallidus increased his vulnerability to developing extrapyr- Dystonia has rarely been reported in patients with AIDS. amidal side effects. They suggest that dopamine related However, generalized, segmental, and focal dystonia have changes are already present pathologically in patients who been described in AIDS patients (Table 1). are prone to develop medication-induced dystonia [38]. However, extrapyramidal reactions are also described in 6.2. Clinical features and etiology of dystonia patients with no apparent neurologic disorder [87]. De Mattos and coworkers in their review of 2460 HIV positive patients reported only one case of hemidystonia 6.4. Treatment of dystonia which was due to toxoplasmosis of the contralateral basal ganglia [21]. A case of postural tremor associated with dystonia and a case of paroxysmal dystonia were described In de Mattos’ case of hemidystonia due to basal ganglia among seven AIDS patients with movement disorders. The toxoplasmosis, treatment with sulfadiazine and pyrimetha- first patient presented with dystonia in both hands and MRI mine improved the lesions radiographically but did not showed small lesions in the left thalamus and posterior change the dystonia [21]. Factor et al. described one patient internal capsule, which did not correlate with the movement with HAD with persistent neuroleptic-induced dystonia, in disorder. The second patient presented with acute parox- which treatment with trihexyphenidyl, diphenhydramine, ysmal dystonia with a left frontal lesion on MRI. No lioresal and carbidopa/levodopa failed to alleviate the information was given with regard to infectious agents [2]. dystonia. The patient was then treated with electroconvul- Abbruzzese et al. reported a patient with generalized sive therapy for paranoid delusions and depression which dystonia involving both axial and segmental muscles. A reduced the dystonia for several hours [38]. In one patient CT scan revealed bilateral, symmetrical lucencies in the with generalized dystonia associated with bilateral striatal putaminal region [7]. A patient with left arm and hand focal lucencies on CT scan, slight improvement of the dystonia dystonia due to a toxoplasmosis abscess in the right was noted with high dose anticholinergic treatment [7]. lenticular nucleus and thalamus has been reported [85]. Given the increased risk of AIDS patients to develop Vielhauer et al. reported one AIDS patient with dystonia on dopamine receptor antagonist medications, disseminated cytomegalovirus (CMV) infection and bilat- extreme caution should be used when prescribing such eral thrombosis of the internal jugular veins presenting with medications. If antiemetic medications are required, non- spasmodic torticollis and an extrapyramidal syndrome. The dopamine antagonists or peripheral acting dopamine authors suggest that the dystonia was caused by the vein antagonists are preferred. 332 W. Tse et al. / Parkinsonism and Related Disorders 10 (2004) 323–334

6.5. Paroxysmal dyskinesias treatment should focus on the aggressive control of HIV infection with HAART. Paroxysmal dyskinesias, a rare movement disorder Finally, it should be noted that HAART has resulted in which presents with dystonic or choreoathetotic movements improved survival times with HIV infection [88]. Higher that occur suddenly and transiently, with complete recovery incidence of comorbid medical conditions is likely to between attacks, have been described in two case reports of emerge with aging of the HIV-infected population [89].It AIDS patients (Table 1). Nath et al. described an AIDS may be predicted that the incidence of comorbid neurode- patient who presented with paroxysmal nonkinesigenic generative conditions such as parkinsonism will also rise dystonia with an MRI showing a lesion in the left frontal over time, although surveys regarding the incidence of region [2]. 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