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PARKINSONISM IN HIV-INFECTED PATIENTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
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NEUROLOGY 2009;73:401-403
"We observed 3 new cases of parkinsonism (all <50 viral load in blood) among our cohort of 2,500 HIV-infected patients over a 2-year period, which is 4-8 times higher than the reported incidence of PD among people age 40-59 years....suggests HIV and HAART may preferentially predispose to the development of parkinsonism. Early HIV disease can rarely be associated with parkinsonism, probably reflecting viral involvement of the basal ganglia soon after seroconversion. Later in the course of HIV, in patients with HIV-associated dementia, features of parkinsonism may also occur, with postmortem studies confirming presence of HIV preferentially in inflammatory infiltrates and glial cells of the basal ganglia including the substantia nigra....The present study extends these observations by confirming that chronic HIV infection with HAART may be associated with parkinsonism of relatively young onset, with rest tremor, that may be indistinguishable from idiopathic PD (Parkinson)"
Stephen Tisch, MBBS, PhD and Bruce Brew, MBBS, MD
From the Department of Neurology, St Vincent's Hospital, University of New South Wales, Darlinghurst, Australia.
Address correspondence and reprint requests to Dr. S. Tisch, Department of Neurology, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW 2010 Australia; stisch@stvincents.com.au
Highly active antiretroviral therapy (HAART) has significantly prolonged the lives of HIV-infected patients but low level chronic immune activation remains in some. Neurodegenerative diseases are often associated with immune activation which likely plays a role in their pathogenesis.1 Recently, increased alpha-synuclein deposition in the substantia nigra in aging HIV-infected patients has been identified,2 although there was no clear clinical correlate. These observations suggest that HIV and HAART may facilitate the development of neurodegeneration and accelerate the appearance of diseases such as Parkinson disease (PD) via mechanisms including inflammation, mitochondrial dysfunction, and interference with the ubiquitin proteasome pathway.1 Here we describe 3 patients with relatively young onset of parkinsonism in the context of HIV and HAART.
Case series. The patients were HIV-infected men aged between 44 and 55 years on HAART who were examined prior to the development of parkinsonism. None had been exposed to neuroleptic medications or recent amphetamine use. All developed initial unilateral upper extremity rest tremor, followed by rigidity, bradykinesia, and mild gait involvement with preserved postural stability. Importantly, cognitive, oculomotor, pyramidal, cerebellar, and autonomic features were absent. Only patient 3 responded well to levodopa; however, the dose in patients 1 and 2 could not be raised due to side effects. In all patients, parkinsonism developed and progressed in the context of effective HAART (plasma HIV viral load <50 copies/mL). Brain MRI was normal apart from reduced N-acetylaspartate spectroscopy peaks (relative to creatine) in the caudate in 2 patients. In 2 patients, CSF showed low levels of HIV RNA and 1 had evidence of inflammation with raised neopterin and 2 microglobulin. The patient details are described in the table.
Discussion. HAART has transformed HIV to a chronic disease with near-normal life expectancy. There is accumulating evidence that HIV and HAART accelerate the aging process, thereby possibly promoting the development of neurodegenerative diseases such as Alzheimer disease and PD.1
We observed 3 new cases of parkinsonism among our cohort of 2,500 HIV-infected patients over a 2-year period, which is 4-8 times higher than the reported incidence of PD among people age 40-59 years.3 This estimate suggests HIV and HAART may preferentially predispose to the development of parkinsonism. Early HIV disease can rarely be associated with parkinsonism, probably reflecting viral involvement of the basal ganglia soon after seroconversion.4 Later in the course of HIV, in patients with HIV-associated dementia, features of parkinsonism may also occur, with postmortem studies confirming presence of HIV preferentially in inflammatory infiltrates and glial cells of the basal ganglia including the substantia nigra.5 The pattern of parkinsonism in the present series differs from these existing reports: 1) patients had chronic HIV infection with viral suppression in the plasma and minor replication in the CSF when symptoms developed, and 2) none had features of dementia. In fact, it remains possible that our patients have PD. We hypothesize that chronic HIV infection with very low level replication and HAART, particularly protease inhibitors, may predispose to neurodegeneration through persistent low level inflammation, mitochondrial dysfunction, and interference with the ubiquitin proteasome pathway.1 Proteasome dysfunction has been described at least with some of the protease inhibitors used in HAART. It may be advisable to avoid their use where possible in patients with parkinsonism.1 In our patients, it was not possible to stop or reduce antiretroviral medications because of risk of HIV progression or the development of drug resistance. There is accumulating evidence that neurodegeneration occurs in patients with chronic HIV, even in the context of maximal viral suppression, at least in the plasma. Several groups have reported a 10%-40% incidence of cognitive impairment among virally suppressed chronically HIV-infected patients, particularly those with longer disease duration.6 Further evidence for neurodegeneration in patients with chronic HIV infection and HAART comes from a recent study which found that incidence of mild extrapyramidal signs is increased in patients with chronic HIV infection and HAART, particularly older patients and those with cognitive impairment.7 This can be interpreted as loss of nigrostriatal neuronal reserve in aging patients with HIV-HAART, which could predispose to the later development of parkinsonism. This view is supported by the significant finding of overexpression of neuritic alpha-synuclein in the substantia nigra of long surviving patients with HIV-HAART in the absence of HIV-associated neuropathology.2 The present study extends these observations by confirming that chronic HIV infection with HAART may be associated with parkinsonism of relatively young onset, with rest tremor, that may be indistinguishable from idiopathic PD.
1 Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharm Epub 2008 Dec 6.
2 Khanlou N, Moore DJ, Chana G, et al. Increased frequency of alpha-synuclein in the substantia nigra in HIV infection. J Neurovirol 2009;15:131-138.[Medline]
3 Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015-1022.[Abstract/Free Full Text]
4 Hersh BP, Rajendran PR, Battinelli D. Parkinsonism as the presenting manifestation of HIV infection: improvement on HAART. Neurology 2001;56:278-279.[Free Full Text]
5 Brew BJ, Rosenblum M, Cronin K, Price RW. AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations. Ann Neurol 1995;38:563-570.[Medline]
6 Cysique LA, Maruff P, Brew J. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 2006;66:1447-1450.[Abstract/Free Full Text]
7 Valcour V, Watters MR, Williams AE, Sacktor N, McMurtray A, Shikuma C. Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy. J Neurovirol 2008;14:1-6.[Medline]
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