AZT has been demonstrated to improve and possibly prevent HIV-induced cognitive dysfuncfion in certain patients. Sidtis and co-workers enrolled 39 patients with AIDS dementia in a placebo-controlled study (ACTG Protocol 005) of AZT (1,000 or 2,000 mg/d). Final analysis showed neuropsychologic function improved in those patients receiving AZT compared with placebo, and raised the question of whether the very high dose of AZT (2,000 mg daily) might have been most effective. This result is consistent with those of earlier studies in adults and children showing similar AZT effect in both treatment and prevention. An open study of three doses of AZT (1,000 mg, 750 mg, or 500 mg/day) in 30 patients with ADC was conducted by Tozzi et al. Response to treatment was sometimes transient, and was not associated with the dose of AZT.
Yarchoan et al. reported on five patients with HIV-related neuropsychiatric impairment who received ddI in a dose-ranging phase I study; all patients experienced significant improvement. A multicenter open label pilot trial of ddI (375 mg or 250 mg) in mild or severe ADC is under way. ACTG 140, a comparative trial of ddI vs. AZT (ddI 250 or 375 mg qd or AZT 1,000 mg qd) is underway at Tulane University and Washington University in St. Louis. Clear evidence of ddI, ddC, d4T, or other antiretroviral effect in AIDS dementia complex awaits further study. These results are anecdotal and some clinicians report less favorable experiences, particularly when setting of AIDS dementia develops or recurrs in patients already being treated with AZT. In such patients the choices include: 1) raising the AZT dose to 1,000 mg per day or more if there has not been evidence of drug intolerance or toxicity (perhaps in concert with GM-CSF if needed); 2) switching to or combining therapy with another anfiretroviral drug; 3) adding an adjunct therapy aimed at interfering with some of the toxic processes underlying brain injury as described below.
At least 3 drugs are being evaluated for their ability to improve neurological function without directly inhibiting virus replication. These adjunctive therapies include: cytokine antagonists, antioxidants, and neuroprotective agents. They are in various stages of testing. Peptide T, which was thought to have some promise as a potential therapy, was found ineffective in a large randomized study.
Some studies suggest that the HIV envelope protein gp-l2O is toxic to neurons by virtue of its effect on calcium channels. An ACTG trial (ACTG 162) with the calcium channel blocker nimodipine is underway to study its effect in ADC.
A parallel syndrome is very common in children with AIDS, eventually causing major developmental delay, loss of milestones, cognitive impairment, and motor deficits in perhaps 75% of patients. Therapeutic studies indicate that AZT is effective in ameliorating neurological deficit in these patients. Preliminary studies suggest that ddI may also be helpful in children with AIDS. Wolters et al. evaluated the effects of ddI on 64 children with symptomatic HIV infection. All patients received ddI for at least 6 months. 42/64 patients received ddI for 12 months. Age-appropriate general intelligence tests were administered to children prior to treatment and after 6 and 12 months of ddI. Overall there was no change in IQ scores associated with ddI. Individually, over the first 6 months of ddI treatment, 2l% of the children showed significant improvement in IQ (10% change and 8 points), 9% declined, and 70% remained stable. There was little further change in IQ scores after the second 6 months of treatment. The investigators suggest a correlation between plasma ddI concentrations and improved IQ scores.
Psychostimulants such as methylphenidate hydrochloride (Ritalin®) may be helpful in some patients with characteristic psychomotor slowing. In those with agitation or frank mania, lithium or neuroleptics (see next section) may be helpful, although therapy should start with very low doses.
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REFERENCES:
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Yachoan R et al. Long term toxicity/activity profile of 2Õ,3Õ-dideoxyinosine in AIDS or AIDS-related complex. Lancet 336: 526-29, 1990.
Brouwers P et al. Effect of continuous-infusion zidovudine therapy on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection. J Pediatr 117: 980-5, 1990.
De Girolami U et al. Neuropathology of the acquired immunodeficiency syndrome. Arch Pathol Lab Med 114: 643-655, 1990.
Gabuzda DH. Neurologic disorders associated with HIV infections. J Am Acad Dermatol 22: 1232-6, 1990.
Heyes, M P et al. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infecfion:
Relationship to clinical and neurological status. Ann Neurol 29(2): 202-9, Feb. 1991.
Ingraham L et al. Neuropsychological effects of early HIV-1 infection: assessment and methodology. J Neuropsych & Clin Neurosci 2: 174-182, 1990.
Kramer E et al. Brain imaging in acquired immunodeficiency syndrome dementia complex. Sem Nuc Med 20(4): 353-63, 1990.
Lechtenberg R. AIDS in thee brain. Intl J STD & AIDS 1: 311-317, 1990.
Lipton S. Models of neuronal injury in AIDS: another role for the NMDA receptor? Trends in Neurosci, 15(3): 75-79, 1992.
Maj M. Organic mental disorders in HIV-1 infection. AIDS 4: 831-840, 1990.
McArthur J. Low prevalence of neurological and neuropsychological abnormalities in otherwise healthy HIV-1-infected individuals: Results from the Multicenter AIDS Cohort Study. Ann Neurol 26: 601-611, 1989.
McArthur J. Neurologic manifestations of AIDS. Medicine (66) 6: 407-437, 1987.
McGrail M et al. Peptide T studies: Neurophysiologic results. VII Ind Conf AIDS, Florence. Vol 1:194(M.B. 2049), 1991.
Mclntyre K et al. Pilot study of zidovudine (AZT) and zalcitabine (ddC) combination in HIV-associated dementia. Abstact #PBO 233, X Intl Conf AIDS, Yokohama, 1994.
Perdices M et al. Neuropsychological investigation of patients with AIDS and ARC.
J AIDS 3: 555-564, 1990.
Perry S. Organic mental disorders caused by HIV: update on early diagnosis and treatment. Am J Psych 147(6): 696-710, 1990.
Portegies P. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. B Med J 299(6703): 819-21, 1989.
Price R et al. The brain in AIDS: Central nervous system HIV-1 infection and the AIDS dementia complex. Science 239: 586-92, 1988.
Price R et al. Central and peripheral nervous system complications of HIV-1 infecfion and AIDS. In: AIDS, Etiology, Diagnosis, Treatment and Prevention, eds. DeVita VT Hellman S and Rosenberg SA. J.B. Lippincott Company, Philadelphia, 3rd ed. 14:237-257, 1992.
Pullian L et al. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 87(2): 503-12, Feb. 1991.
Satriano, J et al. Central nervous system stimulants as symptomatic treatment for AIDS dementia commplex. VII Intl Conf AIDS, Florence. Vol 1: 195 (M.B. 2053),1991.
Sidtis et al. Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial. Ann Neur 1993.
Simpson DM et al. Neurologic Manifestations of HIV Infection. Ann Intem Med 121: 769-785,1994.
Stover E et al. CNS effects of HIV-1 infecfion and AIDS in infants and children: A collaborative research agenda. Ped AIDS and HIV Infection 1: 109-119, Nov. 6, 1990.
Wiley C et al. Human immunodeficiency virus: infection of the nervous system. Curr Topics Microbiol 160: 157-72, 1990.
Worley IM et al. Clinical manifestations of the HIV-1 infection of the nervous system. In: Handbook of Neurovirology, W Stroop and R McKendall, eds. Marcel Dekker, 1992.
Worley JM et al. Management of neurologic complications of HIV-1 infection. In: The Medical Mmagement of AIDS, M Sande md P Volberding, eds. Philadelphia: W.B. Saunders Co., third edition. 13:193-217,1992.
Tozzi V et al. Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex. AIDS 7: 683-92, 1993.
OTHER REPORTS:
Aronow H et al. The management of the neurological complications of HIV infection and AIDS. AIDS 2(suppl 1): S 151-9, 1988.
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