Marshfield Clinic Research Foundation and Marshfield Clinic-Thorp Center; Marshfield, WI
To the Editor:
HIV dementia usually responds to highly active antiretroviral therapy (HAART), despite relatively poor penetration of HAART drugs across the blood-brain barrier.1,2 However, patients on HAART can still have significant cognitive deficits,3,4 and HIV dementia appears to be at least somewhat independent of viral load within the central nervous system,5 raising the specter of increasing numbers of long-term HIV survivors disabled by dementia.
Part of the solution may be cholinesterase inhibitors (donepezil, galantamine, and rivastigmine), now commonly used to treat Alzheimer's disease. Cholinesterase inhibitors compensate for cholinergic deficiency by inhibiting the breakdown of acetylcholine and can delay nursing home placement by typically 6 months to a year,6 in what on the average is a decade-long progression from initial signs to a locked-in end stage. Galantamine also appears to have some effect in directly stimulating nicotinic cholinergic receptors.6 Symptomatic relief from all 3 agents is modest but real and can be quantified by various instruments assessing patients and their caregivers, who note decreased burden of caregiving with the use of cholinesterase inhibitors. Beyond Alzheimer's disease, cholinesterase inhibitors can also improve cognitive functioning in several other neurologic disorders, including dementia of multiple sclerosis,7 Parkinsonian dementia,8 attention deficit disorder,9 traumatic brain injury,10-13 and vascular dementia.14-16 All of these conditions have many subcortical neuropsychological features in common with typical HIV dementia, such as inattention to detail and difficulty learning, suggesting there would be a similar improvement for HIV dementia. In addition, it is important to note that both multiple sclerosis dementia and HIV dementia have prominent white matter lesions. This is especially the case for HIV-associated progressive multifocal leukoencephalopathy, which was common in the pre-HAART era and now seems to be making a resurgence.17 It is thought that most patients with subcortical dementias who improve with cholinesterase inhibitors have cholinergic afferent fibers passing through lesioned areas,16 creating a state of relative cholinergic deficiency relieved by inhibiting breakdown of acetylcholine. If this is correct, many patients with HIV-induced white matter lesions may have an identical situation.
Memantine, a noncompetitive inhibitor of the N-methyl-D-aspartate (NMDA) glutamate receptor, also shows promise for HIV dementia. There is already in vitro and animal data showing memantine neuroprotection against NMDA-mediated neurotoxicity of the HIV gp120 protein,18-20 and clinical trials of memantine for HIV dementia have reportedly begun.21 When used for Alzheimer's disease, memantine significantly attenuates progression from moderate to severe stages22 and has additive effect when coadministered with donepezil.23
Rigorous placebo-controlled multicenter clinical trials of cholinesterase inhibitors and memantine should be expedited, above and beyond what may already be under way. If patients desire to try the medications ahead of randomized controlled studies, HIV clinics could offer small open-label therapeutic trials, carefully monitoring for any drug interactions with HAART. Hopefully, there can be a fast track to determine whether cholinesterase inhibitors and memantine should be a routine part of treatment of HIV dementia.
Joseph Martin Alisky, MD, PhD
Marshfield Clinic Research Foundation and marshfield Clinic-Thorp Center; Marshfield, WI
1. Robertson KR, Robertson WT, Ford S, et al. Highly active antiretroviral therapy improves neurocognitive functioning. J Acquir Immune Defic Syndr. 2004;36:562-566.
2. Gimenez F, Fernandez C, Mabondzo A. Transport of HIV protease inhibitors through the blood-brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins. J Acquir Immune Defic Syndr. 2004;36:649-658.
3. Kusanda L, McGuire D, Pulliam L. Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. AIDS. 2002;16:31-38.
4. Valcour V, Shikuma CM, Watters MR, et al. Cognitive impairment in older HIV-1 seropositive individuals: prevalence and potential mechanisms. AIDS. 2004;18(Suppl 1):79-86.
5. Lazarini F, Seilhean D, Rosenblum O, et al. Human immunodeficiency virus type 1 DNA and RNA load in brains of demented and non-demented patients with acquired immunodeficiency syndrome. J Neurovirol. 1997;3:299-303.
6. Wilkinson DG, Francis PT, Schwann E, et al. Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging. 2004;21:453-478.
7. Greene YM, Tariot PN, Wishart H, et al. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol. 2000;20:350-356.
8. Aarsland D, Hutchinson M, Larsen JP. Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia. Int J Geriatr Psychiatry. 2003;18:937-941.
9. Wilens TE, Biederman J, Wong J, et al. Adjunctive donepezil in attention deficit hyperactivity disorder youth: case series. J Child Adolesc Psychopharmacol. 2000;10:217-222.
10. Zhang L, Plotkin RC, Wang G, et al. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil. 2004;85:1050-1055.
11. Masanic CA, Bayley MT, VanReekum R, et al. Open-label study of donepezil in traumatic brain injury. Arch Phys Med Rehabil. 2001;82:896-901.
12. Morey CE, Cilo M, Berry J, et al. The effect of aricept in persons with persistent memory disorder following traumatic brain injury: a pilot study. Brain Inj. 2003;17:809-815.
13. Whelan FJ, Walter MS, Schultz SK. Donepezil in the treatment of cognitive dysfunction associated with traumatic brain injury. Ann Clin Psychiatry. 2000;12:131-135.
14. Erkinjuntti T, Roman G, Gauthier S. Treatment of vascular dementia: evidence from clinical trials with cholinesterase inhibitors. Neurol Res. 2004;26:603-605.
15. Moretti R, Torre P, Antonello RM, et al. Rivastigmine in subcortical vascular dementia: a randomized, controlled open 12-month study in 208 patients. Am J Alzheimers Dis Other Demen. 2003;18:265-272.
16. Erkinjuntti T, Roman G, Gautheir S, et al. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke. 2004;35:1010-1017.
17. Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leuko-encephalopathy in AIDS patients on antiretroviral therapy. AIDS. 2002;16:1019-1029.
18. Lipton SA. Memantine prevents HIV coat protein-induced neuronal injury in vitro. Neurology. 1992;42:1403-1405.
19. Muller WE, Pergande G, Ushijima H, et al. Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. Prog Mol Subcell Biol. 1996;16:44-57.
20. Toggas SM, Masliah E, Mucke L. Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res. 1996;706:303-307.
21. Manji H, Miller R. The neurology of HIV infection. J Neurol Neurosurg Psychiatry. 2004;75(Suppl 1):i29-i35.
22. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333-1341.
23. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer's disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-324.
© 2005 Lippincott Williams & Wilkins, Inc.