october 2009                                                           THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                                   HIV infection of the central nervous system occurs almost simultaneously with systemic infection. Pri- mary neurological disorders can affect the brain (e.g. HIV-associated dementia), spinal cord (e.g. HIV- asso- ciated vacuolar myelopathy) and meninges.1 HIV-as- sociated dementia (HAD) has also been referred to as HIV encephalopathy or AIDS dementia complex. These terms have been used interchangeably and describe a syndrome that includes the symptom triad of psycho- motor slowing, memory impairment and behavioural problems. We now understand that neurocognitive im- pairment (NCI) in HIV is a spectrum of disorders.2 In addition to HAD, lesser forms of NCI have also been described, namely HIV-associated minor cognitive- motor deficit (now called mild neurocognitive disorder) and asymptomatic neurocognitive impairment (ANI).3 These disorders now fall under the new term HIV-as- sociated neurocognitive disorder (HAND) (Table I). The diagnosis of HAND requires a history, clinical examina- tion, appropriate investigations and neuropsychologi- cal testing. This review presents the clinical features, diagnostic criteria and tools to help diagnose HAND. HIV neuropathogenesis is not fully understood. It is un- clear whether the cognitive decline seen in HIV-infected people is partly or wholly due to the direct effects of HIV, to secondary effects from the chronic hyperimmune ac- tivation, to other immunological factors (e.g. cytokines, chemokines and tumour necrosis factor) in the CNS, or to other factors such as hepatitis co-infection and clade diversity. However, it is understood that:4 n HIV does not infect the neurons and oligodenro- cytes but the monocytes, microglia, astrocytes and endothelial cells. n Once in the CNS the virus persists and evolves into different strains independent of the systemic res- ervoir. n HIV is not evenly distributed in the CNS, and has a predilection for the basal ganglia. n HIV RNA levels in the cerebrospinal fluid do not correlate with those in the peripheral circulation, especially in advanced HIV disease. Involvement of the basal ganglia accounts for the clini- cal distinction between ‘subcortical dementia’ seen in HAD and the ‘cortical dementia’ typically seen in Alz- heimer’s disease. HAD occurs in approximately 10 - 15% of all individu- als with HIV/AIDS and is more common in late stages NEUROCOGNITIVE IMPAIRMENT IN PLWHA: CLINICAL FEATURES AND ASSESSMENT c l i n i c a l : d e m e n t i a Dinesh Singh, MB ChB, MMed (Psych), FCPsych (SA), MS (Epi)(Columbia, USA) Department of Psychiatry, Nelson R Mandela School of Medicine, University of Kwa-Zulu Natal, Durban Neurocognitive impairment (NCI) occurs in 10 - 60% of people living with HIV/AIDS (PLWHA), depending on the severity of the NCI and the stage of the disease. The clinical features and definitions have evolved over the past two decades. HIV-associated neurocognitive disorder (HAND) is a new term used to describe the spectrum of neuro- cognitive impairment seen in HIV/AIDS. The earliest to most advanced stages are asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND) and HIV dementia (HAD), respectively. People with HAND have impairment on multiple cognitive domains, including attention, concentration, memory, executive function, motor functioning and speed of information processing, and sensory perceptual/motor skills deficits. The milder forms of HAND are easily missed. Diagnosis can be made on clinical grounds in the most severe cases; however, milder forms and confirmation of the diagnosis require neuropsychological testing. Screening tests have limited utility, especially in the milder forms of HAND. Individual subtests derived from longer neuropsychological batter- ies may be complementary in the diagnosis of HAND. Highly active antiretroviral therapy (HAART) has led to a 40% decline in the incidence of HAD. In the post-HAART era, HAD runs a more chronic course, is milder and is reversed in about a third of cases. However, HAART is not universally successful because incident cases occur in people on HAART. Overall HAART has been shown to be of benefit, and screening for HAND should be the standard of care for PLWHA. HAD is an AIDS-defining illness and patients qualify for HAART irrespective of their CD4 count. However, the benefit of starting ARVs for people with ANI and MND is currently inconclusive. PatHOGeneSiS ePidemiOlOGY 30 THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                                        october  2009   of infection.1 Less severe forms of HAND occur in 30 - 60% of people infected with HIV, depending on the stage of the disease.1 Approximately 17% of the peo- ple attending a highly active antiretroviral therapy (HAART) primary health clinic in Cape Town had some level of NCI, including HAND.5 The epidemiology of NCI has changed distinctly with the introduction of HAART. In the pre-HAART era HAD was common and more se- vere, with death likely within 6 months of diagnosis.6 The introduction of HAART led to a major decline in the incidence of HAD.1,6,7 However, data from cohorts on long-term HAART in the USA show that incident cases of HAD occur despite HAART, that progression of HAD is variable, and that NCI seems to be milder.1 The overall prevalence of HAND continues to rise, pre- sumably owing to incomplete reversal or prevention of cognitive impairment, longer survival on HAART and an increasing HIV prevalence. At present there are no guidelines that recommend specific HAART regimens for the treatment or preven- tion of HAND. However, epidemiological data suggest at least partial benefit in giving HAART to prevent and reverse HAND.7-9 HAD is an AIDS-defining illness and people with HAD qualify for HAART irrespective of CD4 counts. There is therefore an urgent need to raise awareness and develop rapid screening tools to detect and monitor HAND. Most clinicians can recognise frank HAD, but the more subtle HANDs are easily missed. HAND is: (i) a cognitive disorder, accompanied by (ii) motor dysfunction and/or (iii) behaviour problems. Cognitive changes are problems with memory, de- creased attention and concentration. These patients have decreased ability to learn new information and the speed at which they process information and men- tal tasks is slower than normal. Executive functioning, which includes planning, impulse control, organisation, abstract thinking and judgement, is also affected. Motor changes are more subtle and are often missed. Patients complain of changes in their handwriting, tremor, and ‘clumsiness’. They have gait abnormalities in the late stages. Behaviour problems vary and range from aggression or marked isolation to the vegetative state seen in the late stages when patients are mute, immobile and in- continent. The presentation is similar to that of severe depression, because patients appear very apathetic and amotivated, with lack of initiative and psychomotor slowing. The new classification requires systematic assessment of the following six domains:3 (i) attention-informa- tion processing; (ii) language; (iii) abstraction/execu- tive; (iv) complex perceptual motor; (v) memory; and (vi) sensory perceptual/motor. Assessment of these domains requires neuropsycho- logical tests that are often not intuitive to the clini- cian. Most clinicians can test memory with ‘bedside’ tests; however, assessment of executive functioning and psychomotor speed is more difficult. The challenge is to translate these research criteria and recommend specific tests that can be widely used by non-neu- ropsychologists. We can recommend a few tests that can assess these various domains (Table II). The distinction between ANI, MND and HAD depends on: (i) the severity of impairment (when compared with population age- and education-appropriate norms for the above domains); and (ii) level of functional impair- ment in everyday activities at work, home or socially. asymptomatic neurocognitive minor neurocognitive HiV-associated deficit (ani) disorder (mnd) dementia (Had) Level of impairment None Mild everyday activities: reduced Marked impairment in mental acuity, inefficiency in work, day-to-day activities homemaking or social activities at work, home or affected social functioning Number SD below 1 2 population norm on neuropsychological test Number of domains 2 impaired Attention/working memory; verbal/language; abstraction/executive; complex perceptual motor; memory (learning and recall); speed of information processing; sensory perceptual/motor skills Exclusion criteria Absence of criteria for delirium or other causes for dementia. The condition cannot be explained by another co-morbid condition, e.g. substance abuse, infections, pre-existing neurological condition *Summarised from Antinori et al. 3 taBle i. cRiteRia FOR HiV-aSSOciated neUROcOGnitVe imPaiRment* clinical FeatUReS 31 october 2009                                                           THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                                   aSYmPtOmatic neUROcOGnitiVe imPaiRment This is the mildest form of HAND. The person has no impairment in everyday activities. They may complain of mild slowing in mental acuity and loss of concentra- tion. Abnormalities can only be detected by testing the six domains and comparing against population norms. Patients must have 1 standard deviation (SD) abnor- mality on two of the six domains. ANI can progress to the next stage in the spectrum of HAND. minOR neUROcOGnitiVe diSORdeR MND was previously called HIV- associated minor mo- tor-cognitive disorder. MND has the same criteria as ANI, i.e. the patient has 1 SD abnormality on two of the six domains. Unlike patients with ANI, they have impairment in their daily activities, at work or in social functioning or homemaking. This can be by self-report or by observation by someone who knows the patient. HiV-aSSOciated dementia HAD is the most severe form of HAND. By definition pa- tients have at least 2 SD abnormality on two domains, and these deficits cause significant impairment in eve- ryday activities.3 However, the clinical presentation can vary widely. In early HAD, the patient may appear de- pressed with apathy, lethargy and social withdrawal. Personality changes are not uncommon, and are often reported more by others than by the patient. In late HAD, psychotic symptoms may be prominent along with severe language dysfunction, verbal memory loss, seizures and mutism. The patient may be incontinent of urine and stool. Neurological examination may show interruption of smooth ocular pursuit, slowing or inaccuracy of sac- cades, hyper-reflexia, ‘frontal release’ signs, slowing of rapid alternating movement of fingers, wrist or feet, and ataxia. In the post-HAART era the progression of HAD has changed. Based on clinical observation of long-term treatment cohorts, three sub-types of HAD have been defined:7 1. Sub-acute progressive dementia occurs in ARV- naïve people and has a course similar to that ob- served in the pre-HAART era. 2. Chronic active dementia. These patients are on treatment but have poor adherence leading to vi- ral resistance. They are at risk of developing other neurological complications. 3. Chronic inactive dementia occurs in people who are adherent to HAART and have undetectable vi- ral loads. They have some recovery from neuronal injury and are neurologically stable. HAND is a diagnosis of exclusion. Other diseases that affect CNS functioning, i.e. opportunistic infections, neoplasms, metabolic disturbances and iatrogenic complications, have to be systematically ruled out. De- lirium and substance use are common in HIV-infected patients. Appropriate first-line investigations, e.g. a full blood count, assessment of kidney, liver and thy- roid function, measurement of the vitamin B12 level and serological testing for syphilis, are necessary. Lumbar puncture is also useful to exclude other opportunistic infections. The CSF viral load is not useful in the diag- nosis of HAND and does not correlate with the severity of the impairment. Neuro-radiological investigations, e.g. computed tomography and magnetic resonance imaging, are necessary to exclude conditions such as progressive multifocal leuco-encephalopathy and pri- mary CNS lymphomas that can mimic HAND. However, in resource-constrained settings these investigations are not readily available and they are not vital in the absence of focal localising signs. With delirium and medical causes excluded, the diagnosis of HAND requires testing of the six domains using neu- ropsychological tests. However, these are often imprac- tical or not available in busy clinical settings. Two-stage clinical WORK-UP FOR Hand Neuropsychological test Description Domains assessed Rey Auditory Verbal Learning Test Recall as many words as possible from a list of 15 words Memory Grooved peg-board Motor Digit span forward Patient is given an increasing number of random digits. Attention and concentration They must repeat digits in the same order Digit span backward Patient is given an increasing number of random digits. Attention, concentration They must repeat the digits in reverse order and working memory Trail making test A Join 25 circles with numbers in the correct sequence as Motor and speed of quickly as possible. The numbers are distributed across the information processing page and are not in order Trail making test B Join 25 circles with numbers and letters in alternating Motor and speed of sequence, i.e. join 1, A, 2, B, 3, C as quickly as possible information processing and executive function taBle ii. Selected neUROPSYcHOlOGical teStS and tHe dOmainS aSSeSSed 32 THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                                        october  2009   testing is commonly used in psychiatry. In the first stage a brief, bedside cognitive screening test is administered and people who screen positive can then be subjected to more detailed testing in the form of a neuropsycho- logical battery. See Fig. 1 for algorithm for assessing and managing newly diagnosed patients with HIV. cOGnitiVe ScReeninG WORK-UP The Mini-Mental State Examination (MMSE) was validated for distinguishing Alzheimer’s dementia from other dementing disorders.10 It is loaded with items that are representative of ‘cortical’ functions. Since HAND is primarily affects sub-cortical processes, the MMSE is not ideal. It is not useful in detecting the milder forms of HAND, and it is affected by age, education and cul- tural background.11 The HIV Dementia Scale comprises four items – an anti-saccadic eye movement error task, timed alpha- bet, verbal memory and copying a cube.12 Two of these items are timed and therefore more sensitive to sub- cortical functions. This scale has been used in the USA13 and validated in South Africa.5 However, observing the anti-saccadic eye movement requires training and is difficult for non-neurologists to administer.14 Mental alternation test. Patients are asked to count to 20, say the alphabet, and then alternate between the numbers and letters in the following fashion: ‘1-A, 2-B, 3-C ...’. Progressing from the most recent number or letter to the next letter or number in the sequence is one alternation. The number of correct alternations in 30 seconds, discounting any errors, determines the Fig. 1. Summary assessment and management of neurocognitive function in newly diagnosed PLWHA. Fig. 1. Summary assessment and management of neurocognitive function in newly diagnosed PLWHA. Classify as normal, ANI, MND or HAD Assess all newly diagnosed HIV positive patients with neuropsychological subtests (TMT-A, TMT-B, DSF, DSB) ANI and MND HAD Start ARVs, monitor and reinforce adherence Monitor, repeat in 6 months. If progress to HAD start ARV Treat depression and other medical conditions CD4 <200 CD4 >200 CD4 >200 Baseline investigation e.g. FBC, U& E, LFT – CT and LP (if indicated) 33 october 2009                                                           THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINE                                                   score. The maximum score is 52 points, and a score of ≤15 indicates the need for more extensive cognitive testing. This tests a limited number of cognitive do- mains and is dependent on level of education.15 international HiV dementia Scale (iHdS). The IHDS was tested in the USA and Uganda and developed spe- cifically for resource-constrained settings.14 It has three subtests: timed alternating hand sequence, timed fin- ger tapping, and recall of four items after two minutes. This test has many advantages over its predecessors: it is brief, it can be completed in 2 - 3 minutes, and the patient does not need knowledge of English. It can be performed by non-neurologists and does not require any special equipment other than a stop-watch. The recommended cut-off score of 10 had 80% sensitivity and 55% specificity in the Ugandan study.14 The spe- cificity declines rapidly with small increment changes in the score, and this may limit its utility. While it has many advantages, validation studies are needed for our local population. Neuropsychological battery. Various neuropsycholog- ical test batteries have been proposed. Longer batteries may take as long as 9 hours and brief batteries as little as 1 - 2 hours. Further, the absence of local popula- tion norms may limit their utility.16 Work to develop brief, normed bedside tests is underway (Singh et al. – unpublished data) focusing on the separate domains of memory and recall, attention and working memory, speed of information processing, executive function- ing, and motor abnormalities. We have collected popu- lation norms for the following bedside tests: digit span forward, digit span backwards, trail making test A and trail making test B. While these tests require training to conduct and are likely to be beyond the reach of a busy primary care HIV clinical service, they have an important role to play as part of specialist referral to diagnose HAND. antiRetROViRal tHeRaPY HAART has lowered the incidence of HAND and im- proved patient outcomes, but HAART is not universally successful in reversing or preventing HAND.1 While HAART can effectively suppress viral replication in the systemic circulation, its pharmacodynamics and effects on the virus in the CNS are less clear. ARVs, especially protease inhibitors, do not cross the blood-brain bar- rier easily and do not achieve significant levels in the CSF. There is some evidence that CNS-penetrating HAART (e.g. abacavir and zidovudine) may be effective in improving neuropsychological functioning.8,17 Grow- ing evidence suggests that for milder neurocognitive disorders the use of antiretrovirals may slow progres- sion or at least prevent severe forms of HAND. However, owing to the lack of conclusive evidence that HAART can prevent or reverse neurological damage caused by HIV, the role of initiating HAART in asymp- tomatic individuals is undefined. ReFeRenceS 1. Grant I. Neurocognitive disturbances in HIV 1. Int Rev Psychiatry 2008; 20(1): 33-47. 2. Janssen RS, Saykin AJ, Cannon L, et al. Neurological and neuropsychological manifestations of HIV-1 infection: association with AIDS-related complex but not asymptomatic HIV-1 infection. Ann Neurol 1989; 26(5): 592-600. 3. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV- associated neurocognitive disorders. Neurology 2007; 69(18): 1789-1799. 4. Phair JP, Simpson DM, Cikurel K. Pathogenenesis of the neurological complications of HIV. Available: http://www.clinicaloptions.com/HIV/Management%20Series/ NeuroAIDS.aspx [accessed 10 September 2009]. 5. Ganasen KA, Fincham D, Smit J, Seedat S, Stein D. Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample. J Neurol Sci 2008; 269(1-2): 62-64. 6. Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997; 11(14): 1731-1738. 7. Nath A, Schiess N, Venkatesan A, Rumbaugh J, Sacktor N, McArthur J. Evolution of HIV dementia with HIV infection. Int Rev Psychiatry 2008; 20(1): 25-31. 8. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65(1): 65-70. 9. Sacktor N, Nakasujja N, Skolasky R, et al. Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa. Neurology 2006; 67(2): 311-314. 10. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189-198. 11. Tombaugh TN, McIntyre NJ. The mini-mental state examination. A comprehensive review. J Am Geriatr Soc 1992; 40: 922-935. 12. Power C, Selnes OA, Grim JA, McArthur JC. HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8(3): 273-278. 13. von Giesen HJ, Haslinger BA, Rohe S, Koller H, Arendt G. HIV Dementia Scale and psychomotor slowing – the best methods in screening for neuro-AIDS. J Neuropsychiatry Clin Neurosci 2005; 17(2): 185-191. 14. Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS 2005; 19(13): 1367-1374. 15. Jones BN, Teng EL, Folstein MF, Harrison KS. A new bedside test of cognition for patients with HIV infection. Ann Intern Med 1993; 119(10): 1001-1004. 16. Fernandez AL, Marcopulos BA. A comparison of normative data for the Trail Making Test from several countries: equivalence of norms and considerations for interpretation. Scand J Psychol 2008; 49(3): 239-246. 17. Brew BJ, Halman M, Catalan J, et al. Factors in AIDS dementia complex trial design: results and lessons from the abacavir trial. PLoS ClinTrials 2007; 2(3): e13. tReatment acKnOWledGmentS I would like to thank J Joska for all his assistance in preparing this manuscript. Dinesh Singh was sup- ported by the Fogarty International Centre, NIH, grant 5-D43-TW00231 (AIDS International Training and Research Program, Quarraisha Abdool Karim, PhD, Principal Investigator). 34