Annals of African Medicine

: 2013  |  Volume : 12  |  Issue : 1  |  Page : 1--10

NeuroAIDS in sub-Saharan Africa: A clinical review

Nura H Alkali1, Sunday A Bwala2, Yakubu W Nyandaiti2, Mustapha A Danesi3,  
1 Department of Medicine, National Hospital, PMB 425, Garki, Abuja, Nigeria
2 Department of Medicine, University of Maiduguri Teaching Hospital, PMB 1414, Maiduguri, Borno State, Nigeria
3 Lagos University Teaching Hospital, PMB 12003, Idi Araba, Lagos State, Nigeria

Correspondence Address:
Nura H Alkali
Department of Medicine, Neurology Unit, National Hospital, PMB 425, Garki, Abuja


NeuroAIDS affects half of the 22 million people currently living with HIV/AIDS in sub-Saharan Africa, where cryptococcal meningitis alone is responsible for 504,000 deaths annually. A good understanding of NeuroAIDS may help improve disease-free survival in patients at risk and optimize resource utilization by caregivers. In this review, we aimed to provide a summary of major NeuroAIDS syndromes of relevance in Africa. We searched Medline for English language literature to identify relevant publications, using the search terms �DQ�NeuroAIDS�DQ� and �DQ�HIV AND nervous system.�DQ� The most common NeuroAIDS syndrome is HIV-associated neurocognitive disorders (HAND), which affects over 1.5 million Africans yearly. While incidence of HAND has decreased with the use of highly active antiretroviral therapy, prevalence has increased due to longer life expectancy. Other NeuroAIDS syndromes include tuberculous meningitis and intracerebral tuberculoma, cryptococcal meningitis, toxoplasma encephalitis, progressive multifocal leukoencephalopathy, primary central nervous system lymphoma, stroke, and distal sensory polyneuropathy. NeuroAIDS care and research in Africa are hindered by resource limitations. Inadequate neuroimaging and laboratory facilities result in diagnostic delays and confusion, while limited access to drugs leads to inappropriate treatment. However, the situation may be improving. Better funding of HIV care by African governments and donor agencies have resulted in decreasing HIV prevalence and prolonged survival. Yet, central nervous system opportunistic infections remain important causes of death and disability among African patients with HIV/AIDS. There is the need for additional funding to improve access to antibiotics and to facilitate further research into NeuroAIDS and its treatment.

How to cite this article:
Alkali NH, Bwala SA, Nyandaiti YW, Danesi MA. NeuroAIDS in sub-Saharan Africa: A clinical review.Ann Afr Med 2013;12:1-10

How to cite this URL:
Alkali NH, Bwala SA, Nyandaiti YW, Danesi MA. NeuroAIDS in sub-Saharan Africa: A clinical review. Ann Afr Med [serial online] 2013 [cited 2023 Sep 28 ];12:1-10
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Full Text


Human immunodeficiency virus (HIV) infection is associated with neurologic complications, or NeuroAIDS, which cause significant morbidity and mortality. In a Canadian study of HIV-associated neurologic disease, the risk of an AIDS-related death increased by 39% for every 10-fold increment in plasma HIV viral load. [1] In Burkina Faso, a neurologic syndrome tripled the risk of death among patients infected with HIV. [2]

NeuroAIDS syndromes include acute fulminant encephalopathy, [3] neurologic immune reconstitution inflammatory syndrome (IRIS), [4] HIV-associated neurocognitive disorders (HAND), [5] central nervous system opportunistic infections (CNS-OIs), [6],[7] CNS lymphoma, [8] stroke, [9] vacuolar myelopathy, [10],[11] and distal sensory polyneuropathy (DSP). [12]

Sub-Saharan Africa is home to two-thirds of the 33.3 million people currently living with HIV/AIDS worldwide. [13] The prevalence of HIV-associated neurologic disease in Africa ranges from 34% to 42.5% in Nigeria [14],[15] to as high as 75% in South Africa, [16] suggesting that NeuroAIDS currently affects over 11 million Africans. Among CNS-OIs, cryptococcal meningitis alone is responsible for 504,000 deaths yearly in sub-Saharan Africa. [7] Clearly, NeuroAIDS poses a significant health and economic burden on the African continent.

A good understanding of NeuroAIDS may help improve disease-free survival in patients at risk and optimize resource utilization by care-givers. In this review, we aim to provide a summary of major NeuroAIDS syndromes of relevance in Africa, with emphasis on recent advances made in understanding the neuropathology of HAND.

We searched Medline for English language literature using the search terms "NeuroAIDS" and "HIV AND Nervous System" to identify relevant publications. We included for review articles based on studies conducted in Africa and elsewhere that provided further insight into NeuroAIDS and its treatment.

 Neuropathology of Human Immunodeficiency Virus

Following human infection, HIV breaches the blood-brain barrier and enters the CNS through infected macrophages, a process aided by the cytokine monocyte chemoattractant protein-1 (MCP-1). [17] Within the CNS the virus infects astrocytes and microglia, with neuronal damage resulting from secondary effects of glial reaction and release of neurotoxic viral proteins and cytokines. [18],[19],[20] This phenomenon has been described as the "innocent bystander effect."

Viral envelope glycoprotein gp120 induces neuronal injury by a process involving glutamate-mediated excitotoxicity, in which activation of a caspase cascade results in reactive astrogliosis, synaptodendritic injury, and diffuse loss of pyramidal neurons. [21] Also, gp 120 induces mitochondrial dysfunction in nociceptive neurons and axons, contributing to HIV-associated DSP. [12],[ 22] Transactivating protein of transcription (Tat), produced by infected astrocytes, causes mitochondrial dysfunction and cell death of hippocampal neurons. [23] HIV proteins also cause neuronal and glial injury in the spinal cord, resulting in vacuolar myelopathy. [10] Below is a summary of major CNS NeuroAIDS syndromes:

HIV-associated neurocognitive disorders

The American Academy of Neurology (AAN) published revised criteria for HAND in 2007, [24] based on research work at the HIV Neurobehavioral Research Centre of the University of California San Diego (UCSD). HAND encompasses asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). All are characterized by impairment in at least two cognitive domains among language, abstract-executive function, attention, memory, information processing, sensory perception, and motor skills.

Epidemiology of HIV-associated neurocognitive disorders

Before the introduction of HAART during the 1990s, HAD was prevalent in approximately 16% of HIV/AIDS patients, with a yearly incidence of 7%. [25] However, use of HAART has seen incidence decline by 50%, while prevalence has increased, due to improved survival. [26] Currently, HAND is prevalent in 15-42% of HAART-treated patients in western countries. [27],[28] In Africa, where access to HAART is limited and the clinical picture may be confounded by CNS-OIs, prevalence ranges between 21% in Cameroon, [29] 33% in Zambia, [30] and 53% in Nigeria. [14] Other potential confounders in HAND include disease stage of the study population and presence of comorbid conditions such as chronic hepatitis C virus infection, [31] methamphetamine use, anemia, and depression. [32],[33]

Clinical features and diagnosis of HAND

ANI may be considered as the presymptomatic form of HAND, in which neurocognitive impairment goes unrecognized. However, MND results in noticeable cognitive deficits that interfere with work and social functioning, and is associated with reduced survival, reduced adherence to antiretroviral therapy, and higher rates of HIV encephalitis. [34],[35] HAD is easily recognized, since patients exhibit severe cognitive, behavioral, and motor deficits, including chorea, myoclonus, dystonia, postural tremors, and abnormalities of gait. [36],[37]

HAD may be diagnosed by a bedside examination showing a marked decline in cognitive function, or following neuropsychological testing where at least two cognitive domains are impaired by two or more standard deviations above the population mean. [24] In contrast, the diagnosis of ANI or MND must involve neuropsychological testing, in which two or more cognitive domains are impaired by at least one standard deviation above population means.

Several neuropsychological tests are available for evaluating cognitive function in HAND [Table 1]. The International Neurobehavioral Battery developed at UCSD utilizes these tests, as well as tests of physical and psychiatric functioning, including an Activities of Daily Living scale and the Beck Depression Inventory. Administering the full battery inevitably takes much time and resources. A useful screening tool may be the International HIV Dementia Scale (IHDS), [38] which is easily administered and has shown good sensitivity to HAD in Cameroon [29] and Nigeria, [39] but not in South Africa. [40] Obviously, larger studies are needed to determine the role of the IHDS in cross-cultural settings in Africa.{Table 1}

Treatment of HAND

The cornerstone of treatment is HAART, which improves cognitive dysfunction in as little as 12 weeks after initiation of treatment. [41] Yet, 10% of treated patients experience primary CSF virologic failure, defined as detectable HIV RNA levels in CSF but not in plasma while taking antiretroviral drugs. [42] Predictors of better neuropsychological improvement in HAART-treated patients include higher nadir plasma CD4 cell counts, undetectable CSF viral loads (≤50 copies per mL), lower baseline neuropsychological scores, and better antiretroviral CNS penetration effectiveness (CPE) index. [41],[43]

The CPE index ranks individual antiretroviral compounds according to how effectively they penetrate the CNS and exert antiviral activity. Drugs with high CPE rankings include zidovudine, nevirapine, indinavir, efavirenz, and abacavir, whereas tenofovir, zalcitabine, and saquinavir all display weak CPE indices. While CPE rankings may help guide the choice of individual antiretroviral compounds for use in HAND, other factors must be considered also, including drug availability and tolerability, and drug-drug interactions, especially in patients with comorbid conditions.

Adjuvant therapy has yielded disappointing results in HAND. Minocycline, [43] memantine, [44],[45] sodium valproate, [46] lexipafant, [47] and selegeline [48] have all failed to improve cognitive function in randomized trials but other drugs are currently being investigated, including paroxetine, fluconazole, and rivastigmine. [44]

Central nervous system lymphoma and other tumors

Primary CNS lymphoma (PCNSL) is a non-Hodgkin B-cell lymphoma that arises from malignant transformation of lymphocytes chronically activated by the Ebstein-Barr virus (EBV). [8] EBV DNA is detected in the CSF of most affected patients. [49],[50] PCNSL constitutes an AIDS-defining illness, [51] affecting 5% of all HIV patients during the pre-HAART era. [52] The introduction of HAART has led to a reduction in incidence of non-Hodgkin lymphoma by as much as 20-fold in some populations. [52] However, HIV/AIDS patients still face an increased risk, especially at low serum CD4 cell counts. [53] In one study, each 50 cells per microliter decline in serum CD4 count was associated with a 1.8-fold increased risk of PCNSL in HAART treated patients. [54]

PCNSL presents with visual disturbance, headache, personality change, focal neurological deficits, and seizures. [55] Imaging with brain CT or MRI scan reveals single or multiple ring-enhancing lesions with mass effect and surrounding edema, involving mostly the cerebellum and periventricular white and gray matter. [55],[56]

The treatment of HIV-associated PCNSL has not been addressed in large, controlled trials. Treatment options are based on retrospective studies, or on studies in immunocompetent persons. [55],[57],[58] A German study of non-HIV-related PCNSL showed no advantage of radiotherapy combined with methotrexate over methotrexate alone, [58] while a Japanese study of HIV-associated PCNSL reported prolonged survival with radiotherapy combined with HAART. [57] Meanwhile, ganciclovir has been shown to prolong survival and eradicate CSF EBV. [59] Chemotherapy and radiotherapy are both associated with major side effects, including leucopenia, liver toxicity, and leukoencephalopathy. [57],[58] Irrespective of treatment regimen, better performance status at diagnosis improves survival. [57],[58]

Taking all these into consideration, patients with HIV-associated PCNSL should probably all receive a combination of HAART, ganciclovir, and methotrexate. Additional treatment with radiotherapy is then offered to those with a good performance status.

Other cancers associated with HIV infection include Kaposi sarcoma and carcinoma of the uterine cervix, both of which are AIDS-defining illnesses. [51] Kaposi sarcoma commonly involves the skin and viscera, but brain involvement is extremely rare. [60] HIV infection has been associated also with Hodgkin's disease, anal cancer, and conjuctival carcinoma in Uganda and South Africa, [61],[62] but these cancers do not commonly involve the brain.

CNS opportunistic infections

Toxoplasma encephalitis

Toxoplasma encephalitis (TE) is the most common cause of intracranial mass lesions in AIDS, affecting up to 50% of patients in Europe and Africa during the pre-HAART era. [6] The use of HAART has reduced disease incidence markedly in Europe, but apparently not in Africa. For instance, during 1996-2007 when HAART was already widely available in the UK, TE affected only 0.6% of 31,000 subjects enrolled in the Collaborative HIV Cohort Study. [63] In contrast, 32.6% of HIV/AIDS patients taking HAART in Lagos, Nigeria had positive toxoplasma serology and focal neurologic deficits. [14]

TE is caused by T. gondii, an obligate intracellular protozoon, that infects domestic animals and humans. [64] The prevalence of latent T. gondii infection in adults varies across Africa, ranging from 10.9% among young women in Mozambique to as high as 61.5% among elderly Tanzanians. [65],[66] Latent infection is reactivated during immunosuppression, with 25-50% of HIV patients seropositive for T. gondii ultimately developing toxoplasmosis in the absence of prophylactic therapy. [67]

The clinical and radiologic features of TE may be indistinguishable from PCNSL. [55],[56] In general, multiple lesions on neuroimaging are likely due to TE, while a single lesion suggests PCNSL, but this is not invariable [Figure 1]a and b. Although not highly sensitive, increased tracer uptake on Thalium-201 SPECT is highly specific for PCNSL. [49] A guideline by the AAN recommends stereotactic biopsy when either Thalium-201 SPECT is positive, or a single intracranial mass lesion accompanies negative toxoplasma serology. [67] Empiric treatment for TE is indicated when SPECT is negative, or when intracranial mass lesions, single or multiple, are accompanied by positive toxoplasma serology.{Figure 1}

Recommended treatment is oral pyrimethamine combined with sulfadiazine or clindamycin. Patients are monitored for clinical and radiological response over 10-14 days, and in those who have responded, treatment should continue indefinitely until lesions have regressed. [67]

Cryptococcal meningitis

Each year, cryptococcal meningitis affects 720,000 people and causes 504,000 deaths in sub-Saharan Africa. [7] Cryptococcal meningitis (CM) was diagnosed in 2.6% of HIV-positive patients in Malawi and 8.8% of HIV/AIDS patients admitted at a referral center in Nigeria. [68],[69] In Cape Town, South Africa, CM accounted for 31% of hospital days spent by patients commencing HAART. [70]

Ninety-five percent of all cases of CM are HIV related, with patients having serum CD4 cell counts of 100 per microliter or less at most risk. [71],[72] Clinical features include fever, headache, altered mental status, and neck stiffness. [72] Less than one-third of patients with CM have lateralizing signs including neck stiffness; the organism Cryptoccocus neoformans causes minimal inflammatory changes, unlike the tubercle bacilli. Diagnosis relies on CSF analysis by India ink stain or cryptococcal antigen (CRAG) detection. A new CRAG detection dipstick test was recently approved in Europe and the United States. [73] This test is inexpensive and can be used by untrained personnel, making it ideal for sub-Saharan Africa.

The treatment of cryptococcal meningitis is in three stages, according to guidelines by the Infectious Diseases Society of America. [74] A 2-week induction with amphotericin B and flucytosine is followed by 8-10 weeks consolidation with fluconazole, and then long-term maintenance with fluconazole. A South African guideline recommends the same treatment, but excluded flucytosine, which is not available in much of Africa. [75] HIV patients with serum CD4 counts less than 100 cells per microliter may be offered septrin prophylaxis.

Mortality remains high in sub-Saharan Africa. In a recent study, Wajanga, et al., reported a mortality rate of 66% in Tanzania. [72] Factors contributing to high mortality include delayed presentation, inadequate diagnostic equipment and limited access to antifungal agents and HAART. [72],[76],[77]

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a demyelinating CNS disease caused by the JC virus (JCV), which destroys oligodendrocytes in patients with compromised immune function. [78] The incidence of HIV-associated PML has decreased worldwide with HAART, [79],[80] although unlike other CNS-OIs, PML may develop even in those with normal CD4 counts. [81] Clinical features include hemisensory loss, hemiparesis, hemianopia, aphasia, ataxia, and dysmetria. [78]

PML has not been well studied in sub-Saharan Africa, perhaps due to challenges associated with diagnosis. This involves a brain MRI and detection of JCV DNA by polymerase chain reaction (PCR) of CSF or in situ nucleic acid hybridization of brain specimens. [78] Reports of PML in Africans are limited to few cases diagnosed in western countries. [82],[83] However, Glass and Venter have recently described an improved diagnostic method in a study of 44 patients in South Africa. [84] On brain MRI, PML shows white matter lesions involving the cerebral hemispheres and brainstem. [85] Lesions do not enhance with contrast, which differentiates PML from PCNSL and TE [Figure 1]c.

The only effective treatment is HAART. While mefloquine and interleukin-2 had shown earlier promise, [86],[87] a randomized, controlled trial of mefloquine was aborted recently for lack of benefit. [88]

CNS tuberculosis

Tuberculosis of the CNS manifests as meningitis, intracerebral tuberculoma or tuberculosis of the spinal cord. [89] Tuberculous meningitis (TBM) is associated with significant mortality among Africans with HIV/AIDS. [15] During 2009, TBM accounted for 44% of cases of meningitis at a referral hospital in Cape Town, South Africa. [90] Of this proportion, 88% had HIV infection and 48% had died within 6 months.

Patients present with features of raised intracranial pressure, neck stiffness, confusion, seizures and focal neurologic deficits, [90] or rarely, personality changes and coma. [91] Brain CT or MRI scans reveal basal meningeal enhancement, cerebral infarction and hydrocephalus. [92] Confirmatory diagnosis requires the identification of M. tuberculosis in CSF using Ziehl-Neelsen stain, PCR or culture. [90]

TBM is a medical emergency, and empiric treatment with antituberculous drugs and corticosteroids should be started as soon as the diagnosis is suspected. [89] Following confirmation, antituberculous treatment should continue for 9-12 months. [91] Rifampicin induces cytochrome P450 and reduces plasma levels of nevirapine and protease inhibitors. For this reason, HIV/AIDS patients should receive rifabutin instead, but where this is not available, the US Centers for Disease Control recommend an efavirenz-based HAART with a dose adjustment from 600 mg to 800 mg rifampicin daily. [83] Alternatively, low dose ritonovir (to block the cytochrome P450 stimulating effect of rifampicin) is added to the rifampicin-nevirapine combination. [83],[93]

Cerebrovascular disease

Among patients with HIV/AIDS, stroke may result from coexisting vascular risk factors, infective endocarditis related to injection drug use, the effects of CNS opportunistic infections and lymphoma, or from direct effects of HIV. [94],[95] Studies on HIV-related stroke in sub-Saharan Africa do not quantify individual risks attributable to these factors. [96],[97]

During the pre-HAART era in the United States, HIV/AIDS was associated with a 10.4-fold increased risk of stroke, excluding strokes caused by AIDS-related medical conditions. [94] This risk seems to have increased despite the use of HAART. In a recent study, the incidence of ischemic stroke declined by 7.2% in the US general population between 1997 and 2006, but over the same period, incidence increased by 60.5% in HIV-positive patients. [9] This is only partly explained by a growing US HIV-positive population, which increased by nearly 40% between 1998 and 2006. Other contributory factors were thought to include metabolic derangements resulting from HIV-associated liver disease and age-related atherosclerosis associated with longer survival due to use of HAART.

There are no stroke treatment guidelines specifically targeted to HIV-positive patients, but this may soon change. A recent report has implicated abacavir as a risk factor for cerebrovascular events in Denmark. [95] If this is confirmed, there would then be an urgent need for guidelines on stroke prevention and treatment in patients with HIV/AIDS.

 Conclusions and future directions

Much of the global burden of NeuroAIDS is borne by sub-Saharan Africa, where limited resources have hindered efforts at diagnosis, treatment, and prevention. For instance, in toxoplasma encephalitis and progressive multifocal leukoencephalopathy, diagnosis is often missed or delayed for lack of neuroimaging facilities and techniques for DNA analysis. In cryptococcal meningitis, a correct diagnosis may not lead to treatment, either because the drug is unavailable, as is the case with flucytosine, or unaffordable, as with amphotericin B. The end result is increased morbidity and reduced survival in patients at risk. Other challenges include limited opportunities for research due to inadequate funding and poor health infrastructure in most countries of sub-Saharan Africa. In particular, a paucity of research into PML and HIV-related stroke has undermined efforts at determining the optimal treatment for these syndromes.

Stigma and discrimination are other significant barriers to NeuroAIDS care in sub-Saharan Africa. Recent studies have highlighted the magnitude of this problem. [98],[99],[100],[101] Stigmatization of people living with HIV/AIDS (PLWHA) cuts across all strata of society, and was reported by 22-25% of PLWHA in Northern Nigeria. [98],[99] In Uyo, Southern Nigeria, 37.3% of women attending an antenatal clinic expressed negative attitudes toward PLWHA, suggesting that stigmatization is not simply a matter of perception. [100] Stigma and discrimination induce fear, denial, and social isolation in PLWHA and limit the efficacy of HIV-testing and control programs. [101]

Nevertheless, the state of NeuroAIDS care in sub-Saharan Africa may be improving. Since 2004, a series of meetings on "NeuroAIDS in Africa" were organized and funded by the US National Institute of Mental Health under the auspices of the International AIDS Society. [30],[102],[103] At the third meeting held in 2009 in Cape Town, South Africa, clinicians and researchers discussed the challenges and opportunities in NeuroAIDS care and research in sub-Saharan Africa. [30] Participants revealed data showing decreasing HIV prevalence and improved access to antiretroviral drugs in many nations of Africa. Factors responsible include better funding for HIV care by African governments and the Global Fund, the US president's emergency plan for AIDS relief (PEPFAR) and the roles of donor agencies and nongovernmental organizations. Participants also presented findings on NeuroAIDS research and clinical care in Botswana, Cameroon, Ethiopia, Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. [30]

The future looks promising for NeuroAIDS care and research in sub-Saharan Africa. At present, researchers in Africa are studying several clinical end-points in HAND, often in collaboration with investigators in the United States and other countries. A research study initiated at the University of Maryland Medical School and funded by the US National Institute of Allergy and Infectious Disease is currently recruiting participants at two centers in Nigeria. The study will investigate severity of neurocognitive impairment in relation to monocyte-associated HIV DNA viral load, and the role of viral compartments in the emergence of antiretroviral drug resistance. Insight gained from these efforts will obviously have significant implications for HIV care in sub-Saharan Africa and the rest of the world.


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