Specific neurologic complications of human immunodeficiency virus type 1 (HIV-1) infection in children

Pediatric human immunodeficiency virus type 1 (HIV-1) infection is endemic throughout southern Africa. Neurologic complications are described in 20% to 60% of published series, mostly related to HIV-1 encephalopathy. With increasing HIV prevalence, more atypical cases are presenting. We present, as illustrative cases, seven children (three girls) with unusual neurologic sequelae as a consequence of HIV-1 infection. The median age at presentation was 33 months (range 7 months-6 years). Five of the seven children were developmentally normal before presentation. They presented with progressive multifocal leukoencephalopathy, myelopathy, intractable seizures, acute vasculitis and blindness, hemiplegia, peripheral neuropathy, and paraspinal lymphoma. Neuroimaging of the brain was performed in five patients, of whom one had basal ganglia calcification. All children had poor outcome with incomplete recovery or continued deterioration. In conclusion, children with HIV-1 infection who survive beyond the first year of life can present with a wide variety of neurologic complications. A similar spectrum of neurologic manifestations is likely to occur in other sub-Saharan African countries, characterized by high HIV prevalence. The case histories demonstrate that the neurologic features of pediatric HIV infection do not easily fit into a simplified classification system.     

DSM-IV mental disorders and neurological complications in children and adolescents with human immunodeficiency virus type 1 infection (HIV-1).

AIM: - To study the types of psychiatric problem encountered in children infected with the human immunodeficiency virus (HIV) and their relationship to central nervous system disorder and the severity of infection. METHODS: - 17 HIV-infected children presenting with psychiatric problems were included. Mental disorders were evaluated according to DSM-IV criteria. Neurological disorders and progressive encephalopathy (presence or absence) diagnosis were evaluated by clinical and radiological examination. The severity of infection was assessed by the percentage of CD4 lymphocytes. RESULTS: - The most frequent diagnoses were major depression (MDD: 47%) and attention deficit hyperactivity disorder (ADHD: 29%). Major depression diagnosis was significantly associated with neuroimaging or clinical neurological abnormalities (p < 0.01). In contrast, no association was found between hyperactivity diagnosed according to DSM-IV criteria and central nervous system disorder. Percentage of CD4 lymphocytes were close to 0 for more than 80% of children presenting with psychiatric complications. CONCLUSION: - The very low % of CD4 lymphocytes of these children suggest that the appearance of a psychiatric complication should be regarded as a factor indicating severe HIV infection. Depressive disorders may be a clinical form of encephalopathy.     

Lentiviral encephalitides in the immature host: a comparison of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) brain infection

The human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) are members of the lentivirus subfamily of retroviruses. Both are capable of establishing persistent infection in the nervous system and both demonstrate increased virulence in the immature of their respective host species. Brain infection with these primate lentiviruses share common virologic and neuropathologic features. The available evidence to date suggests that viral factors may determine neuroinvasiveness and possibly neurovirulence, but that host factors may be largely responsible for the neuropathologic changes observed.     

Immunodetection of human immunodeficiency virus type 1 (HIV-1) Vpr in brain tissue of HIV-1 encephalitic patients

Human immunodeficiency virus (HIV) encephalitis (HIVE), the most severe neurological complication associated with HIV-1 infection, leads to the onset of HIV-1-associated dementia (HAD). Several HIV-1 viral proteins have been implicated in HIVE-associated neurodegeneration. HIV-1 viral protein R (Vpr), a virion associated gene product known to induce apoptosis in nonproliferating cells, including neurons, is thought to contribute to the neuropathogenesis associated with HIVE. Though current research suggests that Vpr plays a significant role in neuropathogenesis, the presence of Vpr in the brain tissue of HIVE patients has not been assessed. Using a panel of HIVE patient brain tissue, the authors have shown that Vpr is present in detectable amounts in both the basal ganglia and frontal cortex of all HIVE brain tissue samples tested. Double immunofluorescence indicated that Vpr was found in the macrophages and neurons, but not in the astrocytes, of HIVE patients. These results for the first time show the presence of Vpr in vivo and further support the role of Vpr in neuropathogenesis.     

Quantitative neurologic and neurobehavioral testing of persons infected with human immunodeficiency virus type 1

Assessment of neurobehavioral and peripheral neurologic performance among homosexual men was made on two occasions, using a computer-administered neurobehavioral instrument and quantitative vibration threshold testing, respectively. Persons studied included high-risk human immunodeficiency virus (HIV)-negative men (n = 13), asymptomatic HIV-positive men (n = 30), and patients with acquired immunodeficiency syndrome (AIDS)-related complex of AIDS (n = 17). In addition, subjects were characterized immunologically at the time of neurologic and neuropsychologic assessment via determination of circulating lymphocyte counts (total lymphocytes, helper T cells, suppressor T cells, total T cells, activated T cells) and markers of HIV type 1 (HIV-1) infection. At the first cycle of testing, the results of asymptomatic HIV-positive men were indistinguishable from those of HIV-negative men, while persons with AIDS-related complex or AIDS tended to have lower mean performance. These differences did not achieve statistical significance on any single test, but the group with AIDS-related complex or AIDS had the worst mean performance on 12 of 13 individual performance tests. Thirty-seven men underwent repeated testing after a mean interval of approximately 4.5 months. There was little change in mean neurobehavioral performance and vibratory thresholds among all three groups. Measures of neurobehavioral performance and vibrotactile thresholds were not correlated with measures of immunological status. These results are consistent with the concept that asymptomatic infection with HIV-1 does not imply the presence of measurable or significant neurologic or neurobehavioral impairment.     

Neurologic manifestations of human immunodeficiency virus infections

HIV infection is becoming more common. The recognition of HIV-related neurologic disease is also increasing. Both the central and peripheral nervous systems are affected by HIV infection. Although much of the pathophysiology remains to be elucidated, some of the neurologic syndromes are probably due to direct HIV infection. The most common CNS syndrome, the subacute encephalopathy, appears to be caused by HIV infection. Other cerebral syndromes are caused by viral, fungal, and protozoan opportunistic infections. Current specific therapy is available for many of these infections. Aside from zidovudine, only experimental therapies are currently available for primary HIV infection. Less attention has been focused on the neuromuscular complications of HIV infection. They are probably more common than initially reported. Specific therapies for both inflammatory demyelinating neuropathies and myopathy related to HIV infection are reported. The pathophysiology of these disorders remains incompletely defined. As the population of HIV infected individuals continues to grow, the incidence of coincidental non-HIV neurologic disease will also rise. Attention must be directed to identifying coexistent remediable causes of neurologic dysfunction in this population.     

Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis

The presence of specific neuroinvasive strains and necessity for brain viral replication for disease progression remain controversial issues in neuro-AIDS research. To investigate these questions, the authors injected human monocyte-derived macrophages (MDMs) infected with diverse viral strains were injected into the caudate and putamen of severe combined immunodeficient (SCID) mice. Independent of viral strain, infected MDMs became immunologically activated and elicited profound inflammatory reactions in brain areas most affected in humans. The intensity of neuropathologic changes, including microglial reactions, paralleled levels of viral infection and numbers of infected MDMs. The data suggest that HIV-1-associated neurological disease is related to the level of productive viral infection in activated macrophages. Virus infection, per se, may affect the ability of macrophages to respond to immune stimuli by overproduction of proinflammatory factors and neurotoxins, leading to neuronal dysfunction.     

Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis

The presence of specific neuroinvasive strains and necessity for brain viral replication for disease progression remain controversial issues in neuro-AIDS research. To investigate these questions, the authors injected human monocyte-derived macrophages (MDMs) infected with diverse viral strains were injected into the caudate and putamen of severe combined immunodeficient (SCID) mice. Independent of viral strain, infected MDMs became immunologically activated and elicited profound inflammatory reactions in brain areas most affected in humans. The intensity of neuropathologic changes, including microglial reactions, paralleled levels of viral infection and numbers of infected MDMs. The data suggest that HIV-1-associated neurological disease is related to the level of productive viral infection in activated macrophages. Virus infection, per se, may affect the ability of macrophages to respond to immune stimuli by overproduction of proinflammatory factors and neurotoxins, leading to neuronal dysfunction.     

Neuropsychiatric aspects of human immunodeficiency virus (HIV) infection

Human immunodeficiency virus (HIV) infection with central nervous system (CNS) involvement causes a variety of psychiatric complications among a significant proportion of infected individuals. A cure for the fully developed AIDS related to HIV infection remains elusive, and HIV/AIDS is a leading cause of death among adults between the ages of 25 and 44. Life expectancy, however, has gradually increased over the years, resulting in a concern for a potential increase in the incidence of secondary psychiatric manifestations. Knowledge of the neuropathology of HIV-CNS dysfunction and familiarity with its clinical presentation can aid clinicians in a determination of the appropriate therapy inclusive of psychiatric care that may be useful for a specific individual in their treatment.     

Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) p24 antigen levels in HIV-1–related dementia

Human immunodeficiency virus type 1 (HIV-1) p24 antigen, a putative marker of virus load, was assayed in 79 blood and 83 cerebrospinal fluid (CSF) samples from 90 HIV-1–seropositive individuals with or without demetia. Twenty-eight subjects had no evidence of neuropsychological impairment, 17 had mild impairment without objective evidence of dementia, and 45 were demented. HIV-1 p24 antigen was detected more frequently in CSF samples from demented (19/40) than normal (1/26) or mildly impaired (1/17) subjects and in 67% of individuals with significant dementia (MSK stages 2–4). p24 Antigen was detected less frequently in CSF from demented subjects on antiretroviral drugs than untreated demented individuals. Overall, the sensitivity of the antigen capture assay in CSF among demented individuals was 47.5%; the specificity, 95.0%; positive predictive value, 90.4%; negative predictive value, 66.1%; and the efficieny, 72.2%. A direct relationship was also noted between the degree of congnitive impairment and blood p24 antigen detection frequency and antigen concentration. CD4⁺ blood lymphocyte counts were lower for demented individuals, and HIV-1 p24 antigen was detected more frequently and p24 antigen concentration was higher in blood and CSF from individuals with low CD4⁺ blood lymphocyte counts. β₂-Microglobulin levels were higher in CSF from demented subjects and correlated directly with CSF p24 antigen concentration. However, in contrast to CD4⁺ blood lymphocyte counts and β₂-microglobulin levels, only p24 antigen concentration correlated with dementia severity. Therefore, p24 antigen can be a useful marker for dementia related to HIV-1 infection.     

Neurotrophic activity of monomeric glucophosphoisomerase was blocked by human immunodeficiency virus (HIV-1) and peptides from HIV-1 envelope glycoprotein

Glucophosphoisomerase (GPI), a glycolytic enzyme, was recently described to share 90% sequence homology with neuroleukin, a recently discovered growth factor which promotes motor neuron regeneration in vivo, survival of peripheral and central neurons in vitro, and affects B cell immunoglobulin synthesis. Interestingly, neuroleukin activity was described to be antagonized by the human immunodeficiency virus (HIV-1) envelope glycoprotein (gp120), with which neuroleukin was found to share partial sequence homology. In this study, reduced GPI demonstrated similar activity to neuroleukin in a novel bioassay using human and rat neuroblastoma cell lines. In the presence of reduced GPI, these cells were found to differentiate, in terms of enhanced neurite extension at a reduced proliferation rate. These results demonstrate the existence of a novel growth factor activity of an evolutionary ancient enzyme. The nonreduced commercial form of GPI, probably the dimer, was found to be inactive in this bioassay. Using the neuroblastoma cells model system, we further investigated the significance of the region of homology to HIV-1 envelope glycoprotein (gp120) as the putative binding site of GPI to its receptor on neuronal cells.     

Stroke in patients with human immunodeficiency virus infection

Objective

To report the nature of stroke in patients infected with human immunodeficiency virus (HIV) in a region with high HIV seroprevalence and describe HIV associated vasculopathy.

Methods

Patients with first ever stroke, infected with HIV and prospectively included in the stroke register of the Groote Schuur Hospital/University of Cape Town stroke unit were identified and reviewed.

Results

Between 2000 and 2006, 67 of the 1087 (6,1%) stroke patients were HIV infected. Of these, 91% (n = 61) were younger than 46 years. Cerebral infarction occurred in 96% (n = 64) of the HIV positive patients and intracerebral haemorrhage in 4% (n = 3). HIV infected young stroke patients did not demonstrate hypertension, diabetes, hyperlipidaemia or smoking as significant risk factors for ischaemic stroke. Infection as a risk factor for stroke was significantly more common in HIV positive patients (p = 0.018, OR 6.4, CI 3.1 to 13.2). In 52 (81%) patients with ischaemic stroke, an aetiology was determined. Primary aetiologies comprised infectious meningitides/vasculitides in 18 (28%) patients, coagulopathy in 12 (19%) patients and cardioembolism in nine (14%) patients. Multiple aetiologies were present in seven (11%) patients with ischaemic stroke. HIV associated vasculopathy was identified in 13 (20%) patients. The HIV associated vasculopathy manifested either extracranially (seven patients) as total or significant carotid occlusion or intracranially (six patients) as medium vessel occlusion, with or without fusiform aneurysmal dilation, stenosis and vessel calibre variation.

Conclusion

Investigation of HIV infected patients presenting with stroke will determine an aetiology in the majority of patients. In our cohort, 20% of patients demonstrated evidence of an HIV associated vasculopathy.Infection with the human immunodeficiency virus (HIV) contributes to an increased risk of stroke.^1,2,3,4 In South Africa, 5.4 million people out of a total population of nearly 48 million South Africans are infected with HIV, giving a total prevalence of approximately 11% in 2006.⁵ Isolated reports have identified vasculopathy as a cause of stroke in HIV infected patients.^{6,7,8,9,10,11,12}We report the largest clinical cohort of HIV associated strokes prospectively admitted and investigated by the only tertiary stoke unit in Sub‐Saharan Africa. Groote Schuur Hospital is a university teaching hospital serving an open population of approximately 2.9 million persons. The selection bias of our Stroke Unit favours patients from low socioeconomic income groups (more affluent patients with health insurance tend to seek medical care in the private sector), young stroke patients under the age of 46 years (24% of the sample because of referral from other hospitals) and more severe strokes.Our objective was to describe the nature of stroke in HIV infected patients in clinical practice in a region with a high seroprevalence in the general population and further define HIV associated vasculopathy.     

Neurologic consequences of hepatitis C and human immunodeficiency virus coinfection

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share overlapping, large worldwide distribution. The implications of coinfection are being explored because of the importance of these viruses and demographic factors that favor coinfection. The nervous system is affected by HIV in a variety of ways resulting in significant disease of all levels of the nervous system. Emerging evidence that HCV can also impact the nervous system raises concerns that detrimental interactions might occur. Several reports addressing the manifestations of coinfection support independent contributions for both HIV and HCV on central nervous system performance, but not on distal sensory neuropathy. Neuropsychological testing reveals independent contributions resulting in poorer performance in coinfection in several drug-abusing cohorts. Motor physiologic testing substantiates performance deficits from HCV in coinfected subjects as does testing in treatment naive coinfected subjects. Although ongoing deficits attributed to HCV may be seen during HIV treatment, these deficits may be less apparent in advanced HIV disease. Current evidence supports independent contributions of HCV and HIV to neurological impairment. Preliminary evidence suggests that coinfection-related impairment does not appear to accelerate HIV-1-associated cognitive disease.     

Brain pathology induced by infection with the human immunodeficiency virus (HIV)

Summary Neuropathological examination of brain tissue of 100 patients with infection by the human immunodeficiency virus (HIV), including 98 with clinically manifest acquired immune deficiency syndrome (AIDS), revealed distinct multifocal-disseminated and diffuse brain tissue lesions, which can be regarded as HIV-induced brain lessions: multifocal giant cell encephalitis (MGCE; 4) and progressive diffuse leukoencephalopathy (PDL; 25). These lesions were found in 38 brains, and in 17 in absence of infectious, necrotizing or inflammatory changes of other types. In 13 brains, a combination of MGCE with PDL was seen, suggesting a spectrum of HIV-induced brain lesions. MGCE is characterized by perivascular accumulations predominantly of rod cells, monohistiocytes and macrophages, all of which are strongly labeled with a monoclonal antibody to macrophages. Most conspicuous are multinucleated giant cells which are also labeled by anti-macrophage antibody, and which can be regarded as evidence of the local presence of HIV, as confirmed by electron microscopical detection of HIV particles in four MGCE brains, and by immunocytochemical detection of HIV proteins in two MGCE brains. PDL is characterized by a triad: diffuse myelin loss, astroglial proliferation, and infiltration by mono- and multinucleated macrophages. HIV-induced lesions can be morphologically differentiated from histopathological brain lesions known in immunosuppression, including what is called here nodular encephalitis [subacute encephalitis of the literature, in most cases attributable to cytomegalovirus (CMV) or toxoplasmosis], by their characteristic histopathology including the hallmark presence of multinucleated giant cells, by direct immunocytochemical and electron microscopical demonstration of HIV in the lesions, and by the absence of opportunistic agents (bacteria, fungi, Toxoplasma, CMV, HSV or papovaviruses). Diffuse poliodystrophy (diffuse proliferation of astroglia with swollen nuclei, occasionally minor neuronal loss and rod cell proliferation) was found in the cerebral cortex and other gray matter in half of all brains, including cases with gyral atrophy, and may be another correlate of HIV damage to the brain. Morphological delineation of HIV-induced brain lesions is a necessary prerequisite for a meaningful clinical definition of HIV-induced cerebral disease.Part of this study was presented at the International Scientific Meeting: Medical Brain Research — State and Perspectives, in Vienna, Austria, June 18–20, 1987     

Neurological complications of the human immunodeficiency virus (HIV) infection

Human immunodeficiency virus infection (HIV) is entering into its third decade affecting more than 40 million persons on the plane, with an extraordinary incidence in the underdeveloped world, especially in the African continent where more than 25 million are affected, with more than 3 million new yearly infections and where the life expectancy is at 47 years. Although the vaccination is still far away, the introduction of combined antiretroviral therapy in the middle of the 90's was an important advance that contributed to converting an infection that previously had a very high rate of short-term mortality into a chronic disease. The neurological complications of this infection vary enormously. They affect any location of the neuroaxis and can appear at any stage of infection. It is not rare that more than one neurological complication exists. Such complications may be a consequence of the infection itself (primary) or related with immune depression accompanying it (secondary). Among the former, dementia associated to HIV and peripheral polyneuropathy stand out. Among the latter, opportunistic viral and fungal infections and lymphoma of the nervous systems stand out. In recent years different tests that help to establish the diagnoses of these entities have been developed, a necessary step to initiate adequate therapies. The immune state of the patient, reflected by the peripheral count of CD4 lymphocytes and serum viral load, helps us to establish the most likely causes of the neurological problems that appear in the context of this infection. We briefly review the most outstanding characteristics of each one of them in this work.     

Seizures in human immunodeficiency virus infection

Among 630 patients with human immunodeficiency virus infection, 70 patients with new-onset seizures were studied. Generalized seizures occurred in 66 patients (94%): they occurred as the initial seizure in 56 patients (80%) and during follow-up in another 10 patients (14%). Partial seizures (18 patients), status epilepticus (10 patients), and recurrent seizures (38 patients) were also noted. Identified processes included cerebral toxoplasmosis in 11 patients, cerebral lymphoma in 8, metabolic derangement in 8, cryptococcal meningitis in 7, and vascular infarction in 4. In 32 patients (46%) seizures were not associated with identifiable brain lesions and were believed to result from human immunodeficiency virus cerebral infection. Phenytoin treatment was associated with adverse drug reactions in 16 of 62 patients who received it. Our results suggest that the majority of patients with human immunodeficiency virus and seizures do not have secondary focal brain lesions as the cause of the seizures and that human immunodeficiency virus infection alone can, and often does, cause seizures.     

Kappa light chain predominance in serum and cerebrospinal fluid from human immunodeficiency virus type 1 (HIV-1)-infected patients

We measured kappa/lambda light chain ratios of Ig and IgG in 41 serum and 34 cerebrospinal fluid (CSF) samples from 47 patients at different clinical stages of human immunodeficiency virus type 1 (HIV-1) infection and in serum and CSF samples from control subjects. Both ratios were more elevated in HIV-1 seropositive subjects than controls. The elevation was more evident in samples from asymptomatic seropositive patients (ASP) than those from patients with acquired immunodeficiency syndrome (AIDS). In addition, there was a statistically significant elevation of Ig kappa/lambda ratios in ASP CSF compared to serum. We also delineated the light chain composition of oligoclonal IgG bands (OCB) by isoelectric focusing followed by immunofixation in CSF and serum samples from selected ASP and patients with AIDS who had neurological involvement. Five of six AIDS and all seven ASP samples had IgG OCB exclusively or predominantly of the kappa type. Four IgG OCB of the lambda type and one free lambda chain band were seen in CSF from a pediatric AIDS patient. The presence of an abnormally elevated kappa/lambda ratio correlated with the presence of IgG kappa OCB (p less than 0.02). We conclude that HIV-1 infection is associated with a kappa light chain predominance and with OCB mainly composed of kappa light chains.