Neurological Manifestations of HIV-1 Infection and Markers for HIV Progression

Human immunodeficiency virus, or HIV, is the virus that causes acquired immune deficiency syndrome (AIDS). The acquired immunodeficiency syndrome (AIDS) was first described in 1981 in USA. In 1983, human immunodeficiency virus type-1 (HIV-1) was isolated, and in the following year it was demonstrated clearly that it was the causative agent of AIDS. The disease is a major health problem in many parts of the world. The high prevalence and striking diversi‐ ty of neurological disorders complicating AIDS were recognized in 1983 (Snider et al., 1983). AIDS was associated with distinct neurological syndromes, such as dementia, myelopathy and painful neuropathy that appeared to result from the HIV itself. Over the last 30 years, there has been increasing recognition of the role that auto antibodies play in neurological disorders. Dur‐ ing the past decade, AIDS has become a global health problem with 182,000 000 cases reported from 152 countries. It is estimated that nearly five to ten million people are infected worldwide with HIV-1. With a mean incubation period from time of infection to the development of AIDS of eight to 10 years, it is projected that nearly all HIV-1-infected individual will develop AIDS within the next 15 years (Quinn, 1990). It has become increasingly evident that the vast majori‐ ty of HIV-1 infected people will eventually develop AIDS or an AIDS-related condition (De Wolf and Lange, 1991) with a median time of progression to AIDS of 7-10 years from infection in adults (Lui et al., 1988; Bacchetti and Moss, 1989) and shorter periods in infants and elderly patients (Medley et al., 1987; Auger et al., 1988; Lagakos & DeGruttola, 1989). In the United States alone, 104, 210 cases of AIDS and more than 61,000 deaths have been reported. Sexual, parenteral as well as perinatal transmission routes have remained the major modes of trans‐ mission, although the proportion of cases within each risk behaviour category has changed. Recently, there has been a dramatic increase in the proportion of AIDS patients who have ac‐ knowledged as IV drug user or have heterosexual contact with other individuals at high risk for HIV infection (Quinn, 1990).


Neurological menifestations of HIV-1 infections
HIV is neuroinvasive, it does not directly infect neurons. The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication. HIV-associated neurologic complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins released by infected or activated microglia, macrophages and astrocytes. Neurologic manifestations occur over the entire spectrum of HIV disease. Fifty to 70% of patients experienced acute clinical syndrome 1 to 6 wks after infection, Neuro Manifestations occur in 10% involves Multiple Parts of nervous system. Some Monophonic illness Meningitis, Meningioencephalitis, Seizures, Myelopathy, Cranial and Peripheral Neuropathy linked to primary HIV and recover within 1 week. Neurological opportunistic infections and malignancies predominated in early reports, but it became also clear that AIDS was associated with distinct neurological syndromes, such as Acute/subacute diffuse encephalopathy Progressive dementia, Focal mass lesions, Acute stroke like presentation, Meningitis, Multiple cranial neuropathies and Acute/subacute myelopathy.

HIV encephalopathy
(AIDS Dementia Complex or HIV associated Dementia) is a late complication of HIV infection and progresses slowly over months seen in pts with CD 4 T cell Count >350cells/µl. Dementia is a major feature but aphasia, apraxia and afnofia uncommon, motor abnormality like unsteady gait, poor balance, tremor and in late stage develop apathy & lack of initiative -leads to vegetative state mania (table 1). Neuro imaging: MRI & CT demonstrate cerebral atrophy, Basal ganglia calcification in children. CSF: MonoNucleatz cells increase, Protein increase, RNA can be detected and HIV can be cultured. Infective: CMV ventriculoencephalitis, Varicella encephalitis, Herpes encephalitis, Toxoplasma encephalitis (rare). Treatment: Combination anti retro viral therapy is beneficial and rapid improvement in cognitive function.

HIV-associated dementia
The major direct effect of HIV infection on the immune system is the profound and progressive loss of CD4 lymphocytes. This leads to impaired cellular immunity, and a dysregulation of macrophages, with the overproduction of a variety of proinflammatory cytokines and chemokines (Griffin, 1997). HIV can enter the nervous system early after infection, but productive infection is rarely detectable before immunosuppression has developed. Based upon phylogenetic analysis of HIV gp160, the route of central nervous system (CNS) infection appears to primarily involve infected monocytes (Liu et al., 2000) as well as free viral particles and HIV proteins crossing a disrupted blood-brain barrier. The presentation of HIV-D includes cognitive, behavioral, and motor dysfunction, and suggests a predominant subcortical involvement (Navia et al., 1986). In the early stages, memory loss, mental slowing, reading and comprehension difficulties, and apathy are frequent com plaints (  The cognitive deficits of HIV-D are characterized primarily by (1) memory loss that is selective for impaired retrieval; (2) impaired ability to manipulate acquired knowledge; (3) personality changes including apathy, inertia, and irritability; and (4) general slowing of all thought processes. Gait disturbance and impairment of fine manual dexterity are common early manifestations. Examination findings include impaired rapid movements of eyes and limbs, diffuse hyperreflexia, frontal release signs, and sometimes Parkinsonism (Mirsattari et al., 1998). A recent study suggests that antiretroviral drug combinations with drugs that have better CSF penetration are associated with greater CSF viral load suppression and may be associated with greater improvement in neuropsychological test deficits compared to antiretroviral drug combinations with drugs that have poor CSF penetration (Letendre et al., 2004). Antiretroviral drugs with the highest CSF:plasma ratios or with profound effects on viral replication in the periphery with a resulting decrease in virus entry into the CNS (e.g., zidovudine, stavudine, abacavir, nevirapine, efavirenz, and indinavir) are likely to be the most efficacious for the treatment of HIV-D.

HIV related to myelopathy with polyradiculopathy
The most common cause of spinal cord disease in AIDS patients is AIDS-associated myelopathy, with a reported prevalence of 20% to 55% in different series (Gray et (table 2). The most common finding was spinal cord atrophy, seen in 15 patients (71%) (Fig 2).  AIDS-associated myelopathy is characterized pathologically by discrete or coalescent intramyelin and periaxonal vacuolation, with cellular debris and lipid-laden macrophages, in the white matter of the spinal cord. The axons are usually intact, but in severe vacuolization, they may become disrupted. It typically involves the lateral and posterior columns of the cervical and thoracic cord (Henin et al., 1992;Petito et al., 1985;Dal et al., 1994;Tan et al., 1995). The effect of HAART on improving the symptoms or slowing the progression of HIV-associated myelopathy is not known. A pilot study using high doses of oral L-methionine led to improvement in clinical and electrophysiologic features of the disease in an open-label clinical trial (Dorfman et al., 1997). Uncontrolled clinical experience no benefit from corticosteroids and intravenous immunoglobulin (IVIG).

HIV-Associated Neuromuscular Weakness Syndrome (HANWS)
Toxic events secondary to use of HAART can be observed globally. Recently, Simpson et al. 2004, reported a heterogeneous syndrome termed the HIV-associated neuromuscular weakness syndrome (HANWS) which seems to be related to hyperlactatemia and stavudine and/or didanosine exposure. Rapidly ascending neuromuscular weakness syndrome," associated with lactic acidosis syndrome in HIV-infected patients. Majority dramatic motor weakness developed over days to weeks (resembling GBSrespiratory failure and death in several patients. Systemic symptoms included nausea, vomiting, weight loss, abdominal distention, hepatomegaly, and lipoatrophy. Stavudine, Lamivudine and Efavirenz are most commonly used ARV agent. Muscle weakness worsened even after discontinuation of ARV therapy. Rapidly progressive sensorimotor polyneuropathy and myopathy observed. In recent years, a spectrum of metabolic and morphologic alterations has emerged among HIV-infected patients receiving HAART. Additionally, neurological syndromes, such as antiretroviral toxic neuropathy, have been clinically well characterized (Höke & Cornblath, 2004;Keswani et al., 2002). Diagnostic information find out by severe axonal neuropathy, increase Serum lactate level twice times than normal, decrease Serum bicarbonate and arterial pH level, increase serum CPK level. Electrophysiology; EMG-NCV: severe axonal neuropathy in most of the cases, demyelinating features may be seen admixed or in isolation and myopathic features may be noted. Nerve and Muscle Biopsy: Important in evaluating patients with HANWS.
Mitochondrial studies with morphology assessment and mitochondrial DNA (mtDNA) quantification may be needed to further elucidate the role of mitochondrial toxicity in this syndrome Treatment: As was observed in this report, the antiretroviral most often associated with HANWS was stavudine. Avoiding stavudine or didanosine, the nucleosides with the highest association with mitochondrial toxicity, may be a satisfactory alternative in the long run. The treatment of HANWS is controversial and important since this is potentially a fatal syndrome. Our experience reinforces the recommendation that early interruption of HAART and clinical support is beneficial. Initiate systemic treatment for lactic acidosis syndrome and supportive treatment for the neurologic component in a monitored setting. Neuromuscular weakness -corticosteroids, intravenous immunoglobulins, vitamins (B1, B12), and plasmapheresis have been used (Luciano et al., 2003).

Toxoplasmosis
Toxoplasmosis is the leading cause of focal central nervous system (CNS) disease in AIDS. CNS toxoplasmosis in HIV-infected patients is usually a complication of the late phase of the disease. Toxoplasmosis has been an indicator disease for AIDS since the early days of the

AIDS related primary CNS lymphoma
A relationship between congenital or acquired immune deficiency (AIDS) and lymphoma was first recognised more than 30 years ago. An association between non-Hodgkin's lymphoma (NHL) and the acquired immune deficiency syndrome became evident in the early 1980s. Lymphoma occurring in the HIV-infected individual may be systemic, may primarily involve the central nervous system, or may be localised in the body cavities. Systemic lymphoma is the most common presentation, accounting for approximately 80% of all cases. The histology usually is diffuse large cell, immunoblastic, or small non-cleaved cell lymphoma. Primary CNS lymphoma accounts for approximately 20% of all cases. Most patients are profoundly immunosuppressed and typically have a CD4 lymphocyte count below 50/ml. Approximately twothirds or more of them have AIDS-defining conditions prior to the development of primary CNS lymphoma (Gill et al., 1985;Goldstein, 1991). The lesions are typically few in number (1-3), large (2-4 cm), and contrast enhances approximately 50% of the time (Fine & Mayer 1993).
Lesions are most common in the cerebrum, but also occur frequently in the cerebellum, basal ganglia and brain stem, and are nearly always found to be multifocal at autopsy (Loureiro et al., 1988;MacMahon et al., 1991). The lymphoma cells tend to be distributed along vascular channels as perivascular cuffs, are of B cell origin, display large cell and immunoblastic histologies. Subacute presentation with headache, impaired cognition, focal cerebral dysfunction. D/D -Toxoplasmosis, PML. Imaging -Multiple enhancing periventricular or subependymal lesions, CSF -EBV nucleic acid in CSF being studied. NHL are of higher grade and advanced stage. Response and tolerance to chemotherapy is poor. Systemic lymphoma in patients with HIV infection is a potentially curable disease, although the potential for cure is less than in immunocompetent individuals. Appropriate use of supportive care is an important component of therapy (Table 3) ).
QD. Daily; TID, three times daily; BID, two times daily; QID, four times daily; s.c., subcutaneous; G CSF, granulocyte colony stimulating factor; GM,CSF, granulocyte-macrophage colony stimulating factor, NIH, national institute of health; RTIs, reserve transcript inhibitors. Appropriate supportive care and CNS prophylaxis might improve outcome. In patients with HIV infection, the differential diagnosis of a patient with focal brain lesions includes PCNSL, cerebral toxoplasmosis, and other infections. Focal brain lesions have also been described in conjunction with relapsed systemic lymphoma (Desai et al., 1999). A proposed algorithm for the diagnostic approach to a patient with HIV infection and focal brain lesions is shown in Fig. 3.

Neurological approach to immunocompromized patients due to HIV-1
Central nervous system pathogens in specific immunocompromised-host (HIV-1) categories based upon presentation like Meningitis, Meningoencephalitis, and Encephalitis. Cryptococcal meningitis is seen in populations but cryptococcomas are much more frequent in the latter. Encephalitis and cerebral abscesses usually do not produce cerebrospinal fluid (CSF) changes unless the lesion communicates with the ventricular or subarachnoid spaces. Discrete white matter lesions have a narrower differential including calcineurin-induced demyelination usually in the posterior territory and progressive multifocal leukoencephalopathy (JC papova virus) which is characteristically nonenhancing and without mass effect. Meningoencephalitis due to Toxoplasma gondii continues to be the predominant pathogen in HIV-1 disease even with highly active antiretroviral therapy (HAART) exposure (Peter K. Linden, 2009).

Neurogenic manifestation of HIV infection in children
Twenty percent of children present with severe symptoms or die in infancy, Prognosis is related to: a) Greater inoculation of HIV b) Earlier infection with immature immune system c) Immune escape from mother. Asceptic Meningitis or Meningoencephalitis does not occur in infants. Acquired Microcephali, cerebral vasculopathy and basal ganglia, Calcification are unique in children. OIS are rare in children, here absolute CD 4 T cell count less helpful. HIV-DNA PCR on peripheral blood lymphocytes can help to diagnosis. Avoid vaginal delivery, plan caesarean section and avoid breast feeding.

Immunological and virological markers
Based upon scientific literature, immunological and virological markers have been proven as prognostic indicators for progression of HIV disease. The most widely studied marker, the CD4 + lymphocyte count was found to be the best single indicator of the stage of the illness (Zeller et al., 1996).

CD8+ cell count
There are two types of T cells carry the CD8 surface molecule: T-suppressor cells, which inhibit immune responses, and killer T cells (also known as cytotoxic T lymphocytes, or CTLs), which target and kill infected or cancerous cells. As with CD4 cells, a variety of factors can cause CD8 cell counts to fluctuate. CD8 cell counts typically rise over time in people with HIV, but (unlike CD4 cells) CD8 cell numbers do not independently predict disease progression, and their relation to immune status is not well understood (Vajpayee & Mohan 2011).

CD4 and CD8 cell percentage
Because absolute CD4 and CD8 cell counts are so variable, some physicians prefer to look at CD4 or CD8 cell percentages, the proportion of all lymphocytes that are CD4 or CD8 cells.
Percentages are usually more stable over time than absolute counts. A normal CD4 cell percentage in a healthy person is about 30-60 per cent, while a normal CD8 cell percentage is 15-40 per cent ).

CD4/CD8 cell ratio
The CD4/CD8 cell ratio is calculated by dividing the CD4 cell count by the CD8 cell count. A normal CD4/CD8 cell ratio is about 0.9-3.0 or higher, there are at least 1-3 CD4 cells for every CD8 cell. In people with HIV this ratio may be much lower, with many more CD8 cells than CD4 cells (Giorgi, 1993).

HIV viral load
Viral load tests measure the amount of HIV RNA in the blood. The presence of RNA indicates that the virus is actively replicating or multiplying. Along with the CD4 cell count, viral load is one of the most valuable measures for predicting HIV disease progression and gauging when anti-HIV treatment is indicated and how well it is working. Viral load is expressed either as copies of RNA per milliliter of blood (copies/ml) or in terms of logs. A log change is an exponential or 10-fold change. For example, a change from 100 to 1,000 is a 1 log (10-fold) increase, while a change from 1,000,000 to 10,000 is a 2 log (100-fold) decrease. If the level of HIV is too low to be measured, viral load is said to be undetectable, or below the limit of quantification. However, undetectable viral load does not mean that HIV has been eradicated; people with undetectable viral load maintain a very low level of virus. Even when HIV is not detectable in the blood, it may be detectable in the semen, female genital secretions, cerebrospinal fluid, tissues, and lymph nodes (Calmy et al., 2004;Petti et al., 2006;WHO, 2006). In primary HIV infection, patients may present with flu-like symptoms which usually occur during the first weeks of HIV-1 infection. It is associated with peak levels of HIV-1 RNA viremia, which subsequently declines until reaching a set point, where levels remain for months to years. Initial studies suggested that those with more symptomatic acute infection and longer duration of illness have faster rates of progression to AIDS (Koenig et al., 2006). A viral load of 100,000 copies/ml or more is considered high, while levels below 10,000 copies/ml are considered low. Research has consistently shown that higher viral loads are associated with more rapid HIV disease progression and an increased risk of death. Current U.S. HIV treatment guidelines (Koenig et al., 2006) recommend that people should consider starting treatment if their viral load is above 55,000 copies/ml (revised upward from 10,000 copies/ml in the previous guidelines). Importantly, most studies that have correlated viral load and HIV disease progression have been done in men; more recent research indicates that women may progress to AIDS at lower viral load levels, suggesting that the treatment threshold should perhaps be revised downward for women (Monica et al., 2002).

Beta2-microglobulin (β2-microglobulin)
β2-microglobulin is a low molecular weight protein that forms light chain of the class I major histocompatibility complex (MHC) which present on the surface of most somatic cells including T and B lymphocytes as well as macrophages (Cresswell et al., 1974;Lawlor et al., 1990;De Wolf and Lange 1991

Additional markers
Haematological manifestations of HIV infection are common and more frequently occur with progression of the disease. Therefore the complete blood count (CBC) is one of the important haematological parameters which need to checked for HIV patients.

Summary
The prevalence of neurological associated with HIV-1 is estimated at 15 to 50% of patients