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SEMINAR
Neuropsychiatric manifestations of HIV-AIDS
Subhashish Nath
Postgraduate Trainee of Psychiatry
Silchar Medical College and Hospital
HIV-AIDS: an introduction Acquired immunodeficiency syndrome (AIDS) was first recognized in the United States in the summer of 1981 (US Centre for Disease Control and Prevention). In 1983, the human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy, and in 1984 it was demonstrated clearly as the causative agent of AIDS. HIV is a ribonucleic acid (RNA) virus and belongs to the family of human retroviruses (retroviridae) and the subfamily of lentiviruses. There are two subtypes of HIV: HIV-1 and HIV-2. HIV-1 is the most common cause of AIDS worldwide and in the US. In 1985, enzyme-linked immunosorbent assay (ELISA) was developed as a sensitive test to appreciate the scope and evolution of HIV.
AIDS: case definition According to the current Centres Of Disease Control and Prevention (CDC) classification system for HIV infected adoloscents and adults, any HIV infected person with a CD4 T cell count of <200/microlitre has AIDS by definition, regardless of the presence of symptoms or opportunistic disease.
Clinical spectrum Ranges from primary infection, with or without the acute syndrome, to the asymptomatic stage, to advanced disease.
Prevalence/disease load Global summary of AIDS epidemic (UNAIDS) December 2008:
Number of people living with HIV in 2008 -
Total 33.4 million (31.1 – 35.8 million)
Adults 31.3 million (29.2 – 33.7 million)
Women 15.7 million (14.2 – 17.2 million)
Children under 15 years 2.1 million (1.2 – 2.9 million)
Adults and children estimated to be living with HIV in 2008 are 33.4 million (31.1 – 35.8 million).
People newly infected with HIV in 2008 -
Total 2.7 million (2.4 – 3.0 million)
Adults 2.3 million (2.0 – 2.5 million)
Children under 15 years 4,30,000 (2,40,000 - 6,10,000)
Over 7400 new HIV infections a day in 2008. More than 97% are in low- and middle-income countries. About 1200 are in children under 15 years of age. About 6200 are in adults aged 15 years and older, of whom almost 48% are among women, about 40% are among young people (15–24 years).
AIDS related deaths in 2008 -
Total 2.0 million (1.7 – 2.4 million)
Adults 1.7 million (1.4 - 2.1 million)
Children under 15 years 2,80,000 (1,50,000 – 4,10,000)
HIV and India: The first AIDS case in India was detected in 1986 and since then HIV infection has been detected in every state and union territory. HIV epidemics are highly prevalent in the Southern part and in the North Eastern states. The highest HIV prevalence rates are found in Andhra Pradesh, Maharashtra, Tamil Nadu and Karnataka in the south; and Manipur and Nagaland in the north-east. In the Southern states, HIV is primarily spread through heterosexual contact. Infections in the north-east are mainly found amongst injecting drug users (IDUs) and sex workers. As per National AIDS Control Organization (NACO) sentinel surveillance data (July 2007), number of people living with HIV/AIDS in India is 2.31 million. 39% female. 3.5% children.
Neuropsychiatric manifestations of HIV-AIDS
Neurologic manifestations: Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection. HIV has been recovered from the cerebrospinal fluid (CSF) of patients at any point after infection and also from the brain in several autopsy studies. The neurologic problems that occur in HIV infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms. Overall, secondary disease of the central nervous system (CNS) occurs in 1/3rd of patients with AIDS. Neurologic diseases occur throughout the course of illness and may be inflammatory, demyelinating or degenerative in nature. While only one of these, the AIDS dementia complex or HIV encephalopathy, is considered an AIDS defining illness, most HIV infected individual have some neurological problem during the course of their illness.
Neuropathoggenesis - The main cell types that are infected in the brain in vivo are the perivascular macrophages and microglial cells. Precise mechanisms for the entry of HIV virus into brain are unclear. Ability of the virus infected and immune activated macrophages to induce adhesion molecules such as E-selectin and VCAM-1 on brain endothelium. HIV gp120 enhances the expression of intercellular adhesion molecule in glial cells. This effect may facilitate the entry of HIV infected cells into the CNS and facilitate syncytia formation.
HIV infected individuals may manifest white matter lesion as well as neuronal loss. The HIV mediated effects on neurons and oligodendrocytes are felt to be due to viral proteins, particularly gp120 and Tat, which trigger the release of endogenous neurotoxins from macrophages and to a lesser extent from astrocytes. In addition, HIV gp120 shed by virus infected monocytes could cause neurotoxicity by antagonizing the function of vasoactive intestinal peptide (VIP), by elevating intracellular ca+2 levels and by decreasing nerve growth factor levels in the cerebral cortex. A variety of monocyte derived cytokines can contribute directly or indirectly to the neurotoxic effects in HIV infection. Astrocytes may play a diverse role in HIV neuropathogensis.
Neurological diseases in patients with HIV-AIDS
1. Opportunistic infections - Toxoplasmosis, progressive multifocal leukoencephalopthy, cryptococcosis, cytomegalovirus (CMV) etc.
2. Neoplasms.
3. Result of direct HIV infection - Aseptic meningitis.
4. HIV encephalopathy (AIDS dementia complex).
5. Myelopathy - Vacuolar myelopathy, pure sensory ataxia, paresthesia/dysesthesia.
6. Peripheral neuropathy - Acute inflammatory demyelinating polyneuropathy, AIDP (Guillain-Barre syndrome, GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), mononeuritis multiplex, distal symmetric polyneuropathy.
7. Myopathy.
Opportunistic infections
1. Toxoplasmosis - Most common cause of secondary CNS infection in AIDS patients. Occurs in patients with CD4+ count <200/microltr. Reactivation syndrome. Fever, headache, change in level of alertness, focal neurological signs (~80 % cases), partial/generalized seizures(~30%). Most common cause for intracranial masses in patients with AIDS. Pyrimethamine + sulphadiazine/clindamycin for six weeks and then prophylaxis usually with the same agents.
2. Cryptococcosis - Leading infectious cause of meningitis in patients with AIDS. Generally occurs in patients with CD4+ count <100/microltr. Eight to ten percentage of AIDS cases. Fever, delirium, seizures and focal neurological deficits occur in approximately ten percentage cases. Intracranial tension (ICT) is elevated in 50% of patients. Amphotericin B + flucytosine for two weeks, oral fluconazole for 10 weeks. Secondary prophylaxis can be done with oral fluconazole or intermittent intravenous amphotericin B.
3. Progressive multifocal leukoencephalopathy (PML) - Demyelinating disease of the white matter in immunocompromised patients. Caused by a polyoma virus – JC virus. One to ten percentage (approximately four percentage) of AIDS patients. While AIDS accounts for 3/4th of PML cases. Pathology is demyelination and death of astocytes and oligodendroglia with a multifocal presentation. Multiple focal neurological deficits e.g. mono-/hemiparetic limb weakness, dysarthria, gait disturbances or sensory deficits and progressive dementia with eventual coma and death. Occasional seizures or visual loss. No specific treatment. Support and antiretroviral therapy (ART).
4. Cytomegalovirus (CMV) infection - Found at autopsy in ~30% AIDS patients. In patients with CD4+ count <50/microltr. Two distinct syndromes of CMV CNS infection e.g. encephalitis with dementia (more common) and ventriculoencephalitis. Treatment is supportive.
CNS neoplasms
Lymphoma is the most common neoplasm found in AIDS patients (0.6-3%). Generally afebrile and may develop a single lesion with focal neurological signs or small, multifocal lesions most commonly presenting with a mental status change. Seizures in about 15% patients. Radiation therapy and steroids. Chemotherapy is generally adjunctive. Prognosis is dependent on response to ART.
Direct neurological manifestations of HIV infection
1. Aseptic meningitis - In any but the very late stages of HIV infection. Headache, photophobia and meningismus. Cranial nerve involvement may be seen, predominantly seventh, but occasionally fifth or eighth. CSF shows lymphocytosis, elevated protein, normal glucose. Resolves spontaneously within two to four weeks.
2. Myelopathy - Twenty percentage of AIDS patients, often as part of HIV encephalopathy. Three main types of myelopathy are seen in patients with AIDS e.g. vacuolar myelopathy (~50% patients), pure sensory ataxia (involves the dorsal columns), paresthesias and dysesthesias of lower extremities. Supportive treatment. Myelopahty and polyradiculopathy, in association with CMV infection (spinal cord + peripheral nerve).
3. Peripheral neuropathy - Mostly in the feet. Occur at all stages and may take variety of forms e.g. AIDP, CIDP, mononeuritis multiplex. Nerve biopsy reveals perivascular infiltrate (autoimmune aetiology). Most common neuropathy is distal sensory polyneuropathy. Painful burning sensation in the feet and lower extremities with a stocking type sensory loss to pinprick, temperature and touch sensation and a loss of ankle reflex. Motor changes include weakness of intrinsic foot muscles. Treatment is plasma exchange and intravenous immunoglobulin. Symptomatic with tricyclic antidepressant (TCA), pregabalin, gabapentin, carbamazepine.
Psychiatric manifestations of HIV-AIDS: By virtue of its relationship to risk behaviour, the social stigma it is associated with and the malignant course it usually follows, HIV infection has a number of psychological ramifications –
Patients backgrounds and premorbid personalities are important in determining risk behaviour.
Patients infected with HIV may manifest a number of psychiatric syndromes because of the neurotoxicity of the virus and by its effect on brain tissue.
HIV carries with it tremendous emotional issues such as stigmatization, issues related to terminality and frequent infections leading to psychiatric syndromes.
Patients with psychiatric disorders, because of their faulty judgement might be prone to acquiring HIV infection.
Psychological distress with HIV infection can be divided into several broad categories and includes -
Adjustment reactions to specific illness-related events or social stressors.
Emotional distress related to lifestyle changes.
Bereavement reactions.
Complications derived from pre-existing psychosocial disturbance, intravenous (IV) drug or other substance use.
Neuropsychiatric impairments caused by direct HIV brain infection and opportunistic disorders.
Spectrum of psychiatric disorders seen with HIV infection
1. Anxiety disorders - generalized anxiety disorder (GAD), panic disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD).
2. Adjustment disorders with anxious and depressed mood, major depression.
3. Organic mental disorders - Dementia (AIDS dementia complex), delirium, mild neurocognitive disorders, organic mood disorders, organic personality disorders, organic hallucinosis, organic delusional disorder.
4. Substance use disorders - Alcohol, IV drug abuse.
Anxiety disorders
Anxiety disorders have been reported in nearly 15-20% of HIV infected individuals. GAD, PTSD and OCD are particularly common. In India higher rates are reported.
Depressive disorders
Four to 40% of HIV infected meet diagnostic criteria for depressive disorders. Major depression in five to eight percentage of HIV infected. High prevalence rates are reported in India (35-40%). Adjustment disorder with depressed mood at various points of illness are more common than major depression (5-20%). Major depression is also a risk factor for HIV infection, transmission and inappropriate treatment adherence. HIV increases the risk of developing major depression by a variety of mechanisms - direct injury to subcortical areas, worsening social isolation, chronic stress and intense demoralization. Treatment is with pharmacotherapy, psychotherapy (interpersonal therapy, cognitive behavioural therapy).
HIV associated dementia/AIDS dementia complex
Lifetime prevalence in infected is 15%. Seen in late stages with a CD4+ count <200/microltr. Risk factors are higher HIV viral load, lower educational level, older age, anaemia, illicit drug use and female sex. Autopsy findings are white matter changes and demyelinization, microglial nodules, multinucleated giant cells, and perivascular infiltrates. Basal ganglia and nigrostriatal structures are affected early, with diffuse neuronal loss following. Late findings include 40% reduction in frontal and temporal neurons. Presents with memory and psychomotor speed impairments, depressive symptoms, and movement disorders. Later more global ddementia, marked impairments in naming, language and praxis. Early motor symptoms are occasional stumbling while walking or running, slowing of fine repetitive movements, slight tremor and late are marked difficulty in smooth limb movements. Impaired saccadic eye movements, dysdiadochokinesia, hyperreflexia, and frontal release signs. Psychosis with paranoid ideas. Rapidly progressive course. Death occurs within two years. Treatment with highly active ART (HAART) and associated symptomatic treatment.
Delirium
Forty three to 65% of infected. Causes are general conditions of delirium and opportunistic CNS infections.
Minor cognitive–motor disorder
Sixty percentage of patients till late stage disease. Early in course of illness. Milder manifestations of the symptoms of HIV dementia are cognitive and motor slowing. Impairments in at least two of verbal/language, attention, memory (recall or new learning), abstraction and motor skills. Treatment is HAART.
Substance use disorders
Substance abuse is a primary vector for HIV transmission. HIV itself can lead to substance abuse behaviour. Psychiatric comorbidities like depression, cognitive impairments and suicide are higher among seropositive substance users.
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