NEUROLOGICAL ASPECTS OF TROPICAL DISEASE
In tropical areas, the human T lymphotropic virus type 1 (HTLV-1) infection is often superimposed on the human immunodeficiency virus (HIV) endemic. However, from a clinical point of view, the neurological consequences of HTLV-1 infection are not as prevalent as those of HIV infection. Only 0.25% of the HTLV-1 carriers develop a progressive myelopathy. By contrast, CNS complications of HIV infection are frequent and often lethal. Most (89%) of the 30.6 million HIV infected people are estimated to live in sub-Saharan Africa and developing countries of Asia, but the neurological complications have been well described in other populations. By contrast, HTLV-1 infection is mostly confined to tropical areas. This review highlights the differences in the neurological complications of HIV infection, and the management of these complications in tropical countries from other parts of the world, and discusses HTLV-1 infections.
HIV infection
Neurological disorders complicate HIV infection in 30% to 40% of patients, and any part of the neuraxis may be affected.
Furthermore, some studies have shown neuropathological abnormalities in 75% to 90% of patients dying with AIDS. In tropical countries CNS abnormalities are also frequent in clinical and postmortem studies.
Early CNS infection is usually asymptomatic or responsible for rare disorders such as acute aseptic meningitis or encephalitis. During the later stages of infection both the major CNS opportunistic infections and AIDS dementia complex develop. Since 1996, the use of highly active antiretroviral therapy has decreased morbidity and mortality in HIV infected patients with advanced disease. Incidence rates of neurological manifestations such as HIV associated neuropsychological impairment and opportunistic infections seem to have declined. Unfortunately, in most tropical countries, antiretroviral therapy is not available and diagnostic tools are often limited. Although difficult to determine, the prevalence of neurological complications in tropical countries seems different compared with occidental countries. Thus HIV infections in tropical countries could kill patients before the other neurological manifestations have the time to develop. In these countries, three treatable opportunistic infections— namely, cryptococcal meningitis, toxoplasmosis, and tuberculosis (table 1) cause most of the morbidity and mortality. The different profile of neurological manifestations between tropical and industrialised countries could reflect local geographical or socioeconomic conditions and variation in risk factors.
CRYPTOCOCCAL MENINGITIS (CM)
Cryptococcal meningitis is the most common life threatening fungal opportunistic infection in HIV infected patients. The estimated incidence of CM in these patients varies between 5% and 10% in the United States and 30% in tropical countries such as sub-Saharan Africa, Asia, and South and Central America. In Zimbabwe, CM accounts for 45% of all laboratory proved cases of meningitis in adults. The high rate of cryptococcal infection in tropical countries seems to be due to the usual presence of Cryptococcus neoformans in the environment of patients with AIDS.33 Although unusual (25% to 30% of patients), meningeal symptoms may be seen with CM. If available, the latex agglutination test for cryptococcal antigen detection in both serum and CSF is a highly sensitive and specific procedure in the diagnosis of cryptococcosis and can be used as a screening tool in febrile patients. Despite treatment, mortality in the acute stage of CM remains high (10%-25%) and the 1 year survival rate is about 30%-60%. In Malawi, the median survival was 4 days without treatment after CM had been diagnosed. In a prospective study from Zimbabwe focusing on natural history of CM, the cumulative median survival was 14 days (0 to 233 days) and the 1 month survival rate was 22%. Thus, many patients seem to have an indolent course even without treatment. The treatment consists of intravenous amphotericin B (0.7 mg/kg/day). Cost, need for parenteral administration, and toxicity are the main limitations of use of amphotericin B. Fluconazole has shown similar rates of treatment success to those of low doses (0.4 mg/kg/day) of intravenous amphotericin B. However, in America the 2 week mortality was higher in the fluconazole group than in the amphotericin B group (15%v 8%). The current recommendation for treatment of CM is to use amphotericin B (0.7 mg/kg/day) and flucytosine (25 mg/kg four times daily). After 2 weeks, this combination may be supplanted by oral fluconazole (400 mg/day) for 8 weeks (table 2). This therapy seems very successful (6% of initial mortality and 8% of overall mortality). Lifelong maintenance therapy is essential to prevent relapse of CM.32 Fluconazole (200 mg daily) has now been shown to be more effective and better tolerated than amphotericin B and is the preferred agent for secondary prophylaxis. Unfortunately, in many tropical countries, this antifungal treatment is not available. These antifungal agents were not included in the list of essential drugs needed in Zimbabwe. Cost of the induction phase of therapy for CM amounts to several times the average monthly salary in Zimbabwe and in many resource poor sub-Saharan African countries. Easily managed and cost effective treatments are absolutely necessary for CM in developing countries. A comparative 2 month study of fluconazole (200 mg/day) with flucytosine (150 mg/kg/day) for the first 2 weeks with fluconazole alone at the same dose in 58 Ugandan patients showed a lower initial mortality in the combination group (16% v40%). After 4 months of maintenance therapy (fluconazole at 200 mg three times weekly), survival rate was higher in the combination group (32% v12%).
TOXOPLASMOSIS ENCEPHALITIS (TE)
Toxoplasmosis encephalitis is the most common opportunistic infection causing encephalitis or focal cerebral lesions. About 3% to 40% of patients with AIDS will develop TE (table 1). In tropical countries, the frequency of TE in necropsy series of AIDS patients is high: 34% in Brazil, 23% in Côte d'Ivoire, and 19% in India. Risks factors for TE are a previous Toxoplasma gondii infection and a CD4+ cell count< 100/mm3.40 Geographical differences in TE rates among patients with AIDS may be explained by the worldwide observed variation of Toxoplasma IgG seroprevalence. 0TE presents with a constellation of symptoms and signs, of which only chorea is thought to be pathognomonic in patients with AIDS. Diagnosis is made on the basis of clinical symptoms and CT or MRI findings (contrast enhancing space occupying lesions of the brain). In tropical countries where CT is not available, the diagnosis should be made on clinical grounds and fast response to presumptive therapy.
The current recommended therapy of TE is a 4 to 8 week course of sulfadiazine and pyrimethamine. Adverse reactions to these medications are common, occurring in as many as 25% to 53% of patients. Alternative less toxic medications—namely, azithromycin, clarithromycin, atovaquone, and trimethoprim-sulfamethoxazole (TMP-SMZ)—are under investigation. In an open study, we have followed up 21 patients who were treated with TMP-SMZ (160 mg trimethoprim and 800 mg sulfamethoxazole three times daily by oral or intravenous route for 4 to 6 weeks). Clinical and radiological improvements were achieved in 94% of patients. Severe toxicity leading to alternative treatment occurred in two patients. Considering large availibility, good tolerance, easy management, and low cost, TMP-SMZ seems a treatment of choice for TE in tropical countries.
TUBERCULOSIS (TB)
One third of the world's population is thought to be infected with Mycobacterium tuberculosis. In 1990, the WHO estimated that active disease occurs in 8 to 10 million people and that 3 million people died of TB each year. HIV infection is the strongest risk factor for the progression of latentM tuberculosis infection to active TB. By mid-1995, nearly 7 million people worldwide were estimated to be coinfected with M tuberculosis and HIV, of whom 4 million live in Africa, 3 million in south and south east Asia, and 0.4 million in Latin America and the Caribbean basin. TB is a major cause of death in patients infected with HIV worldwide. In Abidjan (Côte d'Ivoire) TB was seen in 54% of AIDS cadavers. In sub-Saharan African countries, in which the rates of HIV infection are the highest, the incidence of TB has more than doubled since the early 1980s. In Asia, the expanded HIV epidemic has led to occurrence of new cases of TB attributable to HIV, with the same magnitude as in sub-Saharan Africa. In North American or European studies, CNS TB is unusual and occurs in 5% to 10% of patients infected with HIV. HIV infection does not seem to alter the clinical and laboratory manifestations or the prognosis of TB meningitis. By contrast with non-HIV infected patients, CNS mass lesions, including cerebral abscesses and tuberculomas, are more often demonstrated by CT or MRI in patients with AIDS. In tropical countries, TB meningitis is a relatively frequent complication of HIV infection, and such infection is often undiagnosed (table 1). Despite antituberculous drugs, the mortality of TB meningitis remains high. In resource poor tropical countries, antituberculous regimens containing rifampin are often unavailable.
AIDS-DEMENTIA COMPLEX (ADC)
AIDS-dementia complex is an HIV specific syndrome of subcortical dementia characterised by slowness and imprecision of cognition and motor control. The earliest symptoms of ADC are cognitive and patients complain of difficulties in concentration and forgetfulness; and relatives notice difficulties in thinking. Later, diffuse motor abnormalities include ataxia, hyperreflexia, and the appearance of frontal lobe release reflexes such a snout response, are present with possible progression to tetraparesis. ADC is often associated with a vacuolar myelopathy (ataxia, spastic paraparesia, hyperreflexia, and incontinence).
ADC develops mainly in patients with severe immunosuppression. In the United States the incidence rate of ADC over a 5 year period is 7.3 cases per 100 person-years for people with CD4 counts of 100 or less. In Kinshasa, the estimated prevalence of ADC was 8.7% in a cross sectional study of HIV infected patients admitted to hospital. Antiretroviral therapy can only improve ADC symptoms.
NEUROMUSCULAR DISORDERS
Neuromuscular disorders are common and important causes of morbidity. Autoimmune demyelinating neuropathies or inflammatory myopathy usually develops in the early stage of HIV infection. The prognosis is good with corticosteroid therapy. By contrast, during the late stage of HIV infection, CMV polyradiculopathy, CMV mononeuritis multiplex, or HIV polyneuropathy distal, axonal and predominantly sensory are associated with a poor prognosis. There are few data on the frequency of these manifestation in tropical countries.
HIV INFECTION IN CHILDREN
HIV infection of children is rapidly increasing, with more than 1600 children becoming infected each day. Most of these infections occur in sub-Saharan Africa, where over 22 million children are infected with HIV. Most children acquire HIV from their mothers, particularly during labour, but also during pregnancy, and the postnatal period from breast milk. Blood transfusion for the treatment of severe anaemia and malaria is another important source in developing countries.
HIV readily infects the developing CNS of children, and is a major cause of morbidity and contributes to the fatal outcome. Postmortem studies show that most children dying with AIDS have evidence of neurological involvement. Children more often have a HIV encephalitis, and less superimposed infections and lymphoma than adults, particularly children living in tropical countries.
HIV infection of the CNS usually manifests after other clinical features of HIV infection. The most common manifestations in Europe and North America are delayed development, loss of developmental milestones, cerebral atrophy, and pyramidal tract signs. The progressive encephalopathy (with loss of milestones and cerebral atrophy) usually occurs before the age of 3 years, and is associated with a high viral load and early decrease in CD4 lymphocytes. Other neurological manifestations include stroke, extrapyramidal, and cerebellar signs, and peripheral neuropathies.
In Africa, perinatal HIV infection is associated with motor and cognitive delay. In birth cohort studies from Rwanda and Uganda, abnormal neurological signs were elicited in 15%-40% of HIV infected children during the first 2 years of life. Most of these children have developmental delay, with a reduction in the growth of the head circumference, suggesting cerebral atrophy. Studies from Rwanda suggest that progressive encephalopathy is relatively rare.
HTLV-1 infection
In 1964, a progressive thoracic myelopathy was described in Jamaican adults and this disorder was termed tropical spastic paraparesis (TSP). In 1985, Gessainet al clarified the aetiology of TSP by reporting in Martinique that 60% of these patients had antibodies to HTLV-1. In 1986, a similar myelopathy associated with HTLV-1 antibodies in the serum and CSF of Japanese patients was named HAM (HTLV-1-associated myelopathy) by Osame et al. These were the same disease, ultimately labelled HAM/TSP.
CAUSATIVE ORGANISM
HTLV-1 is a type C retrovirus sharing some distinctive features with the bovine leukaemia virus (BLV) and the simian T cell leukaemia virus (STLV). It has two regulatory genes: thetax gene which is responsible for the activation of viral replication, and the rexgene which, conversly, inhibits replication. Molecular analysis of HTLV-1 strains from the known endemic areas have identified three different genotypes—namely, widespread cosmopolitan subtype (HTLV-1 subtype A), large central African genotype (HTLV-1 subtype B), and Melanesian subtype (HTLV-1 subtype C).
EPIDEMIOLOGY
In tropical areas, HTLV-1 infection is endemic near the equator. Caribbean basin, Colombia, and equatorial Africa were the first high frequency pockets to have been reported. Numerous epidemiological studies have shown that HTLV-1 is mainly transmitted from husband to wife and mother to child and that the risk for seroconversion of household contacts is low. Exposure to contaminated blood products is the third known source. HTLV-1 is, however, a mildly infective virus; the prevalence among insular groups (island of Tsushima) or Amerindian populations illustrate the importance of geographical or cultural isolation which seems to be required for its propagation. The average age of onset of HAM/TSP is about 40 years, but it may begin between the ages of 20 and 70 years, although rarely younger than 15. Women are affected more often than men by about 1.5:1. Highest prevalence rates (100/100 000) are found in Tumaco
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