Central Nervous System and HIV/AIDS

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1 UPDATE ARTICLE Central Nervous System and HIV/AIDS Naveet Wig*, J P Wali** Introduction HIV-infection and particularly its late stage of severe immunodeficiency (AIDS) render the nervous system susceptible to an array of neurological disorders. Virtually every component of the nervous system can be afflicted. Neurological disorders cause considerable morbidity and mortality in patients with AIDS. At least 40% of HIV-infected patients develop neurological symptoms during the course of their illness. Central nervous system (CNS) is infected during the primary infection itself and the CNS becomes a watershed for HIV infection thereafter. 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. In a majority of AIDS patients, autopsies demonstrate CNS pathology 1. Pathologies include direct HIV-1 infection of the brain, opportunistic infections, and malignancies. Determining the specific cause of CNS lesions in the individual patient may be difficult, but it is essential for the prescribing of appropriate therapy. Although in many cases clinical and radiographic features alone are not sufficiently distinct to allow definitive diagnosis, routine brain biopsy is not recommended for several reasons. It is important to remember that aseptic meningitis may be seen in any but the very late stages of HIV infection. In acute primary infection patients may experience a syndrome of headache, photophobia and occasionally frank encephalitis. CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level. The syndrome * Assistant Professor, ** Professor & Head, Medicine-1, Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi , India. usually resolves within 2 to 4 weeks; however, in some patients, signs and symptoms persist chronically. Such episodes may occur any time in the course of HIV infection; however, they are rare following the development of AIDS. Diagnostic Approach The basic principle of the diagnostic approach is neuroanatomic localization. Main advantages of this time-tested approach are that different disease processes including opportunistic infections, have predilections for damaging particular structures and thus cause anatomically defined syndromes. Anatomic localization guides further diagnostic evaluation like neuroimaging in case of CNS and electrophysiological testing in diseases of peripheral nervous system. The important diagnostic element is the time course of the evolution of symptoms and signs. The temporal profile narrows the different possibilities. The third important variable in diagnostic approach is patient s risk background. The most important variable here is the stage of systemic HIV infection and resultant immunosuppression. Severe compromise of cell mediated immunity increases vulnerability to a group of disorders that dominate the course. Tuberculosis, syphilis, bacterial meningitis etc., can occur at any CD4 count. However, cryptococcal meningitis, toxoplasma encephalitis, progressive multifocal encephalopathy and CMV encephalitis occur in AIDS patients with CD4 count <200/ cubic mm. CNS involvement may be diffuse, as is typical of HIV encephalopathy, or associated with more discrete solitary or multifocal lesions. Nonfocal Brain Diseases These conditions present with diffuse alterations in cognition and symmetrical motor dysfunction that is not readily explained by one or a few

2 macroscopic focal lesions of the brain. There is no aphasia, apraxia, or agnosia to provide discrete cortical localization, nor hemiparesis or dysmetria to point to a lesion in a cerebral or cerebellar hemisphere. These non-focal disorders can be further clinically segregated into those in which cognition is altered in the face of preserved alertness and those in which these two elements are altered in parallel. The most important disorder in the first category is AIDS dementia complex (ADC). The examples of disorders in the other category are cryptococcal meningitis, toxic/ metabolic encephalopathies, CMV/HSV encephalitis, etc. AIDS Dementia Complex (ADC) In the advanced stages of HIV infection, a minority of patients develop a progressive encephalopathy that has been termed AIDS dementia complex (ADC) or HIV dementia. The pathogenesis of the disease is only partly understood, but HIV replication in the CNS plays a key role. HIV appears to be present and replicating in the CNS of most, if not all, infected individuals soon after the primary infection. The major site of virus accumulation seems to be within macrophages in the perivascular spaces and multinucleated giant cells (MGCs) 2. Clinically this is a subcortical dementia that is characterized by disturbances in cognition, motor performance and behaviour. An essential feature in the diagnosis of ADC is the presence of welldocumented cognitive decline and the exclusion of other neurological complications of HIV infection, such as cerebral toxoplasmosis, lymphoma, and progressive multifocal leukoencephalopathy 3. Therefore, cerebrospinal fluid (CSF) examination and imaging studies of the brain are mandatory. CSF analysis should exclude infectious agents other than HIV, and imaging scans should show cortical atrophy, enlarged ventricles, diffusely decreased attenuation of the deep white matter, and an absence of focal abnormalities in patients with ADC. Neuropsychological assessment may also be helpful in confirming the clinical diagnosis of ADC. The treatment of ADC is highly active antiretroviral therapy (HAART) with drugs that have good CSF penetration. The therapeutic and prophylactic efficacy of zidovudine in ADC has been well documented. Encouraging preliminary results have been seen with lamivudine, abacavir and stavudine. At this point, it is impossible to make definitive recommendations about the optimum antiretroviral therapy for HIV dementia. Good CSF virologic suppression has been reported for regimens consisting of NRTIs plus indinavir, efavirenz, nelfinavir, or nevirapine, but not for ritonavir/saquinavir without NRTIs. Cryptococcal Meningitis Cryptococcus neoformans is an encapsulated yeast that has worldwide distribution. It is transmitted from soil contaminated with bird excreta. The portal of entry is respiratory tract from where the organisms reach alveoli and cause disseminated infection. The main organs involved include CNS, lungs, skin, prostate, eye and blood. CNS involvement is seen in 70-90% patients with cryptococcal disease. In India, cryptococcal meningitis accounts of 6% of all opportunistic infections in AIDS (NACO, 2000). The commonest mode of presentation is sub-acute meningoencephalitis; acute fulminant onset is rare. Common clinical features include fever and headache in 65-90%, neck stiffness in 30%, altered sensorium in 20% and seizure/focal deficit in less than 10% of patients. The diagnosis is made by positive CSF India ink stain (yeast cells with capsules without buds or single bud), CSF cryptococcal antigen titre > 1:8, and positive CSF culture. Assays for CSF and serum cryptococcal antigen, however, are highly sensitive and specific 4. CT/MRI are done to rule out space occupying lesion. Focal lesions are formed by either dilatation of perivascular spaces or direct parenchymal invasion (cryptococcoma). Dilated perivascular spaces appear as small nonenhancing hypodense lesions on CT scan and have a predilection for 164 Journal of Indian Academy of Clinical Medicine Vol. Journal 5 No. of Indian 2 Academy of Clinical Medicine Vol. 5 No

3 the basal ganglia, thalamus, and midbrain 5. On MRI, cryptococcomas appear hypodense on T1- weighted images and hyperintense on T2- weighted images 6. They are generally not associated with surrounding oedema, but may have a thin rim of enhancement. The poor prognostic factors of cryptococcal meningitis include elevated CSF opening pressure, alteration in mental status, low CSF leukocyte count, positive extrameningeal culture and hyponatraemia. Currently, amphotericin B with flucytosine is considered the therapy of choice for the treatment of active cryptococcal disease. Recommended regimen includes amphotericin B 1 mg/kg/day I.V. plus flucytosine 150 mg/kg/day administered orally in 4 divided doses for 14 days. This is followed by fluconazole or itraconzole for 10 weeks. Patients who complete initial therapy for cryptococcosis should receive lifelong suppressive treatment with fluconazole 200 to 400 mg once daily. Focal Brain Diseases Focal brain involvement may be discrete, solitary or multifocal. Toxoplasma gondii, primary CNS lymphoma, and progressive multifocal leukoencephalopathy (PML) are common focal neurological lesions. Other lesions include infection with M. tuberculosis, C. neoformans. Less frequent causes include pyogenic abscess and infection with Nocardia asteroids, Treponema pallidum, cytomegalovirus (CMV), varicella-zoster virus (VZV) and Histoplasma capsulatum. Multicentric lesions may represent more than one disease in a single patient, and the inability to biopsy all lesions may lead to misdiagnoses 7. These patients may be at greater risk for biopsyassociated complications. Toxoplasma Encephalitis (TE) Toxoplasma gondii is an obligate intracellular protozoon. The definitive host is cat. It is acquired by oral ingestion of raw or undercooked meat (tissue cysts) and cat excreta (oocysts). It may occur due to reactivation of latent infection or newly acquired infection. The prevalence of latent infection, as evidenced by seropositivity, varies with geographic region and population studied. Toxoplasmosis is the most prevalent cause of latent infection of CNS. More than 30% of AIDS patients with positive serology will develop CNS infection. The commonest CNS manifestation of toxoplasma is toxoplasma encephalitis. TE presents as focal nercotizing encephalitis with one or more intracerebral mass lesions. Nearly 90% of patients who develop Toxoplasma encephalitis have less than 200 CD4+ T cells/mm3. The greatest risk occurs when the CD4+ T-cell count falls below 100/mm3. It can also present as diffuse encephalitis or meningo-encephalitis. The common presenting clinical features include focal neurological signs (69%), headache (55%), confusion (52%) and seizures (29%). Disseminated toxoplasma infection may result in encephalitis, myocarditis, pneumonitis, and retinitis. The diagnosis is made by positive anti-toxoplasma antibodies, antibody to toxoplasma in the CSF and multiple lesions in multiple locations or single ring enhancing lesion on MRI or double dose contrast CT. On MRI, lesions appear as low signal intensity on T1-weighted images and moderately hyperintense relative to the brain parenchyma on T2-weighted images. Enhancement may be subtle because of poor cell-mediated immunity 5. Lesions are most often located in the cerebral hemispheres and basal ganglia. Haemorrhage and calcification are occasionally seen. Brain biopsy can establish the diagnosis by demonstrating toxoplasma on microscopy or culture. Empirically treated patients should have clear clinical response in 2 weeks and clear radiographic response in 3 weeks. In case of treatment failure, brain biopsy is resorted to after 3 weeks to confirm the diagnosis. A presumptive diagnosis of Toxoplasma encephalitis is based on the triad of positive Toxoplasma serology, characteristic radiographs, and response to empiric antitoxoplasma therapy. The currently preferred regimen for toxoplasma encephalitis is Journal of Indian Academy of Clinical Medicine Vol. 5 No

4 pyrimethamine 200 mg orally, divided in two equal doses on day 1 followed by 50 to 100 mg/day orally, plus sulfadiazine 1 to 2 g orally, administered daily in four divided doses, plus calcium folinate (folinic acid; leucovorin) 10 to 20 mg IV or orally, administered daily to preclude the toxicity associated with pyrimethamine. Induction therapy for TE continues for 4 to 6 weeks. Patients intolerant to sulfadiazine may alternatively be treated with clindamycin 450 to 600 mg orally or 600 to 1200 mg IV administered daily in divided doses, in combination with pyrimethamine 8. Other agents with some demonstrated efficacy in TE include TMP-SMZ 9, clarithromycin plus minocycline 10 and atovaquone. Patients who have had TE should receive lifelong suppressive therapy with drugs active against Toxoplasma to prevent relapse 11. The combination of pyrimethamine plus sulfadiazine and leucovorin is highly effective for this purpose. A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin; however, only the combination of pyrimethamine plus sulfadiazine appears to provide protection against PCP as well. Toxoplasma-seropositive patients with a CD4+ lymphocyte count of <100/mm3 should receive life-long prophylaxis against TE. The doses of TMP-SMZ recommended for PCP prophylaxis appear to be effective against TE as well 12. Primary CNS Lymphoma Primary CNS lymphoma without extracranial involvement occurs in approximately 5% of AIDS patients. These tumours are usually aggressive, high-grade, diffuse B-cell neoplasms, which consist of either large immunoblastic or small noncleaved cells. Epstein-Barr virus (EBV) DNA has been detected by in situ hybridization in most AIDSrelated primary CNS lymphomas 13. Symptoms generally evolve over weeks to months. The time course of disease progression is intermediate between that of Toxoplasma encephalitis and PML, although rapidity of progression does not reliably distinguish these diseases. Nonspecific signs of increased intracranial pressure are noted initially; however focal neurological findings are common by the time of diagnosis 14,15. On CT scan, lymphomas appear as iso- to hyperdense space-occupying lesions with mass effect and uniform contrast. With MRI, lesions appear hypo- to isointense on T1-weighted images and are obscured by surrounding oedema. Signal intensity may be variable on T2-weighted images, with lesions appearing isointense, hyperintense, or with mixed increased and decreased signal intensity. Multicentric lesions are noted in 50% to 80% of patients 16, although a large solitary lesion on MRI strongly suggests lymphoma rather than Toxoplasma encephalitis or PML. Spinal fluid examination is abnormal with some combination of mild pleocytosis, protein elevation, and hypoglycorrhachia; however, tumour cells are identified in fewer than 25% 14. Biopsy is necessary for a definitive diagnosis. Although complete or partial clinical response to whole-brain irradiation occurs in most patients, the length of survival averages only 4 to 5 months following treatment. Much of this mortality, however, is attributed to infections rather than to tumour progression. Progressive Multifocal Leukoencephalopathy PML is a fatal demyelinating disease caused by the human polyomavirus JC. PML generally represents reactivation of latent infection. The incidence of PML in HIV-infected patients is approximately 4%. As with toxoplasmosis and CNS lymphoma, patients with PML develop progressive focal symptoms. However, constitutional symptoms are generally absent. Speech difficulties, hemiparesis, cranial nerve palsies, and gait abnormalities, including cerebellar ataxia, occur in most patients. Seizures are uncommon, reflecting the lack of gray-matter involvement 17. Unlike toxoplasmosis, altered consciousness and other symptoms of diffuse encephalitis are initially absent, and clinical progression is generally more protracted than either toxoplasmosis or CNS lymphoma. The median time from first symptom 166 Journal of Indian Academy of Clinical Medicine Vol. 5 No. 2

5 to death is 3.5 months, and the vast majority of patients die within 1 year. However, partial recovery and prolonged survival have been reported in as many as 7% of cases. On CT scan, PML lesions have low attenuation. With MRI, they demonstrate low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. Contrast enhancement is typically absent, and generally no mass effect is seen 18. Lesions occur at the interface between gray and white matter, with a predilection for the parietal lobes, but may involve the periventricular white matter, posterior fossa, and brain stem. Gray-matter involvement has been reported. The clinical course and neuroradiography suggest the diagnosis of PML; yet a definitive diagnosis can only be made by brain biopsy. There is no proven effective treatment. A variety of antivirals including amantadine, adenosine arabinoside, and cytosine arabinoside have been tried with little success. Cidofovir is being studied in the US (ACTG 363) and also in Europe for treatment of PML, but its nephrotoxicity may limit its tolerability. A topoisomerase inhibitor, topotecan, is in trial in the USA; however, its toxicity will probably also limit the use of this agent. Current practice is to give HAART and if possible to use alpha interferon 3MU SC daily. This is usually well tolerated and clear remissions have been seen. Tuberculosis Tuberculosis is a common problem in India. Tubercular involvement can occur at any stage of HIV infection. Multiple infections should always be kept in mind. The presenting signs and symptoms vary according to the stage of disease. Two patterns of focal involvement have been described. Tuberculomas are small foci of caseation surrounded by a collagenous capsule, inflammatory cells, and few bacilli. The MRI appearance may vary, showing multiple or solitary lesions smaller than 1cm in size, with nodular or ring enhancement, and no associated mass effect or oedema. In contrast, tuberculous abscesses are large solitary lesions with central liquefaction containing numerous tubercle bacilli. They appear hyperintense on T2-weighted MRI images and are generally associated with mass effect, ring enhancement, and oedema 19. Lesions may be located in the supratentorial area, posterior fossa, or brain stem. Hydrocephalus, basilar meningitis, or cerebral infarction develops in at least one third of patients with CNS tuberculosis. Other Focal Conditions These include infection with polymicrobial organisms including bacteria, nocardia, syphilis, varicella-zoster virus, candida, etc. Conclusions CNS involvement in HIV/AIDS is common. To decrease the morbidity, it is very important that these conditions are suspected and diagnosed early. Multiple infections should always be kept in mind while evaluating these patients. Diagnostic approach includes staging of HIV and whether disease is nonfocal or focal. If disease is non-focal, without constitutional symptoms, and major defect is cognitive, then the possible diagnosis is ADC. In presence of constitutional symptoms, headache and some alteration of sensorium, cryptococcal or tuberculous meningitis should be ruled out. In presence of focal disease with constitutional symptoms, mass effect and ring enhancement on imaging, then toxoplasmosis, tuberculosis and primary CNS lymphoma should be considered. CSF toxoplasma serology and PCR for tuberculosis can be helpful investigations. Focal disease without constitutional symptoms and with absence of mass effect, as also contrast enhancement without ventriculomegaly is suggestive of PML. A diagnostic approach thus minimizes both empiricism and the need for brain biopsy. References 1. Anders KH, Guerra WF, Tomiyasu U et al. The neuropathology of AIDS: UCLA experience and review. Am J Pathol 1986; 124: Journal of Indian Academy of Clinical Medicine Vol. 5 No

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