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Neurological complications of HIV
NATURAL HISTORY AND CLINICAL FEATURES
Neurological complications of HIV
CMV and HSV encephalitis typically present more rapidly and may be associated with disease elsewhere (e.g. CMV retinitis, colitis). Clinical features – HIV encephalopathy causes cognitive, motor and behavioural abnormalities developing over months. Early cognitive problems include poor concentration and memory loss, which may progress to severe dementia. Poor balance, incoordination and clumsiness are common early motor complaints, followed by generalized hyper-reflexia, ataxia, leg weakness, seizures and incontinence. Depression, apathy and lack of initiative, or agitation and hyperactivity, are common. Diagnosis is clinical. MRI and CT show cerebral atrophy with wide sulci and enlarged ventricles. MRI reveals white matter abnormalities, particularly in periventricular areas. Management – HIV encephalopathy can be prevented by successful HAART. Once HIV encephalopathy has become established, however, response to HAART is variable; marked improvement occurs in some patients.
David Wilks
Before the advent of effective highly active antiretroviral therapy (HAART), about 10% of AIDS patients in developed countries presented with neurological opportunistic infections and malignancies, typically accompanying advanced immunodeficiency. These presentations are now less common, but peripheral neuropathy is common as a complication of therapy. Primary HIV infection: HIV seroconversion is often associated with neurological symptoms including meningitis, ataxia and cranial or peripheral neuropathy. Recovery usually occurs over weeks.
Toxoplasmosis Primary infection with the protozoan Toxoplasma gondii results in deposition of viable cysts in the brain and other tissues. In advanced immunodeficiency, the cysts reactivate, causing necrotic abscesses throughout the cerebral hemispheres. Clinical features include fever, confusion, fits and focal neurological deficit developing over a few days. There may be concomitant chorioretinitis. Diagnosis – Toxoplasma serology is positive in more than 95% of patients with Toxoplasma encephalitis, but changes in antibody titre are seldom helpful. Polymerase chain reaction (PCR) analysis of CSF is available and is helpful if positive; the reported specificity is almost 100%, but the sensitivity is low (about 50%). CT shows hypodense lesions (usually multiple, and particularly in the basal ganglia and at the hemispheric corticomedullary junction) that usually develop ring enhancement (Figure 1) with contrast. MRI is more sensitive and almost always shows multiple lesions. Management – treatment with pyrimethamine and sulfadiazine is usually effective within a few weeks and is often given as a therapeutic trial in those with focal cerebral lesions, even when the radiological appearances are atypical. Corticosteroids and anticonvulsants may also be required. Clindamycin and clarithromycin are alternatives to sulfadiazine. Life-long maintenance therapy is required, unless the CD4 count can be restored by HAART.
Neurological presentations in advanced HIV disease: neurological opportunistic infections and malignancies are generally seen only in patients with advanced disease (e.g. CD4 count < 50/µl) and may present as diffuse or focal encephalopathy, or meningitis. • Diffuse encephalopathy1 suggests HIV encephalopathy (also termed ‘AIDS–dementia complex’). Less common causes include cytomegalovirus (CMV) and herpes simplex virus (HSV) encephalitis, and toxoplasmosis. Hypoxia or sepsis secondary to systemic infection and hepatic encephalopathy may have to be excluded. • Focal cerebral disease2 is commonly caused by toxoplasmosis, lymphoma or progressive multifocal leucoencephalopathy (PML). Rare causes include tuberculosis, cryptococcosis, candidiasis, HSV and varicella-zoster virus. • CSF abnormalities such as mild lymphocytic pleocytosis and moderate elevation of protein are common in HIV-positive patients at all stages. Bacterial meningitis is uncommon, but cryptococcal meningitis is relatively common. Tuberculous and lymphomatous meningitis also occur.
HIV encephalopathy HIV encephalopathy is the direct result of HIV infection of the CNS. Neuropathological changes correlate to some extent with the clinical picture, particularly affecting the central white matter, basal ganglia, brain stem and spinal cord. Untreated, 30–50% of AIDS patients develop symptomatic HIV encephalopathy, but neuropsychological testing reveals subclinical abnormalities in many more.
Progressive multifocal leucoencephalopathy PML is caused by reactivation of the polyomavirus JC virus. Clinical features – progressive, inexorable neurological dysfunction occurs, typically including hemiparesis, ataxia or aphasia, usually over weeks or months. Fever is absent and there is no clouding of consciousness. A relapsing and remitting course is occasionally described. Diagnosis is by CT or MRI, which shows multiple, nonenhancing white-matter lesions without mass effect (Figure 2). There are no specific changes in the CSF, but JC virus can usually be demonstrated by PCR analysis, which has a published sensitivity of 74–93% and a specificity of 92–100%.
David Wilks is Consultant Physician in the Regional Infectious Diseases Unit at Western General Hospital, Edinburgh, UK. Conflict of interests: none declared.
MEDICINE 33:6
22
© 2005 The Medicine Publishing Company Ltd
NATURAL HISTORY AND CLINICAL FEATURES
There may be clinical or radiological evidence of simultaneous or recent cryptococcal pneumonia. Management – amphotericin B is administered, usually with 5-flucytosine, followed by fluconazole. Patients with raised intracranial pressure are at risk of blindness; daily lumbar puncture for removal of CSF is required until the opening pressure is controlled In the absence of a response to HAART, life-long antifungal therapy is required.
1 MRI of AIDS-associated cerebral toxoplasmosis. There is a central lesion adjacent to the basal ganglia, showing strong ring enhancement. Other common features not shown by this example include surrounding oedema, mass effect and multiple lesions.
Peripheral neuropathy4 • Sensory polyneuropathy is common, causing ‘glove-andstocking’ distribution numbness, paraesthesiae and dysaesthesiae, mainly in the feet and legs. • Although peripheral neuropathy can result from HIV infection per se, it is more commonly seen as a complication of therapy. Nucleoside reverse transcriptase inhibitors (didanosine, stavudine, zalcitabine) are particularly likely to cause peripheral neuropathy, which is often a treatment-limiting adverse effect. Tricyclic antidepressants, analgesics, carbamazepine and gabapentin may relieve symptoms. • CMV can cause progressive radiculopathy affecting the sacral and lumbar roots, causing flaccid paralysis of the legs with sacral pain and sphincter disturbance.
2 MRI of progressive multifocal leucoencephalopathy. High signal is seen in the white matter of the right occipital lobe, with no surrounding oedema or mass effect.
Management – the prognosis of untreated PML is poor, but progression can often be halted by initiation of HAART. Established neurological deficits do not usually improve. There is no proven specific therapy.
REFERENCES 1 Anderson E, Zink W, Xiong H et al. HIV-1-associated dementia: a metabolic encephalopathy perpetrated by virus-infected and immune-competent mononuclear phagocytes. J Acquir Immune Defic Syndr 2002; 31: S43–53. 2 Skiest D J. Focal neurological disease in patients with acquired immunodeficiency syndrome. Clin Infect Dis 2002; 34: 103–15. 3 Brouwer A E, Rajanuwong A, Chierakul W et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363: 1764–7. 4 Luciano C A, Pardo C A, McArthur J C. Recent developments in the HIV neuropathies. Curr Opin Neurol 2003; 16: 403–9.
Cerebral lymphoma Clinical features – CNS lymphomas usually present with gradual onset of confusion, lethargy, cognitive loss, fits and focal signs such as hemiplegia, aphasia and cranial nerve palsies. Diagnosis – CT or MRI shows one or two discrete white-matter lesions, which may be weakly contrast-enhancing. Differentiation from toxoplasmosis can be difficult on radiological grounds alone. Epstein–Barr virus DNA is found in association with almost all lymphomas in AIDS and can usually be detected in the CSF by PCR analysis (sensitivity 83–100%, specificity 93–100%). Management – the prognosis remains poor despite HAART; median survival is a few months.
Practice points • Neurological complications of HIV are associated with advanced immunodeficiency and have been seen less often since the advent of HAART • Differentiation of the three major causes of focal CNS lesions can be difficult on radiological grounds, but sensitive and specific PCR testing is now available for Toxoplasma, JC virus and Epstein–Barr virus • Toxoplasmosis responds to antibiotics, so a therapeutic trial is often undertaken even when the radiological appearances are atypical • Peripheral neuropathy often occurs as a complication of antiviral therapy
Cryptococcal meningitis3 Cryptococcus neoformans is a fungus that is widespread in the environment, in bird droppings. It is present worldwide, and infection occurs via inhalation. Clinical features – cryptococcal meningitis usually presents insidiously with fever, headache and malaise. Nausea, vomiting and altered mental state are common; neck stiffness and photophobia are uncommon. Fits or focal signs occur occasionally. Diagnosis – India ink staining of CSF reveals capsulate yeasts in about 70% of patients. Antigen detection, performed on serum or CSF, is positive in almost every case. Raised opening pressure is common on lumbar puncture, but routine CSF examination and CT/MRI of the head are often normal or nonspecifically abnormal.
MEDICINE 33:6
23
© 2005 The Medicine Publishing Company Ltd
Neurological complications of HIV
CMV and HSV encephalitis typically present more rapidly and may be associated with disease elsewhere (e.g. CMV retinitis, colitis). Clinical features – HIV encephalopathy causes cognitive, motor and behavioural abnormalities developing over months. Early cognitive problems include poor concentration and memory loss, which may progress to severe dementia. Poor balance, incoordination and clumsiness are common early motor complaints, followed by generalized hyper-reflexia, ataxia, leg weakness, seizures and incontinence. Depression, apathy and lack of initiative, or agitation and hyperactivity, are common. Diagnosis is clinical. MRI and CT show cerebral atrophy with wide sulci and enlarged ventricles. MRI reveals white matter abnormalities, particularly in periventricular areas. Management – HIV encephalopathy can be prevented by successful HAART. Once HIV encephalopathy has become established, however, response to HAART is variable; marked improvement occurs in some patients.
David Wilks
Before the advent of effective highly active antiretroviral therapy (HAART), about 10% of AIDS patients in developed countries presented with neurological opportunistic infections and malignancies, typically accompanying advanced immunodeficiency. These presentations are now less common, but peripheral neuropathy is common as a complication of therapy. Primary HIV infection: HIV seroconversion is often associated with neurological symptoms including meningitis, ataxia and cranial or peripheral neuropathy. Recovery usually occurs over weeks.
Toxoplasmosis Primary infection with the protozoan Toxoplasma gondii results in deposition of viable cysts in the brain and other tissues. In advanced immunodeficiency, the cysts reactivate, causing necrotic abscesses throughout the cerebral hemispheres. Clinical features include fever, confusion, fits and focal neurological deficit developing over a few days. There may be concomitant chorioretinitis. Diagnosis – Toxoplasma serology is positive in more than 95% of patients with Toxoplasma encephalitis, but changes in antibody titre are seldom helpful. Polymerase chain reaction (PCR) analysis of CSF is available and is helpful if positive; the reported specificity is almost 100%, but the sensitivity is low (about 50%). CT shows hypodense lesions (usually multiple, and particularly in the basal ganglia and at the hemispheric corticomedullary junction) that usually develop ring enhancement (Figure 1) with contrast. MRI is more sensitive and almost always shows multiple lesions. Management – treatment with pyrimethamine and sulfadiazine is usually effective within a few weeks and is often given as a therapeutic trial in those with focal cerebral lesions, even when the radiological appearances are atypical. Corticosteroids and anticonvulsants may also be required. Clindamycin and clarithromycin are alternatives to sulfadiazine. Life-long maintenance therapy is required, unless the CD4 count can be restored by HAART.
Neurological presentations in advanced HIV disease: neurological opportunistic infections and malignancies are generally seen only in patients with advanced disease (e.g. CD4 count < 50/µl) and may present as diffuse or focal encephalopathy, or meningitis. • Diffuse encephalopathy1 suggests HIV encephalopathy (also termed ‘AIDS–dementia complex’). Less common causes include cytomegalovirus (CMV) and herpes simplex virus (HSV) encephalitis, and toxoplasmosis. Hypoxia or sepsis secondary to systemic infection and hepatic encephalopathy may have to be excluded. • Focal cerebral disease2 is commonly caused by toxoplasmosis, lymphoma or progressive multifocal leucoencephalopathy (PML). Rare causes include tuberculosis, cryptococcosis, candidiasis, HSV and varicella-zoster virus. • CSF abnormalities such as mild lymphocytic pleocytosis and moderate elevation of protein are common in HIV-positive patients at all stages. Bacterial meningitis is uncommon, but cryptococcal meningitis is relatively common. Tuberculous and lymphomatous meningitis also occur.
HIV encephalopathy HIV encephalopathy is the direct result of HIV infection of the CNS. Neuropathological changes correlate to some extent with the clinical picture, particularly affecting the central white matter, basal ganglia, brain stem and spinal cord. Untreated, 30–50% of AIDS patients develop symptomatic HIV encephalopathy, but neuropsychological testing reveals subclinical abnormalities in many more.
Progressive multifocal leucoencephalopathy PML is caused by reactivation of the polyomavirus JC virus. Clinical features – progressive, inexorable neurological dysfunction occurs, typically including hemiparesis, ataxia or aphasia, usually over weeks or months. Fever is absent and there is no clouding of consciousness. A relapsing and remitting course is occasionally described. Diagnosis is by CT or MRI, which shows multiple, nonenhancing white-matter lesions without mass effect (Figure 2). There are no specific changes in the CSF, but JC virus can usually be demonstrated by PCR analysis, which has a published sensitivity of 74–93% and a specificity of 92–100%.
David Wilks is Consultant Physician in the Regional Infectious Diseases Unit at Western General Hospital, Edinburgh, UK. Conflict of interests: none declared.
MEDICINE 33:6
22
© 2005 The Medicine Publishing Company Ltd
NATURAL HISTORY AND CLINICAL FEATURES
There may be clinical or radiological evidence of simultaneous or recent cryptococcal pneumonia. Management – amphotericin B is administered, usually with 5-flucytosine, followed by fluconazole. Patients with raised intracranial pressure are at risk of blindness; daily lumbar puncture for removal of CSF is required until the opening pressure is controlled In the absence of a response to HAART, life-long antifungal therapy is required.
1 MRI of AIDS-associated cerebral toxoplasmosis. There is a central lesion adjacent to the basal ganglia, showing strong ring enhancement. Other common features not shown by this example include surrounding oedema, mass effect and multiple lesions.
Peripheral neuropathy4 • Sensory polyneuropathy is common, causing ‘glove-andstocking’ distribution numbness, paraesthesiae and dysaesthesiae, mainly in the feet and legs. • Although peripheral neuropathy can result from HIV infection per se, it is more commonly seen as a complication of therapy. Nucleoside reverse transcriptase inhibitors (didanosine, stavudine, zalcitabine) are particularly likely to cause peripheral neuropathy, which is often a treatment-limiting adverse effect. Tricyclic antidepressants, analgesics, carbamazepine and gabapentin may relieve symptoms. • CMV can cause progressive radiculopathy affecting the sacral and lumbar roots, causing flaccid paralysis of the legs with sacral pain and sphincter disturbance.
2 MRI of progressive multifocal leucoencephalopathy. High signal is seen in the white matter of the right occipital lobe, with no surrounding oedema or mass effect.
Management – the prognosis of untreated PML is poor, but progression can often be halted by initiation of HAART. Established neurological deficits do not usually improve. There is no proven specific therapy.
REFERENCES 1 Anderson E, Zink W, Xiong H et al. HIV-1-associated dementia: a metabolic encephalopathy perpetrated by virus-infected and immune-competent mononuclear phagocytes. J Acquir Immune Defic Syndr 2002; 31: S43–53. 2 Skiest D J. Focal neurological disease in patients with acquired immunodeficiency syndrome. Clin Infect Dis 2002; 34: 103–15. 3 Brouwer A E, Rajanuwong A, Chierakul W et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363: 1764–7. 4 Luciano C A, Pardo C A, McArthur J C. Recent developments in the HIV neuropathies. Curr Opin Neurol 2003; 16: 403–9.
Cerebral lymphoma Clinical features – CNS lymphomas usually present with gradual onset of confusion, lethargy, cognitive loss, fits and focal signs such as hemiplegia, aphasia and cranial nerve palsies. Diagnosis – CT or MRI shows one or two discrete white-matter lesions, which may be weakly contrast-enhancing. Differentiation from toxoplasmosis can be difficult on radiological grounds alone. Epstein–Barr virus DNA is found in association with almost all lymphomas in AIDS and can usually be detected in the CSF by PCR analysis (sensitivity 83–100%, specificity 93–100%). Management – the prognosis remains poor despite HAART; median survival is a few months.
Practice points • Neurological complications of HIV are associated with advanced immunodeficiency and have been seen less often since the advent of HAART • Differentiation of the three major causes of focal CNS lesions can be difficult on radiological grounds, but sensitive and specific PCR testing is now available for Toxoplasma, JC virus and Epstein–Barr virus • Toxoplasmosis responds to antibiotics, so a therapeutic trial is often undertaken even when the radiological appearances are atypical • Peripheral neuropathy often occurs as a complication of antiviral therapy
Cryptococcal meningitis3 Cryptococcus neoformans is a fungus that is widespread in the environment, in bird droppings. It is present worldwide, and infection occurs via inhalation. Clinical features – cryptococcal meningitis usually presents insidiously with fever, headache and malaise. Nausea, vomiting and altered mental state are common; neck stiffness and photophobia are uncommon. Fits or focal signs occur occasionally. Diagnosis – India ink staining of CSF reveals capsulate yeasts in about 70% of patients. Antigen detection, performed on serum or CSF, is positive in almost every case. Raised opening pressure is common on lumbar puncture, but routine CSF examination and CT/MRI of the head are often normal or nonspecifically abnormal.
MEDICINE 33:6
23
© 2005 The Medicine Publishing Company Ltd