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HIV and Neurological Disease
AIDS/HIV and Neurological Disease JR Brosch, Indiana University School of Medicine, Indianapolis, IN, USA r 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by John R Corboy, Steven C Johnson, volume 1, pp 66–76, r 2003, Elsevier Inc.
Introduction
Recent Developments in Human Immunodeficiency Virus Treatment
Recognized 30 years ago as the cause of the acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection has rapidly become one of the leading causes of morbidity and mortality worldwide. The World Health Organization (WHO) estimates that by the end of 2010, approximately 40 million people worldwide were infected with HIV. Owing to improvements in education/ prevention, rapid diagnosis, and the availability of treatment, the rate of new HIV infections has been steadily decreasing over the last decade. The number of people dying from AIDS-related illnesses also began dropping after 2005. Despite this, HIV remains a major global health concern. In the US, by the end of 2009, approximately 1.2 million Americans were HIV infected. In the US, the epidemic has shifted over time, with an increasing number of persons living with HIV and a decreasing number dying from AIDS. According to the WHO, the number of people dying from AIDS in the US peaked at 55 000 in 1993 and was 17 000 in 2009, despite a 63% increase in the number of HIV-infected persons over that same period.
Pathogenesis of Human Immunodeficiency Virus Infection HIV is transmitted through contact with HIV-infected blood, semen, vaginal secretions, or breast milk. The major specific means of transmission are through anal and vaginal intercourse, sharing of needles for injection drug use, and motherto-infant transmission. Within 2–6 weeks of infection, most persons develop an acute febrile illness termed primary HIV infection. This illness is self-limited and most individuals will then have a relatively long period of clinical latency before the illness develops. However, viral replication is active throughout the course of the disease. The cluster differentiation 4 (CD4 þ ) T lymphocyte is the primary target of HIV infection and the loss of this cell population produces an immunodeficiency that allows opportunistic infections (OIs) and malignancies to occur. The rate of viral replication predicts the rate at which clinical immunodeficiency develops and can be estimated by measuring the plasma HIV-1 ribonucleic acid (RNA) level (also called the viral load). Although most individuals with HIV infection will develop progressive immunodeficiency, a small proportion of ‘long-term nonprogressors’ may not. Antiretroviral medications inhibit HIV replication and its destruction of CD4 þ T lymphocytes. In early HIV infection, these medications can prevent the development of immunodeficiency. In advanced disease, these medications can lead to immune reconstitution.
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The recent decline in the mortality of HIV-infected people in the US is primarily due to the licensure of potent antiretroviral medications against HIV. HIV replication involves a series of steps that include attachment of the virus to host cell receptors, fusion of the virus with the cell membrane, uncoating of the virus, reverse transcription of viral RNA into deoxyribonucleic acid (DNA), integration of the viral DNA into the host genome, DNA replication, transcription of viral RNA, translation of viral proteins, cleavage of protein precursors into enzymes and structural proteins using a protease, assembly of the virus, and budding from the cell membrane (Figure 1). Each of these steps offers an opportunity for inhibition with a drug. The currently available antiretroviral agents inhibit reverse transcriptase (nucleoside and nonnucleoside reverse transcriptase inhibitors (RTI)), protease inhibitors, integrase strand transfer inhibitors, fusion inhibitors, and C–C chemokine receptor 5 (CCR5) antagonists. Selected characteristics of these medications are listed in Table 1. Antiretroviral medications are typically used in combinations of three or four drugs. Current antiretroviral treatment guidelines reflect combinations that have been most successful in terms of clinical efficacy and safety profile. The efficacy of an individual treatment regimen is measured by improvement in the clinical manifestations of HIV infection, immunological improvement (i.e., rising CD4 lymphocyte counts), and virological improvement (i.e., reduction in the plasma HIV-1 RNA level). These medications do have potential limitations, including side effects, drug interactions, and the development of drug resistance. Antiretroviral therapy has also dramatically reduced the rate of HIV transmission from mother to infant. Studies done before the availability of antiretroviral therapy indicated that the risk of transmission from an HIV-infected mother to infant was approximately 25%. Combination antiretroviral therapy of mother and infant reduces this risk to less than 5%. Another important aspect of HIV care is the treatment and prevention of OIs. Many of these infections can be effectively managed with specific antibiotic therapy, and the immunological improvement associated with antiretroviral therapy also helps to control these diseases. A number of these infections, including Pneumocystis jirovecii (carinii) pneumonia, toxoplasmosis, tuberculosis, and disseminated Mycobacterium avium complex disease, are common enough that primary prevention through antibiotic prophylaxis is recommended. Recent studies demonstrate that these prophylactic therapies can often be discontinued once immunological improvement on antiretroviral therapy has occurred. Current guidelines for the prevention and treatment of OIs are also available online.
Encyclopedia of the Neurological Sciences, Volume 1
doi:10.1016/B978-0-12-385157-4.00370-5
AIDS/HIV and Neurological Disease
Reverse transcription inhibitors HIV viron
Protease inhibitors
Host chromosome cDNA
Chemokine co-receptor
Genomic RNA
Protease inhibitors New HIV viron
CD4 lymphocyte
CD4 receptor
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Capsid proteins
Protein
RER Proviral DNA Unintegrated ds DNA Genomic
RNA Nucleus
Attachment
Reverse transcription
Uncoating
Integration
Transcription
Translation and processing
Assembly and release
Figure 1 Life cycle of HIV.
Table 1
Currently available antiretroviral agents
Agent
Trade name in US
Drug class
Side effects
Zidovudine (ZDV, AZT) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Tenofovir Emtricitabine Nevirapine Delavirdine Efavirenz Rilpivirine Etravirine Saquinavir
Retrovir Videx Hivid Zerit Epivir Ziagen Viread Emtriva Viramune Rescriptor Sustiva Edurant Intelence Invirase Fortovase Norvir Crixivan Viracept Kaletra Reyataz Prezista Lexiva Aptivus Fuzeon
Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Protease inhibitor
Anemia, leukopenia, and myopathy Pancreatitis, hepatitis, and peripheral neuropathy Peripheral neuropathy Peripheral neuropathy and neuromuscular Nausea Hypersensitivity reaction Renal impairment and nausea
Ritonavir Indinavir Nelfinavir Lopinavir with ritonavir Atazanavir Darunavir Fosamprenavir Tipranavir Enfuvirtide Elvitegravir Raltegravir Maraviroc
Isentress Selzentry
Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Fusion inhibitor Integrase inhibitor Integrase inhibitor CCR5 antagonist
Hepatitis and skin rash Skin rash Skin rash, dizziness, and other CNS side effects Increased lipids Stevens–Johnson syndrome Prolonged Q-T interval on electrocardiogram (EKG), nausea, and diarrhea Nausea, diarrhea, and hyperlipidemia Nausea and nephrolithiasis Diarrhea Elevated liver enzymes and hyperlipidemia Increased serum bilirubin Nausea, diarrhea, and hepatotoxicity
Nausea, diarrhea, and headache
Abbreviations: CNS, central nervous system; AZT, azidothymidine. Note: Formulations combining several drugs are available and not listed here.
Human Immunodeficiency Virus and Neurological Disease HIV infects the nervous system early after exposure to the virus and clinical manifestations may affect all areas of the nervous system. Initial manifestations of AIDS occur in the nervous system in up to 20% of patients, but the frequency of
neurological complications related to AIDS increases significantly over time and with a decline in the CD4 þ T lymphocyte count. Clinical symptoms occur in the central nervous system (CNS) and the peripheral nervous system (PNS) and may result from the direct effects of HIV infection, OIs or neoplasms related to immunosuppression, or iatrogenic effects of pharmacological intervention. The most common disorders
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Table 2 infection
Etiology of selected neurological syndromes in HIV
Syndrome
Common etiologies
Meningitis
Pneumococcus, Treponema pallidum, Mycobacterium tuberculosis, Cryptococcus, Histoplasma, and HIV Toxoplasmosis, PCNSL, bacterial brain abscess, and progressive multifocal leukoencephalopathy Didanosine, stavudine, zalcitabine, ritonavir, autoimmune reaction, and HIV VZV, CMV, HSV, B12 deficiency, PCNSL, and HIV Zidovudine, bacterial infection, and HIV CMV, carcinomatous, or lymphomatous meningitis
Focal CNS deficits
Diffuse peripheral neuropathy Myelopathy Myopathy/myositis Polyradiculopathy
Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; HSV, herpes simplex virus; PCNSL, primary CNS lymphoma; VZV, varicella zoster virus.
are peripheral neuropathy, HIV-associated neurocognitive disorder (HAND), primary CNS lymphoma (PCNSL), and OIs, including CNS toxoplasmosis and progressive multifocal leukoencephalopathy (PML) (Table 2).
Central Nervous System Human Immunodeficiency Virus-Associated Neurocognitive Disorder HAND (also known as AIDS dementia complex) represents a range of neurocognitive decline beginning with asymptomatic neurocognitive impairment, progressing to mild neurocognitive disorder (MND) and ending with HIV-associated dementia (HAD). The development of HAND is directly proportional to the CD4 þ T lymphocyte count, which supports the early initiation of antiretroviral therapy. Before the introduction of zidovudine (ZDV) and the subsequent development of combination antiretroviral therapy, HAD was described in up to approximately 27% of patients in the late stages of AIDS. Pathological changes associated with HAD were seen in an even greater percentage of AIDS patients at autopsy. Although reliable estimates of the current prevalence of HAND are difficult to obtain, the introduction of combination antiretroviral therapy appears to have had a profound impact on decreasing the prevalence of the more severe HAD, but the prevalence of asymptomatic neurocognitive impairment and MND persist among patients. Asymptomatic neurocognitive impairment reflects minor deficits in two or more neuropsychological domains; MND is categorized as 41 standard deviation below average in two or more cognitive domains; HAD requires 42 standard deviations below average in two or more cognitive domains along with impairment in activities of daily living. The usual symptoms reflect damage to the white matter and subcortical gray matter structures of the brain, especially the basal ganglia, thalamus, and brainstem. These include difficulties with
attention, concentration, information processing speed and response time, memory, verbal fluency, visuospatial and visuoconstructive capacity, and abstract reasoning. There may be significant personality changes, irritability, social withdrawal, and emotional lability. Patients often have signs similar to those of Parkinson’s disease, including bradykinesia, tremor, and gait disturbance, and may have increased reflexes on neurological examination. Examination of the cerebrospinal fluid (CSF) often reveals a modest lymphocytic pleocytosis, an elevated protein, and a normal glucose level. Magnetic resonance imaging (MRI) scans show diffuse atrophy and a variable amount of T2-weighted lesions affecting primarily the subcortical white matter and basal ganglia. These lesions may be punctate, diffuse, or confluent. Enhancement after the injection of contrast material is usually not seen. Pathological abnormalities include microglial nodules, multinucleated giant cells, myelin pallor, and astrocytic gliosis. Neuronal dropout can be severe, especially in the frontal cortex, basal ganglia, and the limbic system. HAD appears to be caused by HIV, although the pathogenesis remains unclear. HIV enters the nervous system early after infection. This probably occurs as infected monocytes and CD4 þ T lymphocytes traffic through the CNS (the Trojan Horse theory) or via infection of endothelial cells. Cell-free invasion also may be possible. HIV-1 is found in the brains of patients with and without symptoms of HAD, and clinical symptoms and pathological damage are not closely correlated with viral load assessed in the brain or CSF. Significant, productive HIV infection in the CNS appears to be limited to cells of the macrophage lineage and CD4 þ T lymphocytes; symptoms of HAD do appear to correlate with these infected cells. A variety of HIV protein products and cellular products, such as cytokines and chemokines, and the associated chronic inflammatory process have been implicated as potential direct or indirect mediators of pathological damage. Consistent with the idea that HAD is a direct result of HIV infection in the brain, the widespread use of combination antiretroviral therapy appears to be associated with a significant reduction in the incidence and prevalence of HAD. However, antiretroviral treatment failure may lead to a rebound of HIV infection and increased risk for HAD. There are probably relatively isolated cellular and anatomical reservoirs of HIV infection in treated patients, including resting CD4 þ T lymphocytes carrying integrated viral DNA, the male urogenital tract, and the CNS. Penetration of antiretroviral drugs, such as protease inhibitors, into the CNS may be limited by the membrane efflux transporter P-glycoprotein in the capillary epithelium. HIV protease inhibitor concentrations may be increased in these reservoir sites by the addition of inhibitors of this P-glycoprotein or of low-dose Ritonavir to regimens with indinavir, saquinavir, amprenavir, or lopinavir. Some of the antiretroviral medicines have increased CNS penetration compared with others, and specific treatment regimens, which take this into account are currently being studied in the context of potentially improving cognitive decline.
Vacuolar Myelopathy Although clinical symptoms are rarely seen during life, signs of a thoracic myelopathy associated with vacuoles (VM) are seen
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in 40–55% in autopsy series. Clinical features include painless leg weakness, gait instability, sensory loss in the legs, impotence in men, and urinary and bowel dysfunctions. When diagnosed during life, VM is almost exclusively found in patients with HAD and CD4 þ T lymphocyte counts less than 200 cells per mm3. Some studies have shown that the myelopathy may be related to the vitamin B12-dependent transmethylation pathway with a decrease in methionine, but methionine supplementation has not proven efficacious. There are no characteristic CSF features, and MRI scans of the spinal cord demonstrate thoracic atrophy and/or T2-weighted hyperintense lesions. Pathologically, it is similar to the myelopathy caused by B12 deficiency with white matter vacuolation in the lateral and posterior columns. Peripheral neuropathy is seen concomitantly in approximately 50% of the patients and may produce symptoms that overlap with or mimic VM. Somatosensory-evoked potentials may be useful in distinguishing VM from peripheral neuropathy. VM often progresses to severe paraparesis and sphincteric dysfunction, and it is a bad prognostic sign in AIDS patients. Other causes of myelopathy, including varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV), PCNSL, and vitamin B12 deficiency, should be excluded. The pathogenesis of VM is unknown, and there is no significant evidence that treatment with antiretroviral therapy has any impact on VM.
Opportunistic Infections Patients infected with HIV-1 are prone to develop OIs, especially when the CD4 þ T lymphocyte count falls below 200 cells per mm3. The nervous system may be infected by bacteria, fungi, parasites, or viruses, with many of these infections seen almost exclusively in immunocompromised patients. Bacterial infections of the CNS are common in HIVinfected patients. Syphilis may present symptomatically with either focal lesions, such as stroke, optic neuropathy, or seventh cranial nerve palsy, or, in a more generalized fashion, with meningitis or dementia. The natural history of syphilis may be accelerated in the setting of HIV infection, with various forms of neurosyphilis occurring soon after primary, secondary, or latent syphilis. Tuberculosis may also occur, typically producing basilar meningitis affecting multiple cranial nerves and inducing hydrocephalus leading to death in upward of 50% of patients. Bacterial abscesses, either intracerebral or epidural, especially may be seen in intravenous drug users with infected cardiac valves. Diagnosis of specific bacterial infections is made by a combination of imaging studies, CSF analyses, microbiological studies, and serologies. Antibiotic treatment is directed toward the specific bacterium involved, and abscesses may also require surgical drainage. Occurring in up to 15% of AIDS patients in the preantiretroviral era, CNS toxoplasmosis is the most common OI of the CNS. Toxoplasma gondii infection in humans occurs after ingestion of oocysts shed by cat feces or bradyzoites found in undercooked meat, and the primary infection is usually asymptomatic. Cerebral toxoplasmosis in AIDS patients represents reactivation of previously acquired infection and typically occurs when the CD4 þ T-lymphocyte count is below 200 cells per mm3. Manifestations include fever, headache,
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confusion/altered mental status, seizures, and focal deficits. Brain MRI typically reveals ring-enhancing or nodularenhancing lesions with surrounding edema and mass effect. There are multiple lesions in two-thirds of the cases, and they may be widespread. These lesions may be difficult to distinguish from the other OIs, especially PCNSL. Imaging with thallium-201 single-photon emission computed tomography (SPECT) may be quite helpful in this regard because brain uptake is typically negative with toxoplasmosis and positive with PCNSL. The absence of serum anti-Toxoplasma antibodies makes the diagnosis unlikely, with one study suggesting that nearly all patients with CNS toxoplasmosis have titers greater than 1:256 with titers below this level being evidence against CNS toxoplasmosis. In combination, thallium-201 and serological evaluation lead to the greatest diagnostic accuracy. Some authors recommend treating empirically for toxoplasmosis if the brain MRI shows multiple lesions; a single lesion or treatment-resistant multiple lesions will often require further workup with SPECT and/or stereotactic brain biopsy. Polymerase chain reaction (PCR) can detect T. gondii DNA in CSF in up to 81% of untreated patients. Thus, PCR may also be helpful if positive. Treatment with sulfadiazine, folinic acid, and pyrimethamine is highly effective. Patients with positive Toxoplasma serology and a CD4 þ T-lymphocyte count less than 100 cells per mm3 should be treated with prophylactic trimethoprim–sulfamethoxazole to prevent CNS toxoplasmosis. A variety of fungal infections of the nervous system have been described in HIV-infected patients. These infections will produce either intracerebral abscesses or meningitis. The most common fungal infection of the CNS is cryptococcal meningitis. This infection typically presents with a subacute headache, stiff neck, and fever. Communicating hydrocephalus or tumor-like cryptococcomas may also be seen along with multiple cranial neuropathies. Examination of the CSF will reveal an increased opening pressure, variable number of white blood cells, an elevated protein concentration, and a normal or slightly reduced glucose concentration. Both CSF and serum cryptococcal antigen tests will be positive in most of the patients. Acute treatment is with amphotericin B and oral flucytosine, followed by secondary prophylaxis with fluconazole, along with aggressive intracranial pressure management with multiple high-volume spinal taps or a ventriculostomy. Histoplasmosis can lead to infection in HIV patients as well, producing ring-enhancing mass lesions and meningitis. Viral infections of the CNS are common in HIV patients most often by JC virus (JCV), CMV, and herpes viruses. PML is a demyelinating disorder of the CNS that occurs in up to 5% of the HIV-1-infected patients. It results from JCV (a member of the papillomavirus family) infection of oligodendrocytes, the cells that produce CNS myelin. JCV is probably spread by respiratory means, and immunoglobulin G (IgG) antibodies to JCV are seen in approximately 10% of young children and up to 90% of adults. This suggests that clinical disease represents a reactivation of latent infection. The clinical presentation of PML is typically multifocal, with combinations of weakness, sensory loss, visual loss, and ataxia. Seizures may be seen less common. Cognitive impairments may also occur, including poor attention, memory problems, aphasia, and
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behavioral and personality changes. Pathologically, the lesions vary in size from 1-mm punctate lesions to confluent demyelinating subcortical lesions of several centimeters, and they consist of oligodendrocytes with enlarged, hyperchromatic nuclei and bizarre astrocytes with lobulated, hyperchromatic nuclei. Lesions are typically not associated with inflammation, but this may be seen, especially in patients with CD4 þ T-lymphocyte counts above 300 cells per mm3. Similarly, brain MRI usually does not reveal enhancement after the injection of contrast material unless there is a significant inflammatory component to the lesions. The brain MRI is not absolutely diagnostic, and brain biopsy is still frequently required for definitive diagnosis. CSF PCR for JCV is improving in sensitivity and clinicians need to order quantitative PCRs with the highest sensitivity. If the PCR is negative twice and high suspicion still remains, brain biopsy may be required. Prognosis remains poor, and preliminary studies of treating PML with cidofovir have been disappointing. Reconstitution of the immune system with highly active antiretroviral therapy (HAART) sometimes may lead to clinical stabilization. CMV infection is often seen in the brain, although it is commonly asymptomatic. CMV in the brain may cause a panencephalitis, presenting as a subacute or acute encephalopathy with confusion and disorientation. More focal findings, such as seizures, weakness, or sensory loss, may also occur. Many patients will have concomitant retinitis requiring rapid evaluation and treatment to prevent blindness. The adrenal glands may also be affected leading to hyponatremia. MRI scans may reveal nonspecific white and gray matter changes, meningeal enhancement, or a ventricular/periventricular enhancement. Diagnosis is often made by CSF PCR as this is highly sensitive. Spinal fluid often demonstrates a predominance of neutrophils. Interestingly, HSV encephalitis is not increased in incidence in HIV-infected patients. When present, its clinical and pathological features are similar to those seen in immunocompetent patients. VZV may produce a diffuse meningoencephalitis, a myelitis, or a focal arteritis resulting in stroke. In all these herpes family infections, there will be a variable lymphocytic pleocytosis in the CSF, with mildly elevated protein and normal glucose. All are diagnosed with reasonably high specificity and sensitivity with PCR analysis in the CSF. Treatment of HSV and VZV CNS infections is with intravenous acyclovir, whereas CMV is treated with ganciclovir and/or foscarnet.
Neoplastic Primary Central Nervous System Lymphoma Neoplastic PCNSL is seen in up to 4% of AIDS patients and is second to toxoplasmosis as a cause of focal CNS lesions in these patients. The vast majority of PCNSLs occur when the CD4 þ T-lymphocyte count is less than 100 cells per mm3. The lesions of PCNSL are multifocal in more than two-thirds of the cases and are seen throughout the brain. Clinical signs are usually focal or multifocal. MRI scans show multifocal, heterogeneously enhancing lesions. As noted in the section Opportunistic Infections, the major differential diagnosis is with T. gondii, and these clinical entities may be distinguished by a combination of MRI, SPECT, serologies, and PCR in the CSF. Again, some authors recommend empirical treatment for
T. gondii and if there is no improvement, to use SPECT imaging and/or whole body imaging to rule out systemic lymphoma or neoplasm, and ultimately brain biopsy to determine the diagnosis. Quantitative CSF PCR for Epstein–Barr virus DNA can be helpful in improving the specificity of the presence of PCNSL. If possible, it is best to avoid the use of corticosteroids during the time of diagnostic uncertainty because these agents will decrease swelling due to infection and decrease the size of lymphomas, potentially enhancing the clinical response, and confusing the diagnostic issues. Survival of untreated patients with PCNSL is limited to a few weeks, whereas treatment with radiation therapy and corticosteroids will lengthen survival to 3 or 4 months. Chemotherapy has not been associated with improvement in survival.
Headache Headache in HIV-1 patients is a common symptom. Headache occurs in more than 50% of HIV-1 patients, which reflects the fact that headaches, such as the common tension-type and migraine, are prevalent throughout society and that HIV-1 patients take many medicines that might induce headache. For example, one study showed that headaches in HIV-1 patients were associated with anxiety, depression, drug use, and nonHIV-1 neurological disease, and that headache at baseline did not predict onset of new HIV-1-associated systemic or neurological disease. However, new-onset headache in this population should raise concern for an intracranial infection or neoplasm. Headache may occur at any time throughout the infection, including during primary HIV infection. Many HIV-1 patients have a low-level, chronic meningitis or meningoencephalitis that presumably is a direct result of HIV-1 and results in a modest lymphocytic pleocytosis and elevation of protein in the CSF. There does not appear to be a significant correlation, however, between headache and abnormality of typical CSF parameters. This may complicate initial evaluation of a patient with headache and HIV-1 infection, especially when the CD4 þ T lymphocyte count is below 200 per mm3. HIV-1 viral load in the CSF, however, is significantly higher in patients with neurological symptoms, such as headache and signs of meningitis. Thus, a significant question for the practitioner confronted with an HIV-1-infected patient and headache is when to do laboratory testing, including an imaging study and/or a lumbar puncture. Several studies have addressed the question of when to do an imaging study, typically a computed tomography (CT) scan. Utilization of three clinical findings as screening tools, namely, change in quality of headache, seizure, or depressed or altered orientation would have identified 95% of the new intracranial lesions and resulted in 53% less head CTs ordered in the emergency department in one study of 110 HIV patients. Addition of the clinical symptom of a headache prolonged for 3 or more days as a screening tool would have identified all new intracranial lesions, with a 37% reduction in CTs ordered. In a different study, in patients with headache but without altered mental status, meningeal signs, focal neurological abnormalities, or signs of subarachnoid hemorrhage, 76% of CT scans were negative or had atrophy only. The other 24%
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showed mass lesions or white matter lesions. All these positive cases occurred in patients with CD4 þ T-lymphocyte counts less than 200 per mm3. Thus, a significant number of head CT scans in HIV-1 patients and headache can be avoided by utilizing the previously mentioned clinical and laboratory studies as guidelines. Lumbar puncture should be reserved for patients with new or worsening headache and/or signs of meningeal irritation when a diagnosis has not been determined and an imaging study shows no sign of a lesion with mass effect.
Stroke The incidence and prevalence of stroke, both hemorrhagic and nonhemorrhagic, appears to be slightly increased in HIV-1 patients. Nonhemorrhagic stroke in HIV-1 patients is associated with intracranial infection, nonbacterial thrombotic endocarditis, cocaine or other drug use, and possibly protein S deficiency. Rarely, a patient will have an idiopathic CNS vasculitis. Hemorrhagic stroke is associated with thrombocytopenia and tumors, such as PCNSL and Kaposi’s sarcoma.
Immune-Mediated Syndromes A number of autoimmune disorders, such as thrombocytopenia and Reiter’s syndrome, are more common in HIV1-infected patients. These commonly occur early in the course of the illness, long before immunosuppression sets in. Immune reconstitution inflammatory syndrome (IRIS) occurs in approximately 10–15% of all HIV patients upon initiation of antiretroviral therapy. IRIS can lead to an inflammatory response to an underlying OI. Only approximately 1% of HIV patients develop CNS IRIS after initiation of antiviral therapy (particularly in those with a low CD4 þ count before initiation). The acuity of response is caused by a rapid influx of activated CD4 þ T cells into the brain. Cryptococcal infection or JC virus infection (PML) are the most frequently associated underlying OIs. CNS IRIS may also be unrelated to an underlying infection, often appearing as an encephalopathic syndrome. IRIS may take on several forms, such as a monophasic event similar to acute disseminated encephalomyelitis (ADEM), a relapsing–remitting episodic CNS disease similar to multiple sclerosis (MS), or a fulminant, fatal encephalopathy presentation. Corticosteroids are often used to decrease the inflammatory response and are indicated in the case of impending herniation. Steroids may be useful in Cryptococcus-based IRIS and also in noninfectious encephalitis.
Seizures Seizures are common in HIV-infected patients. The incidence of new seizures has been noted to be approximately 3% per year with a prevalence of more than 11%. Although seizures occur most often during the later stages of the illness, they may be the presenting sign of HIV infection. All types of seizures are seen, with multiple causes identified. Simple partial and complex partial seizures are less common and are often associated with intracranial infections and neoplasms, including toxoplasmosis, cryptococcal meningitis, PML, and PCNSL. The majority of seizures, however, are generalized tonic–clonic, and these
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tend to be associated with metabolic derangements and drug toxicities. Notably, in one quarter to one-half of all seizures, a cause is not identified. This suggests that HIV infection is a prominent cause of seizures. Imaging studies should be done in all HIV patients with new-onset seizures, including those with a generalized seizure and a nonfocal neurological examination, because of the relatively high likelihood of identifying an intracranial infection or neoplasm requiring treatment. Treatment of new-onset seizures should be directed at identifiable causes. An important issue in the treatment of seizures is the interaction of many of the anticonvulsants with the antiretroviral medications in use for treatment of the HIV infection. Many of the commonly used anticonvulsants induce the cytochrome P450 3A4 enzymes in the liver and thus enhance metabolism of many of the anti-HIV drugs. In addition, a number of anticonvulsants are highly protein bound and typically displace other protein-bound drugs from albumin. In the case of antiretroviral medicines, this may result in supratherapeutic antiretroviral drug levels and intolerable side effects. Attempting to predict the actual effects of these interactions is quite difficult. Finally, valproic acid may enhance HIV replication and thus should be used with caution in HIV patients until more information is available. In practice, from the standpoint of drug interactions, levetiracetam, gabapentin, and topiramate may be the best choices of anticonvulsants in HIV patients. The American Academy of Neurology published guidelines in 2012 on the use of older antiepileptic drugs and how to tailor treatment as many developing countries may not have new antiepileptic drugs available.
Peripheral Nervous System A number of disorders affecting the peripheral nerve and muscles have been described in HIV-1 patients. As a group, the peripheral neuropathies are the most common type of neurological complication seen in HIV infection. One convenient manner of classification of neuropathy relates to the timing of the neuropathy in relation to onset of HIV infection. In the early stages of infection, before onset of an immunodeficient state, immune-mediated neuropathies, such as acute inflammatory demyelinating polyneuropathy (AIDP) or chronic inflammatory demyelinating polyneuropathy (CIDP), are most common. In the middle and late stages, when immunodeficiency becomes more apparent, a distal sensory polyneuropathy (DSP) and autonomic neuropathy, probably secondary to HIV infection, predominate. In the very late stages associated with very low CD4 þ T lymphocyte counts, the peripheral nerves are most likely to be affected by OIs, nutritional deficiencies, and malignancies. Finally, patients are also at risk throughout the course of HIV infection to toxic damage to their peripheral nerves due to use of antiretroviral and other therapies. Similarly, myopathy secondary to either HIV or antiretroviral therapy has been well described.
Neuropathy Immune-mediated neuropathy As with HIV-1-related neurological illness in the CNS, a small number of HIV-1-infected patients develop neuropathies in
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the early phase of the illness that appear to be autoimmune in nature. Most common are AIDP and CIDP, which act similarly in immunocompromised and immunocompetent patients. Smaller numbers of patients develop cranial mononeuropathies, brachial plexopathies, and vasculitic neuropathies that also appear to be autoimmune in nature. The pathogenesis of these autoimmune neuropathies in HIV-1 patients is unclear, but the treatment is identical to nonHIV-infected patients. AIDP may be the initial presenting sign of HIV-1 infection and can occur at the time of seroconversion or after other viral infections. It is an acute, monophasic disorder that evolves over 7–21 days and is manifested by progressive, asymmetrical, motor more than sensory loss of all four extremities. It may ascend or be more patchy, and ultimately it may be quite confluent and involve muscles of respiration. Electrical studies initially show only delayed F waves but eventually demonstrate delayed distal latencies, slow conduction velocities, and conduction blocks typical of demyelination. CSF analysis is slightly different from that of patients without HIV-1 in that ‘albuminocytological dissociation’ is not present. HIV-1 patients have both an elevation of CSF protein and a modest lymphocytic pleocytosis (10–50 cells per mm3), whereas patients without HIV-1 usually do not have pleocytosis. Pathology is notable for perivenular lymphocytic infiltrates and segmental demyelination associated with macrophages. Treatment consists of either intravenous immunoglobulin (IVIg) or plasma exchange, and the response appears to be similar to that in non-HIV-1 patients. This usually results in significant improvement in symptoms and signs of the disease. CIDP is very similar to AIDP with regard to signs, symptoms, and pathology and may be more common in the setting of HIV, but the overall epidemiology is not known. In distinction, it evolves over weeks to months, is not monophasic, usually does not follow a viral illness (other than HIV-1), and has a less favorable prognosis. CIDP is also treated with corticosteroids, in addition to IVIg and plasma exchange. Mononeuritis multiplex is relatively uncommon. In this disorder, there are multiple cranial nerve and peripheral nerve palsies in a patient with a high CD4 þ cell count. The disorder is self-limited and often resolves spontaneously in this circumstance.
Distal sensory polyneuropathy Approximately one-third of HIV patients eventually develop a distal, primarily sensory, peripheral neuropathy. It is not possible to easily distinguish DSP from antiretroviral toxic neuropathy – only clinical circumstances related to timing can provide insight. DSP is typically seen in middle-to-late stages of infection, often with CD4 þ T-lymphocyte counts below 200 cells per mm3. The most debilitating symptom is pain, which begins in the soles and dorsum of the feet and may move further up both legs in a relatively symmetric fashion. There also is loss of sensory function in a graded fashion. Reflexes are diminished. Nerve conduction studies may reveal diminished amplitudes of sensory nerve action potentials with relatively preserved velocities, as seen in disorders affecting primarily the axon and relatively sparing the myelin sheath. The etiology of DSP is unknown but presumed secondary to HIV infection. Whether this is via direct or indirect
mechanisms is not known. Some studies have found HIV infection in dorsal root ganglion cells, whereas others have not. Macrophage activation and an underlying inflammatory response in the dorsal root ganglion may lead to hyperexcitability. Many treatments for DSP have been tried with positive results shown for topical capsaicin/lidocaine, amitriptyline, and lamotrigine. Narcotic pain medicines may also be necessary to alleviate the pain.
Antiretroviral toxic neuropathy The dideoxynucleoside analog drugs didanosine (ddI), zalcitabine (ddC), and stavudine (d4T) are the most peripheral neurotoxic drugs leading to painful (or painless) sensory neuropathies. The neuropathy often occurs within 3 months after beginning the drug and may affect the hands more often than in DSP related to HIV. The neuropathy is dose related and reversible, and occurs in 23% of patients treated with these medicines for 10 or more months. This neuropathy may be dose limiting, and symptoms are very similar to those of DSP. A previous history of DSP or other neuropathy is associated with greater susceptibility to nucleoside analog-related neuropathy. The pathogenesis of this neuropathy is believed to be interference with mitochondrial DNA synthesis. HIV-1 patients are also exposed to a variety of cancer chemotherapeutic agents that can cause toxic neuropathies, including vincristine, isoniazid, and thalidomide. Treatment of all toxic neuropathies is withdrawal or dose reduction. Symptom improvement may take up to 3 months after withdrawal.
Opportunistic infections Unlike the CNS, OIs of the PNS are relatively uncommon in AIDS. Neurosyphilis and tuberculosis may cause polyradiculopathy due to arachnoiditis. VZV infection of the peripheral nerves producing the characteristic shingles is a well-known complication of AIDS. As in other immunocompromised states, it is more likely to result in multidermatomal spread and invasion of the spinal cord producing myelitis.
Cytomegalovirus polyradiculopathy A rare but potentially devastating complication of AIDS is progressive polyradiculopathy of the lumbosacral roots due to CMV infection. There is subacute-to-acute development of a painful, asymmetric cauda equina syndrome manifested by back pain radiating into one or both legs and urinary incontinence. This is followed by the development of saddle anesthesia and progressive leg weakness. If untreated, this condition progresses to flaccid paraplegia with urinary and bowel incontinence, and there may also be invasion of the spinal cord with myelopathy, respiratory insufficiency, and death within weeks. Electrodiagnostic studies are consistent with multiple lumbosacral radiculopathies. Sural nerve biopsy is probably not helpful. CSF examination reveals polymorphonuclear pleocytosis with elevated protein and depressed glucose levels. Amplification of viral DNA sequences by PCR is the quickest way to confirm the diagnosis and is highly sensitive and specific. MRI may show thickening of the nerve roots. Early treatment with ganciclovir, even before confirmation of the diagnosis, is recommended, and it may result in significant improvement of symptoms. Ganciclovir
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resistance may occur, and it should be suspected in individuals who progress despite therapy. Foscarnet may be substituted in this circumstance. CMV may also be associated with a mononeuritis multiplex syndrome late in the course of AIDS, and this may progress rapidly to quadriparesis.
Myopathy Human immunodeficiency virus myopathy Myopathy may occur at any time during HIV-1 infection and clinically resemble idiopathic polymyositis. Typical symptoms of proximal muscle weakness, difficulty rising from a chair, weight loss, and myalgia are seen. A mild elevation in creatinine kinase (CK) is found in almost all patients with this myopathy, although modest CK elevation is also noted in HIV-1 patients without clinical signs of myopathy. Electromyography shows typical features of myopathic damage, often with irritative signs. Muscle biopsy usually reveals scattered myofiber degeneration, and there are occasional associated inflammatory infiltrates. Myofiber inclusions and cytoplasmic bodies are also sometimes seen. Treatment with corticosteroids will most often lead to improvement. It is likely that there are multiple etiologies of myopathy in HIV patients. Immune mechanisms similar to non-HIV polymyositis seem likely, and opportunistic organisms may rarely infect muscle directly. ZDV therapy may cause a myopathy probably secondary to mitochondrial dysfunction. This has become less common as other nucleoside reverse transcriptase inhibitors do not cause the same degree of mitochondrial dysfunction as ZDV, and doses of these drugs are typically lower. Patients taking ZDV who develop HIV myopathy are often treated with drug withdrawal, with variable effectiveness. Treatment with corticosteroids, nonsteroidal agents, and IVIg may be helpful. Rare patients with an identifiable OI associated with myopathy should be treated with appropriate antibiotic agents.
See also: Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Dementia. HIV Infection, Neurological Complications of. Human T-Cell Lymphotropic Viruses (HTLVs). Meningitis, Viral. Progressive Multifocal Leukoencephalopathy (PML). Viral Vaccines and Antiviral Therapy
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Further Reading AIDSinfo.org, US Department of Health and Human Services (2012) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arvguidelines/0/ (accessed 22.12.12). d’Arminio Monforte A, Duca PG, Vago L, Grassi MP, and Moroni M (2000) Decreasing incidence of CNS AIDS-defining events associated with antiretroviral therapy. Neurology 54: 1856–1859. Berger JR and Sabet A (2002) Infectious myelopathies. Seminars in Neurology 22: 133–141. Birbeck GL, French JA, Perucca E, et al. (2012) Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: Report of the quality standards subcommittee of the american academy of neurology and the ad hoc task force of the commission on therapeutic strategies of the international league against epilepsy. Neurology 78: 139–145. Kranick SM and Nath A (2012) Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy. Continuum Lifelong Learning in Neurology 18: 1319–1337. Lyons J, Venna N, and Cho TA (2011) Atypical nervous system manifestations of HIV. Seminars in Neurology 31: 254–265. Marra CM (1999) Bacterial and fungal brain infections in AIDS. Seminars in Neurology 19: 177–184. Maschke M, Kastrup O, Esser S, et al. (2000) Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). Journal of Neurology, Neurosurgery, and Psychiatry 69: 376–380. McArthur JC, Brew BJ, and Nath A (2005) Neurological complications of HIV infection. Lancet Neurology 4: 543–555. Quereda C, Corral I, Laguna F, et al. (2000) Diagnostic utility of a multiplex herpesvirus PCR assay performed with cerebrospinal fluid from human immunodeficiency virus-infected patients with neurological disorders. Journal of Clinical Microbiology 38: 3061–3067. Romanelli F, Jennings HR, Nath A, Ryan M, and Berger J (2000) The use of anticonvulsants in HIV-positive individuals. Neurology 54: 1404–1407. Rothman RE, Keyl PM, McArthur JC, et al. (1999) A decision guideline for emergency department utilization of noncontrast head computed tomography in HIV-infected patients. Academic Emergency Medicine 6: 1010–1019. Saag MS, Graybill RJ, Larsen RA, et al. (2000) Practice guidelines for the management of cryptococcal disease. Clinical Infectious Diseases 30: 710–718. Infectious Diseases Society of America. Skiest DJ, Erdman W, Chang WE, et al. (2000) SPECT thallium-201 combined with toxoplasma serology for the presumptive diagnosis of focal central nervous system mass lesions in patients with AIDS. Journal of Infection 40: 274–281. Tan IL, Smith BR, von Geldern G, Mateen FJ, and McArthur JC (2012) HIVassociated opportunistic infections of the CNS. Lancet Neurology 11: 605–617. Wong MC, Suite ND, and Labar DR (1990) Seizures in human immuodeficiency virus infection. Archives of Neurology 47: 640–642. World Health Organization (2011) Global HIV/AIDS Response Progress Report 2011. Available at: http://www.who.int/hiv/pub/progress_report2011/en/ index.html (accessed 22.12.12). Wulff EA and Simpson DM (1999) Neuromuscular complications of the human immunodeficiency virus type 1 infection. Seminars in Neurology 19: 157–164.
Introduction
Recent Developments in Human Immunodeficiency Virus Treatment
Recognized 30 years ago as the cause of the acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection has rapidly become one of the leading causes of morbidity and mortality worldwide. The World Health Organization (WHO) estimates that by the end of 2010, approximately 40 million people worldwide were infected with HIV. Owing to improvements in education/ prevention, rapid diagnosis, and the availability of treatment, the rate of new HIV infections has been steadily decreasing over the last decade. The number of people dying from AIDS-related illnesses also began dropping after 2005. Despite this, HIV remains a major global health concern. In the US, by the end of 2009, approximately 1.2 million Americans were HIV infected. In the US, the epidemic has shifted over time, with an increasing number of persons living with HIV and a decreasing number dying from AIDS. According to the WHO, the number of people dying from AIDS in the US peaked at 55 000 in 1993 and was 17 000 in 2009, despite a 63% increase in the number of HIV-infected persons over that same period.
Pathogenesis of Human Immunodeficiency Virus Infection HIV is transmitted through contact with HIV-infected blood, semen, vaginal secretions, or breast milk. The major specific means of transmission are through anal and vaginal intercourse, sharing of needles for injection drug use, and motherto-infant transmission. Within 2–6 weeks of infection, most persons develop an acute febrile illness termed primary HIV infection. This illness is self-limited and most individuals will then have a relatively long period of clinical latency before the illness develops. However, viral replication is active throughout the course of the disease. The cluster differentiation 4 (CD4 þ ) T lymphocyte is the primary target of HIV infection and the loss of this cell population produces an immunodeficiency that allows opportunistic infections (OIs) and malignancies to occur. The rate of viral replication predicts the rate at which clinical immunodeficiency develops and can be estimated by measuring the plasma HIV-1 ribonucleic acid (RNA) level (also called the viral load). Although most individuals with HIV infection will develop progressive immunodeficiency, a small proportion of ‘long-term nonprogressors’ may not. Antiretroviral medications inhibit HIV replication and its destruction of CD4 þ T lymphocytes. In early HIV infection, these medications can prevent the development of immunodeficiency. In advanced disease, these medications can lead to immune reconstitution.
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The recent decline in the mortality of HIV-infected people in the US is primarily due to the licensure of potent antiretroviral medications against HIV. HIV replication involves a series of steps that include attachment of the virus to host cell receptors, fusion of the virus with the cell membrane, uncoating of the virus, reverse transcription of viral RNA into deoxyribonucleic acid (DNA), integration of the viral DNA into the host genome, DNA replication, transcription of viral RNA, translation of viral proteins, cleavage of protein precursors into enzymes and structural proteins using a protease, assembly of the virus, and budding from the cell membrane (Figure 1). Each of these steps offers an opportunity for inhibition with a drug. The currently available antiretroviral agents inhibit reverse transcriptase (nucleoside and nonnucleoside reverse transcriptase inhibitors (RTI)), protease inhibitors, integrase strand transfer inhibitors, fusion inhibitors, and C–C chemokine receptor 5 (CCR5) antagonists. Selected characteristics of these medications are listed in Table 1. Antiretroviral medications are typically used in combinations of three or four drugs. Current antiretroviral treatment guidelines reflect combinations that have been most successful in terms of clinical efficacy and safety profile. The efficacy of an individual treatment regimen is measured by improvement in the clinical manifestations of HIV infection, immunological improvement (i.e., rising CD4 lymphocyte counts), and virological improvement (i.e., reduction in the plasma HIV-1 RNA level). These medications do have potential limitations, including side effects, drug interactions, and the development of drug resistance. Antiretroviral therapy has also dramatically reduced the rate of HIV transmission from mother to infant. Studies done before the availability of antiretroviral therapy indicated that the risk of transmission from an HIV-infected mother to infant was approximately 25%. Combination antiretroviral therapy of mother and infant reduces this risk to less than 5%. Another important aspect of HIV care is the treatment and prevention of OIs. Many of these infections can be effectively managed with specific antibiotic therapy, and the immunological improvement associated with antiretroviral therapy also helps to control these diseases. A number of these infections, including Pneumocystis jirovecii (carinii) pneumonia, toxoplasmosis, tuberculosis, and disseminated Mycobacterium avium complex disease, are common enough that primary prevention through antibiotic prophylaxis is recommended. Recent studies demonstrate that these prophylactic therapies can often be discontinued once immunological improvement on antiretroviral therapy has occurred. Current guidelines for the prevention and treatment of OIs are also available online.
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Reverse transcription inhibitors HIV viron
Protease inhibitors
Host chromosome cDNA
Chemokine co-receptor
Genomic RNA
Protease inhibitors New HIV viron
CD4 lymphocyte
CD4 receptor
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Capsid proteins
Protein
RER Proviral DNA Unintegrated ds DNA Genomic
RNA Nucleus
Attachment
Reverse transcription
Uncoating
Integration
Transcription
Translation and processing
Assembly and release
Figure 1 Life cycle of HIV.
Table 1
Currently available antiretroviral agents
Agent
Trade name in US
Drug class
Side effects
Zidovudine (ZDV, AZT) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Tenofovir Emtricitabine Nevirapine Delavirdine Efavirenz Rilpivirine Etravirine Saquinavir
Retrovir Videx Hivid Zerit Epivir Ziagen Viread Emtriva Viramune Rescriptor Sustiva Edurant Intelence Invirase Fortovase Norvir Crixivan Viracept Kaletra Reyataz Prezista Lexiva Aptivus Fuzeon
Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Nonnucleoside RTI Protease inhibitor
Anemia, leukopenia, and myopathy Pancreatitis, hepatitis, and peripheral neuropathy Peripheral neuropathy Peripheral neuropathy and neuromuscular Nausea Hypersensitivity reaction Renal impairment and nausea
Ritonavir Indinavir Nelfinavir Lopinavir with ritonavir Atazanavir Darunavir Fosamprenavir Tipranavir Enfuvirtide Elvitegravir Raltegravir Maraviroc
Isentress Selzentry
Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Protease inhibitor Fusion inhibitor Integrase inhibitor Integrase inhibitor CCR5 antagonist
Hepatitis and skin rash Skin rash Skin rash, dizziness, and other CNS side effects Increased lipids Stevens–Johnson syndrome Prolonged Q-T interval on electrocardiogram (EKG), nausea, and diarrhea Nausea, diarrhea, and hyperlipidemia Nausea and nephrolithiasis Diarrhea Elevated liver enzymes and hyperlipidemia Increased serum bilirubin Nausea, diarrhea, and hepatotoxicity
Nausea, diarrhea, and headache
Abbreviations: CNS, central nervous system; AZT, azidothymidine. Note: Formulations combining several drugs are available and not listed here.
Human Immunodeficiency Virus and Neurological Disease HIV infects the nervous system early after exposure to the virus and clinical manifestations may affect all areas of the nervous system. Initial manifestations of AIDS occur in the nervous system in up to 20% of patients, but the frequency of
neurological complications related to AIDS increases significantly over time and with a decline in the CD4 þ T lymphocyte count. Clinical symptoms occur in the central nervous system (CNS) and the peripheral nervous system (PNS) and may result from the direct effects of HIV infection, OIs or neoplasms related to immunosuppression, or iatrogenic effects of pharmacological intervention. The most common disorders
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Table 2 infection
Etiology of selected neurological syndromes in HIV
Syndrome
Common etiologies
Meningitis
Pneumococcus, Treponema pallidum, Mycobacterium tuberculosis, Cryptococcus, Histoplasma, and HIV Toxoplasmosis, PCNSL, bacterial brain abscess, and progressive multifocal leukoencephalopathy Didanosine, stavudine, zalcitabine, ritonavir, autoimmune reaction, and HIV VZV, CMV, HSV, B12 deficiency, PCNSL, and HIV Zidovudine, bacterial infection, and HIV CMV, carcinomatous, or lymphomatous meningitis
Focal CNS deficits
Diffuse peripheral neuropathy Myelopathy Myopathy/myositis Polyradiculopathy
Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; HSV, herpes simplex virus; PCNSL, primary CNS lymphoma; VZV, varicella zoster virus.
are peripheral neuropathy, HIV-associated neurocognitive disorder (HAND), primary CNS lymphoma (PCNSL), and OIs, including CNS toxoplasmosis and progressive multifocal leukoencephalopathy (PML) (Table 2).
Central Nervous System Human Immunodeficiency Virus-Associated Neurocognitive Disorder HAND (also known as AIDS dementia complex) represents a range of neurocognitive decline beginning with asymptomatic neurocognitive impairment, progressing to mild neurocognitive disorder (MND) and ending with HIV-associated dementia (HAD). The development of HAND is directly proportional to the CD4 þ T lymphocyte count, which supports the early initiation of antiretroviral therapy. Before the introduction of zidovudine (ZDV) and the subsequent development of combination antiretroviral therapy, HAD was described in up to approximately 27% of patients in the late stages of AIDS. Pathological changes associated with HAD were seen in an even greater percentage of AIDS patients at autopsy. Although reliable estimates of the current prevalence of HAND are difficult to obtain, the introduction of combination antiretroviral therapy appears to have had a profound impact on decreasing the prevalence of the more severe HAD, but the prevalence of asymptomatic neurocognitive impairment and MND persist among patients. Asymptomatic neurocognitive impairment reflects minor deficits in two or more neuropsychological domains; MND is categorized as 41 standard deviation below average in two or more cognitive domains; HAD requires 42 standard deviations below average in two or more cognitive domains along with impairment in activities of daily living. The usual symptoms reflect damage to the white matter and subcortical gray matter structures of the brain, especially the basal ganglia, thalamus, and brainstem. These include difficulties with
attention, concentration, information processing speed and response time, memory, verbal fluency, visuospatial and visuoconstructive capacity, and abstract reasoning. There may be significant personality changes, irritability, social withdrawal, and emotional lability. Patients often have signs similar to those of Parkinson’s disease, including bradykinesia, tremor, and gait disturbance, and may have increased reflexes on neurological examination. Examination of the cerebrospinal fluid (CSF) often reveals a modest lymphocytic pleocytosis, an elevated protein, and a normal glucose level. Magnetic resonance imaging (MRI) scans show diffuse atrophy and a variable amount of T2-weighted lesions affecting primarily the subcortical white matter and basal ganglia. These lesions may be punctate, diffuse, or confluent. Enhancement after the injection of contrast material is usually not seen. Pathological abnormalities include microglial nodules, multinucleated giant cells, myelin pallor, and astrocytic gliosis. Neuronal dropout can be severe, especially in the frontal cortex, basal ganglia, and the limbic system. HAD appears to be caused by HIV, although the pathogenesis remains unclear. HIV enters the nervous system early after infection. This probably occurs as infected monocytes and CD4 þ T lymphocytes traffic through the CNS (the Trojan Horse theory) or via infection of endothelial cells. Cell-free invasion also may be possible. HIV-1 is found in the brains of patients with and without symptoms of HAD, and clinical symptoms and pathological damage are not closely correlated with viral load assessed in the brain or CSF. Significant, productive HIV infection in the CNS appears to be limited to cells of the macrophage lineage and CD4 þ T lymphocytes; symptoms of HAD do appear to correlate with these infected cells. A variety of HIV protein products and cellular products, such as cytokines and chemokines, and the associated chronic inflammatory process have been implicated as potential direct or indirect mediators of pathological damage. Consistent with the idea that HAD is a direct result of HIV infection in the brain, the widespread use of combination antiretroviral therapy appears to be associated with a significant reduction in the incidence and prevalence of HAD. However, antiretroviral treatment failure may lead to a rebound of HIV infection and increased risk for HAD. There are probably relatively isolated cellular and anatomical reservoirs of HIV infection in treated patients, including resting CD4 þ T lymphocytes carrying integrated viral DNA, the male urogenital tract, and the CNS. Penetration of antiretroviral drugs, such as protease inhibitors, into the CNS may be limited by the membrane efflux transporter P-glycoprotein in the capillary epithelium. HIV protease inhibitor concentrations may be increased in these reservoir sites by the addition of inhibitors of this P-glycoprotein or of low-dose Ritonavir to regimens with indinavir, saquinavir, amprenavir, or lopinavir. Some of the antiretroviral medicines have increased CNS penetration compared with others, and specific treatment regimens, which take this into account are currently being studied in the context of potentially improving cognitive decline.
Vacuolar Myelopathy Although clinical symptoms are rarely seen during life, signs of a thoracic myelopathy associated with vacuoles (VM) are seen
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in 40–55% in autopsy series. Clinical features include painless leg weakness, gait instability, sensory loss in the legs, impotence in men, and urinary and bowel dysfunctions. When diagnosed during life, VM is almost exclusively found in patients with HAD and CD4 þ T lymphocyte counts less than 200 cells per mm3. Some studies have shown that the myelopathy may be related to the vitamin B12-dependent transmethylation pathway with a decrease in methionine, but methionine supplementation has not proven efficacious. There are no characteristic CSF features, and MRI scans of the spinal cord demonstrate thoracic atrophy and/or T2-weighted hyperintense lesions. Pathologically, it is similar to the myelopathy caused by B12 deficiency with white matter vacuolation in the lateral and posterior columns. Peripheral neuropathy is seen concomitantly in approximately 50% of the patients and may produce symptoms that overlap with or mimic VM. Somatosensory-evoked potentials may be useful in distinguishing VM from peripheral neuropathy. VM often progresses to severe paraparesis and sphincteric dysfunction, and it is a bad prognostic sign in AIDS patients. Other causes of myelopathy, including varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV), PCNSL, and vitamin B12 deficiency, should be excluded. The pathogenesis of VM is unknown, and there is no significant evidence that treatment with antiretroviral therapy has any impact on VM.
Opportunistic Infections Patients infected with HIV-1 are prone to develop OIs, especially when the CD4 þ T lymphocyte count falls below 200 cells per mm3. The nervous system may be infected by bacteria, fungi, parasites, or viruses, with many of these infections seen almost exclusively in immunocompromised patients. Bacterial infections of the CNS are common in HIVinfected patients. Syphilis may present symptomatically with either focal lesions, such as stroke, optic neuropathy, or seventh cranial nerve palsy, or, in a more generalized fashion, with meningitis or dementia. The natural history of syphilis may be accelerated in the setting of HIV infection, with various forms of neurosyphilis occurring soon after primary, secondary, or latent syphilis. Tuberculosis may also occur, typically producing basilar meningitis affecting multiple cranial nerves and inducing hydrocephalus leading to death in upward of 50% of patients. Bacterial abscesses, either intracerebral or epidural, especially may be seen in intravenous drug users with infected cardiac valves. Diagnosis of specific bacterial infections is made by a combination of imaging studies, CSF analyses, microbiological studies, and serologies. Antibiotic treatment is directed toward the specific bacterium involved, and abscesses may also require surgical drainage. Occurring in up to 15% of AIDS patients in the preantiretroviral era, CNS toxoplasmosis is the most common OI of the CNS. Toxoplasma gondii infection in humans occurs after ingestion of oocysts shed by cat feces or bradyzoites found in undercooked meat, and the primary infection is usually asymptomatic. Cerebral toxoplasmosis in AIDS patients represents reactivation of previously acquired infection and typically occurs when the CD4 þ T-lymphocyte count is below 200 cells per mm3. Manifestations include fever, headache,
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confusion/altered mental status, seizures, and focal deficits. Brain MRI typically reveals ring-enhancing or nodularenhancing lesions with surrounding edema and mass effect. There are multiple lesions in two-thirds of the cases, and they may be widespread. These lesions may be difficult to distinguish from the other OIs, especially PCNSL. Imaging with thallium-201 single-photon emission computed tomography (SPECT) may be quite helpful in this regard because brain uptake is typically negative with toxoplasmosis and positive with PCNSL. The absence of serum anti-Toxoplasma antibodies makes the diagnosis unlikely, with one study suggesting that nearly all patients with CNS toxoplasmosis have titers greater than 1:256 with titers below this level being evidence against CNS toxoplasmosis. In combination, thallium-201 and serological evaluation lead to the greatest diagnostic accuracy. Some authors recommend treating empirically for toxoplasmosis if the brain MRI shows multiple lesions; a single lesion or treatment-resistant multiple lesions will often require further workup with SPECT and/or stereotactic brain biopsy. Polymerase chain reaction (PCR) can detect T. gondii DNA in CSF in up to 81% of untreated patients. Thus, PCR may also be helpful if positive. Treatment with sulfadiazine, folinic acid, and pyrimethamine is highly effective. Patients with positive Toxoplasma serology and a CD4 þ T-lymphocyte count less than 100 cells per mm3 should be treated with prophylactic trimethoprim–sulfamethoxazole to prevent CNS toxoplasmosis. A variety of fungal infections of the nervous system have been described in HIV-infected patients. These infections will produce either intracerebral abscesses or meningitis. The most common fungal infection of the CNS is cryptococcal meningitis. This infection typically presents with a subacute headache, stiff neck, and fever. Communicating hydrocephalus or tumor-like cryptococcomas may also be seen along with multiple cranial neuropathies. Examination of the CSF will reveal an increased opening pressure, variable number of white blood cells, an elevated protein concentration, and a normal or slightly reduced glucose concentration. Both CSF and serum cryptococcal antigen tests will be positive in most of the patients. Acute treatment is with amphotericin B and oral flucytosine, followed by secondary prophylaxis with fluconazole, along with aggressive intracranial pressure management with multiple high-volume spinal taps or a ventriculostomy. Histoplasmosis can lead to infection in HIV patients as well, producing ring-enhancing mass lesions and meningitis. Viral infections of the CNS are common in HIV patients most often by JC virus (JCV), CMV, and herpes viruses. PML is a demyelinating disorder of the CNS that occurs in up to 5% of the HIV-1-infected patients. It results from JCV (a member of the papillomavirus family) infection of oligodendrocytes, the cells that produce CNS myelin. JCV is probably spread by respiratory means, and immunoglobulin G (IgG) antibodies to JCV are seen in approximately 10% of young children and up to 90% of adults. This suggests that clinical disease represents a reactivation of latent infection. The clinical presentation of PML is typically multifocal, with combinations of weakness, sensory loss, visual loss, and ataxia. Seizures may be seen less common. Cognitive impairments may also occur, including poor attention, memory problems, aphasia, and
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behavioral and personality changes. Pathologically, the lesions vary in size from 1-mm punctate lesions to confluent demyelinating subcortical lesions of several centimeters, and they consist of oligodendrocytes with enlarged, hyperchromatic nuclei and bizarre astrocytes with lobulated, hyperchromatic nuclei. Lesions are typically not associated with inflammation, but this may be seen, especially in patients with CD4 þ T-lymphocyte counts above 300 cells per mm3. Similarly, brain MRI usually does not reveal enhancement after the injection of contrast material unless there is a significant inflammatory component to the lesions. The brain MRI is not absolutely diagnostic, and brain biopsy is still frequently required for definitive diagnosis. CSF PCR for JCV is improving in sensitivity and clinicians need to order quantitative PCRs with the highest sensitivity. If the PCR is negative twice and high suspicion still remains, brain biopsy may be required. Prognosis remains poor, and preliminary studies of treating PML with cidofovir have been disappointing. Reconstitution of the immune system with highly active antiretroviral therapy (HAART) sometimes may lead to clinical stabilization. CMV infection is often seen in the brain, although it is commonly asymptomatic. CMV in the brain may cause a panencephalitis, presenting as a subacute or acute encephalopathy with confusion and disorientation. More focal findings, such as seizures, weakness, or sensory loss, may also occur. Many patients will have concomitant retinitis requiring rapid evaluation and treatment to prevent blindness. The adrenal glands may also be affected leading to hyponatremia. MRI scans may reveal nonspecific white and gray matter changes, meningeal enhancement, or a ventricular/periventricular enhancement. Diagnosis is often made by CSF PCR as this is highly sensitive. Spinal fluid often demonstrates a predominance of neutrophils. Interestingly, HSV encephalitis is not increased in incidence in HIV-infected patients. When present, its clinical and pathological features are similar to those seen in immunocompetent patients. VZV may produce a diffuse meningoencephalitis, a myelitis, or a focal arteritis resulting in stroke. In all these herpes family infections, there will be a variable lymphocytic pleocytosis in the CSF, with mildly elevated protein and normal glucose. All are diagnosed with reasonably high specificity and sensitivity with PCR analysis in the CSF. Treatment of HSV and VZV CNS infections is with intravenous acyclovir, whereas CMV is treated with ganciclovir and/or foscarnet.
Neoplastic Primary Central Nervous System Lymphoma Neoplastic PCNSL is seen in up to 4% of AIDS patients and is second to toxoplasmosis as a cause of focal CNS lesions in these patients. The vast majority of PCNSLs occur when the CD4 þ T-lymphocyte count is less than 100 cells per mm3. The lesions of PCNSL are multifocal in more than two-thirds of the cases and are seen throughout the brain. Clinical signs are usually focal or multifocal. MRI scans show multifocal, heterogeneously enhancing lesions. As noted in the section Opportunistic Infections, the major differential diagnosis is with T. gondii, and these clinical entities may be distinguished by a combination of MRI, SPECT, serologies, and PCR in the CSF. Again, some authors recommend empirical treatment for
T. gondii and if there is no improvement, to use SPECT imaging and/or whole body imaging to rule out systemic lymphoma or neoplasm, and ultimately brain biopsy to determine the diagnosis. Quantitative CSF PCR for Epstein–Barr virus DNA can be helpful in improving the specificity of the presence of PCNSL. If possible, it is best to avoid the use of corticosteroids during the time of diagnostic uncertainty because these agents will decrease swelling due to infection and decrease the size of lymphomas, potentially enhancing the clinical response, and confusing the diagnostic issues. Survival of untreated patients with PCNSL is limited to a few weeks, whereas treatment with radiation therapy and corticosteroids will lengthen survival to 3 or 4 months. Chemotherapy has not been associated with improvement in survival.
Headache Headache in HIV-1 patients is a common symptom. Headache occurs in more than 50% of HIV-1 patients, which reflects the fact that headaches, such as the common tension-type and migraine, are prevalent throughout society and that HIV-1 patients take many medicines that might induce headache. For example, one study showed that headaches in HIV-1 patients were associated with anxiety, depression, drug use, and nonHIV-1 neurological disease, and that headache at baseline did not predict onset of new HIV-1-associated systemic or neurological disease. However, new-onset headache in this population should raise concern for an intracranial infection or neoplasm. Headache may occur at any time throughout the infection, including during primary HIV infection. Many HIV-1 patients have a low-level, chronic meningitis or meningoencephalitis that presumably is a direct result of HIV-1 and results in a modest lymphocytic pleocytosis and elevation of protein in the CSF. There does not appear to be a significant correlation, however, between headache and abnormality of typical CSF parameters. This may complicate initial evaluation of a patient with headache and HIV-1 infection, especially when the CD4 þ T lymphocyte count is below 200 per mm3. HIV-1 viral load in the CSF, however, is significantly higher in patients with neurological symptoms, such as headache and signs of meningitis. Thus, a significant question for the practitioner confronted with an HIV-1-infected patient and headache is when to do laboratory testing, including an imaging study and/or a lumbar puncture. Several studies have addressed the question of when to do an imaging study, typically a computed tomography (CT) scan. Utilization of three clinical findings as screening tools, namely, change in quality of headache, seizure, or depressed or altered orientation would have identified 95% of the new intracranial lesions and resulted in 53% less head CTs ordered in the emergency department in one study of 110 HIV patients. Addition of the clinical symptom of a headache prolonged for 3 or more days as a screening tool would have identified all new intracranial lesions, with a 37% reduction in CTs ordered. In a different study, in patients with headache but without altered mental status, meningeal signs, focal neurological abnormalities, or signs of subarachnoid hemorrhage, 76% of CT scans were negative or had atrophy only. The other 24%
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showed mass lesions or white matter lesions. All these positive cases occurred in patients with CD4 þ T-lymphocyte counts less than 200 per mm3. Thus, a significant number of head CT scans in HIV-1 patients and headache can be avoided by utilizing the previously mentioned clinical and laboratory studies as guidelines. Lumbar puncture should be reserved for patients with new or worsening headache and/or signs of meningeal irritation when a diagnosis has not been determined and an imaging study shows no sign of a lesion with mass effect.
Stroke The incidence and prevalence of stroke, both hemorrhagic and nonhemorrhagic, appears to be slightly increased in HIV-1 patients. Nonhemorrhagic stroke in HIV-1 patients is associated with intracranial infection, nonbacterial thrombotic endocarditis, cocaine or other drug use, and possibly protein S deficiency. Rarely, a patient will have an idiopathic CNS vasculitis. Hemorrhagic stroke is associated with thrombocytopenia and tumors, such as PCNSL and Kaposi’s sarcoma.
Immune-Mediated Syndromes A number of autoimmune disorders, such as thrombocytopenia and Reiter’s syndrome, are more common in HIV1-infected patients. These commonly occur early in the course of the illness, long before immunosuppression sets in. Immune reconstitution inflammatory syndrome (IRIS) occurs in approximately 10–15% of all HIV patients upon initiation of antiretroviral therapy. IRIS can lead to an inflammatory response to an underlying OI. Only approximately 1% of HIV patients develop CNS IRIS after initiation of antiviral therapy (particularly in those with a low CD4 þ count before initiation). The acuity of response is caused by a rapid influx of activated CD4 þ T cells into the brain. Cryptococcal infection or JC virus infection (PML) are the most frequently associated underlying OIs. CNS IRIS may also be unrelated to an underlying infection, often appearing as an encephalopathic syndrome. IRIS may take on several forms, such as a monophasic event similar to acute disseminated encephalomyelitis (ADEM), a relapsing–remitting episodic CNS disease similar to multiple sclerosis (MS), or a fulminant, fatal encephalopathy presentation. Corticosteroids are often used to decrease the inflammatory response and are indicated in the case of impending herniation. Steroids may be useful in Cryptococcus-based IRIS and also in noninfectious encephalitis.
Seizures Seizures are common in HIV-infected patients. The incidence of new seizures has been noted to be approximately 3% per year with a prevalence of more than 11%. Although seizures occur most often during the later stages of the illness, they may be the presenting sign of HIV infection. All types of seizures are seen, with multiple causes identified. Simple partial and complex partial seizures are less common and are often associated with intracranial infections and neoplasms, including toxoplasmosis, cryptococcal meningitis, PML, and PCNSL. The majority of seizures, however, are generalized tonic–clonic, and these
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tend to be associated with metabolic derangements and drug toxicities. Notably, in one quarter to one-half of all seizures, a cause is not identified. This suggests that HIV infection is a prominent cause of seizures. Imaging studies should be done in all HIV patients with new-onset seizures, including those with a generalized seizure and a nonfocal neurological examination, because of the relatively high likelihood of identifying an intracranial infection or neoplasm requiring treatment. Treatment of new-onset seizures should be directed at identifiable causes. An important issue in the treatment of seizures is the interaction of many of the anticonvulsants with the antiretroviral medications in use for treatment of the HIV infection. Many of the commonly used anticonvulsants induce the cytochrome P450 3A4 enzymes in the liver and thus enhance metabolism of many of the anti-HIV drugs. In addition, a number of anticonvulsants are highly protein bound and typically displace other protein-bound drugs from albumin. In the case of antiretroviral medicines, this may result in supratherapeutic antiretroviral drug levels and intolerable side effects. Attempting to predict the actual effects of these interactions is quite difficult. Finally, valproic acid may enhance HIV replication and thus should be used with caution in HIV patients until more information is available. In practice, from the standpoint of drug interactions, levetiracetam, gabapentin, and topiramate may be the best choices of anticonvulsants in HIV patients. The American Academy of Neurology published guidelines in 2012 on the use of older antiepileptic drugs and how to tailor treatment as many developing countries may not have new antiepileptic drugs available.
Peripheral Nervous System A number of disorders affecting the peripheral nerve and muscles have been described in HIV-1 patients. As a group, the peripheral neuropathies are the most common type of neurological complication seen in HIV infection. One convenient manner of classification of neuropathy relates to the timing of the neuropathy in relation to onset of HIV infection. In the early stages of infection, before onset of an immunodeficient state, immune-mediated neuropathies, such as acute inflammatory demyelinating polyneuropathy (AIDP) or chronic inflammatory demyelinating polyneuropathy (CIDP), are most common. In the middle and late stages, when immunodeficiency becomes more apparent, a distal sensory polyneuropathy (DSP) and autonomic neuropathy, probably secondary to HIV infection, predominate. In the very late stages associated with very low CD4 þ T lymphocyte counts, the peripheral nerves are most likely to be affected by OIs, nutritional deficiencies, and malignancies. Finally, patients are also at risk throughout the course of HIV infection to toxic damage to their peripheral nerves due to use of antiretroviral and other therapies. Similarly, myopathy secondary to either HIV or antiretroviral therapy has been well described.
Neuropathy Immune-mediated neuropathy As with HIV-1-related neurological illness in the CNS, a small number of HIV-1-infected patients develop neuropathies in
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the early phase of the illness that appear to be autoimmune in nature. Most common are AIDP and CIDP, which act similarly in immunocompromised and immunocompetent patients. Smaller numbers of patients develop cranial mononeuropathies, brachial plexopathies, and vasculitic neuropathies that also appear to be autoimmune in nature. The pathogenesis of these autoimmune neuropathies in HIV-1 patients is unclear, but the treatment is identical to nonHIV-infected patients. AIDP may be the initial presenting sign of HIV-1 infection and can occur at the time of seroconversion or after other viral infections. It is an acute, monophasic disorder that evolves over 7–21 days and is manifested by progressive, asymmetrical, motor more than sensory loss of all four extremities. It may ascend or be more patchy, and ultimately it may be quite confluent and involve muscles of respiration. Electrical studies initially show only delayed F waves but eventually demonstrate delayed distal latencies, slow conduction velocities, and conduction blocks typical of demyelination. CSF analysis is slightly different from that of patients without HIV-1 in that ‘albuminocytological dissociation’ is not present. HIV-1 patients have both an elevation of CSF protein and a modest lymphocytic pleocytosis (10–50 cells per mm3), whereas patients without HIV-1 usually do not have pleocytosis. Pathology is notable for perivenular lymphocytic infiltrates and segmental demyelination associated with macrophages. Treatment consists of either intravenous immunoglobulin (IVIg) or plasma exchange, and the response appears to be similar to that in non-HIV-1 patients. This usually results in significant improvement in symptoms and signs of the disease. CIDP is very similar to AIDP with regard to signs, symptoms, and pathology and may be more common in the setting of HIV, but the overall epidemiology is not known. In distinction, it evolves over weeks to months, is not monophasic, usually does not follow a viral illness (other than HIV-1), and has a less favorable prognosis. CIDP is also treated with corticosteroids, in addition to IVIg and plasma exchange. Mononeuritis multiplex is relatively uncommon. In this disorder, there are multiple cranial nerve and peripheral nerve palsies in a patient with a high CD4 þ cell count. The disorder is self-limited and often resolves spontaneously in this circumstance.
Distal sensory polyneuropathy Approximately one-third of HIV patients eventually develop a distal, primarily sensory, peripheral neuropathy. It is not possible to easily distinguish DSP from antiretroviral toxic neuropathy – only clinical circumstances related to timing can provide insight. DSP is typically seen in middle-to-late stages of infection, often with CD4 þ T-lymphocyte counts below 200 cells per mm3. The most debilitating symptom is pain, which begins in the soles and dorsum of the feet and may move further up both legs in a relatively symmetric fashion. There also is loss of sensory function in a graded fashion. Reflexes are diminished. Nerve conduction studies may reveal diminished amplitudes of sensory nerve action potentials with relatively preserved velocities, as seen in disorders affecting primarily the axon and relatively sparing the myelin sheath. The etiology of DSP is unknown but presumed secondary to HIV infection. Whether this is via direct or indirect
mechanisms is not known. Some studies have found HIV infection in dorsal root ganglion cells, whereas others have not. Macrophage activation and an underlying inflammatory response in the dorsal root ganglion may lead to hyperexcitability. Many treatments for DSP have been tried with positive results shown for topical capsaicin/lidocaine, amitriptyline, and lamotrigine. Narcotic pain medicines may also be necessary to alleviate the pain.
Antiretroviral toxic neuropathy The dideoxynucleoside analog drugs didanosine (ddI), zalcitabine (ddC), and stavudine (d4T) are the most peripheral neurotoxic drugs leading to painful (or painless) sensory neuropathies. The neuropathy often occurs within 3 months after beginning the drug and may affect the hands more often than in DSP related to HIV. The neuropathy is dose related and reversible, and occurs in 23% of patients treated with these medicines for 10 or more months. This neuropathy may be dose limiting, and symptoms are very similar to those of DSP. A previous history of DSP or other neuropathy is associated with greater susceptibility to nucleoside analog-related neuropathy. The pathogenesis of this neuropathy is believed to be interference with mitochondrial DNA synthesis. HIV-1 patients are also exposed to a variety of cancer chemotherapeutic agents that can cause toxic neuropathies, including vincristine, isoniazid, and thalidomide. Treatment of all toxic neuropathies is withdrawal or dose reduction. Symptom improvement may take up to 3 months after withdrawal.
Opportunistic infections Unlike the CNS, OIs of the PNS are relatively uncommon in AIDS. Neurosyphilis and tuberculosis may cause polyradiculopathy due to arachnoiditis. VZV infection of the peripheral nerves producing the characteristic shingles is a well-known complication of AIDS. As in other immunocompromised states, it is more likely to result in multidermatomal spread and invasion of the spinal cord producing myelitis.
Cytomegalovirus polyradiculopathy A rare but potentially devastating complication of AIDS is progressive polyradiculopathy of the lumbosacral roots due to CMV infection. There is subacute-to-acute development of a painful, asymmetric cauda equina syndrome manifested by back pain radiating into one or both legs and urinary incontinence. This is followed by the development of saddle anesthesia and progressive leg weakness. If untreated, this condition progresses to flaccid paraplegia with urinary and bowel incontinence, and there may also be invasion of the spinal cord with myelopathy, respiratory insufficiency, and death within weeks. Electrodiagnostic studies are consistent with multiple lumbosacral radiculopathies. Sural nerve biopsy is probably not helpful. CSF examination reveals polymorphonuclear pleocytosis with elevated protein and depressed glucose levels. Amplification of viral DNA sequences by PCR is the quickest way to confirm the diagnosis and is highly sensitive and specific. MRI may show thickening of the nerve roots. Early treatment with ganciclovir, even before confirmation of the diagnosis, is recommended, and it may result in significant improvement of symptoms. Ganciclovir
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resistance may occur, and it should be suspected in individuals who progress despite therapy. Foscarnet may be substituted in this circumstance. CMV may also be associated with a mononeuritis multiplex syndrome late in the course of AIDS, and this may progress rapidly to quadriparesis.
Myopathy Human immunodeficiency virus myopathy Myopathy may occur at any time during HIV-1 infection and clinically resemble idiopathic polymyositis. Typical symptoms of proximal muscle weakness, difficulty rising from a chair, weight loss, and myalgia are seen. A mild elevation in creatinine kinase (CK) is found in almost all patients with this myopathy, although modest CK elevation is also noted in HIV-1 patients without clinical signs of myopathy. Electromyography shows typical features of myopathic damage, often with irritative signs. Muscle biopsy usually reveals scattered myofiber degeneration, and there are occasional associated inflammatory infiltrates. Myofiber inclusions and cytoplasmic bodies are also sometimes seen. Treatment with corticosteroids will most often lead to improvement. It is likely that there are multiple etiologies of myopathy in HIV patients. Immune mechanisms similar to non-HIV polymyositis seem likely, and opportunistic organisms may rarely infect muscle directly. ZDV therapy may cause a myopathy probably secondary to mitochondrial dysfunction. This has become less common as other nucleoside reverse transcriptase inhibitors do not cause the same degree of mitochondrial dysfunction as ZDV, and doses of these drugs are typically lower. Patients taking ZDV who develop HIV myopathy are often treated with drug withdrawal, with variable effectiveness. Treatment with corticosteroids, nonsteroidal agents, and IVIg may be helpful. Rare patients with an identifiable OI associated with myopathy should be treated with appropriate antibiotic agents.
See also: Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Dementia. HIV Infection, Neurological Complications of. Human T-Cell Lymphotropic Viruses (HTLVs). Meningitis, Viral. Progressive Multifocal Leukoencephalopathy (PML). Viral Vaccines and Antiviral Therapy
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Further Reading AIDSinfo.org, US Department of Health and Human Services (2012) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arvguidelines/0/ (accessed 22.12.12). d’Arminio Monforte A, Duca PG, Vago L, Grassi MP, and Moroni M (2000) Decreasing incidence of CNS AIDS-defining events associated with antiretroviral therapy. Neurology 54: 1856–1859. Berger JR and Sabet A (2002) Infectious myelopathies. Seminars in Neurology 22: 133–141. Birbeck GL, French JA, Perucca E, et al. (2012) Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: Report of the quality standards subcommittee of the american academy of neurology and the ad hoc task force of the commission on therapeutic strategies of the international league against epilepsy. Neurology 78: 139–145. Kranick SM and Nath A (2012) Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy. Continuum Lifelong Learning in Neurology 18: 1319–1337. Lyons J, Venna N, and Cho TA (2011) Atypical nervous system manifestations of HIV. Seminars in Neurology 31: 254–265. Marra CM (1999) Bacterial and fungal brain infections in AIDS. Seminars in Neurology 19: 177–184. Maschke M, Kastrup O, Esser S, et al. (2000) Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). Journal of Neurology, Neurosurgery, and Psychiatry 69: 376–380. McArthur JC, Brew BJ, and Nath A (2005) Neurological complications of HIV infection. Lancet Neurology 4: 543–555. Quereda C, Corral I, Laguna F, et al. (2000) Diagnostic utility of a multiplex herpesvirus PCR assay performed with cerebrospinal fluid from human immunodeficiency virus-infected patients with neurological disorders. Journal of Clinical Microbiology 38: 3061–3067. Romanelli F, Jennings HR, Nath A, Ryan M, and Berger J (2000) The use of anticonvulsants in HIV-positive individuals. Neurology 54: 1404–1407. Rothman RE, Keyl PM, McArthur JC, et al. (1999) A decision guideline for emergency department utilization of noncontrast head computed tomography in HIV-infected patients. Academic Emergency Medicine 6: 1010–1019. Saag MS, Graybill RJ, Larsen RA, et al. (2000) Practice guidelines for the management of cryptococcal disease. Clinical Infectious Diseases 30: 710–718. Infectious Diseases Society of America. Skiest DJ, Erdman W, Chang WE, et al. (2000) SPECT thallium-201 combined with toxoplasma serology for the presumptive diagnosis of focal central nervous system mass lesions in patients with AIDS. Journal of Infection 40: 274–281. Tan IL, Smith BR, von Geldern G, Mateen FJ, and McArthur JC (2012) HIVassociated opportunistic infections of the CNS. Lancet Neurology 11: 605–617. Wong MC, Suite ND, and Labar DR (1990) Seizures in human immuodeficiency virus infection. Archives of Neurology 47: 640–642. World Health Organization (2011) Global HIV/AIDS Response Progress Report 2011. Available at: http://www.who.int/hiv/pub/progress_report2011/en/ index.html (accessed 22.12.12). Wulff EA and Simpson DM (1999) Neuromuscular complications of the human immunodeficiency virus type 1 infection. Seminars in Neurology 19: 157–164.