Jun. 10, 2022
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Of the almost 38 million people living with HIV worldwide at the end of 2020, it is estimated that at some point in their disease, over 50% will experience neurologic complications directly or indirectly attributable to HIV or its treatment (115; 143). The neurologic manifestations experienced by people living with HIV are diverse, affecting every aspect of the central and peripheral nervous systems, and can be mediated by direct viral invasion, immunologic dysregulation, opportunistic infections, or antiretroviral therapy side effects (Table 1). Neurologists should be familiar with HIV-associated neurologic complications to enable timely, precise diagnosis and treatment.
Central nervous system disorders
Peripheral nervous system disorders
HIV-associated neurocognitive disorders
Meningitis or encephalitis
Spinal cord disorders
Inflammatory demyelinating polyradiculoneuropathy
Opportunistic infections associated with HIV infection
• HIV can affect the entire nervous system, including the brain, spinal cord, peripheral nerve, and muscle.
• The most common neurologic manifestations of HIV are HIV-associated neurocognitive disorders and polyneuropathy; however, diseases traditionally associated with aging (eg, cerebrovascular disease) are becoming increasingly important.
• Neurologists should be aware of specific neurologically relevant toxicities and drug-drug interactions associated with antiretroviral therapy.
• Neurologic manifestations of immune reconstitution inflammatory syndrome must be recognized when people living with HIV are started on antiretroviral therapy.
Different neurologic sequelae can occur at various stages of HIV infection. Primary, acute, or early HIV infection should be considered in individuals presenting with meningitis, acute disseminated encephalomyelitis, acute fulminant leukoencephalopathy, encephalopathy or encephalitis, acute cerebellar ataxia, cerebral granulomatous angiitis, acute myelopathy, transverse myelitis, unilateral or bilateral facial nerve palsy, bilateral brachial neuritis, Guillain-Barre syndrome, cauda equina syndrome, or rhabdomyolysis (81; 150; 50; 92; 18). Therefore, in individuals who present with these conditions and are not known to be infected with HIV, the clinician must consider HIV infection as a potential underlying cause. A screening ELISA for both HIV antibodies and p24 antigen (ie, fourth-generation assay) and plasma HIV RNA viral levels are suggested in these individuals as an ELISA may be negative, but HIV RNA is detected on a viral load assay (Table 2).
Screening ELISA Immunoassay for HIV Antibody and p24 Antigen
Plasma HIV RNA Viral Load by RT-PCR
No HIV infection
Early HIV infection
Early or established HIV infection
In individuals known to be HIV-positive, recent CD4+ T cell count (hereafter “CD4 count”) and HIV RNA viral load will potentially focus the differential diagnosis of neurologic signs and symptoms. Knowledge about the timing of HIV diagnosis, nadir CD4 count, achievement of HIV viral suppression, and timing of immune reconstitution may also be important in determining the potential influence of HIV infection on the clinical presentation. For example, opportunistic infections usually occur when the CD4 count is less than 200 cells/uL (74). Cryptococcal meningitis and cerebral toxoplasmosis typically occur in patients with a CD4 count of fewer than 200 cells/uL; CNS cytomegalovirus typically is seen in individuals with a CD4 count of fewer than 50 cells/uL. Other opportunistic infections, such as progressive multifocal leukoencephalopathy, typically occur with a CD4 count below 200 cells/uL but can occur in patients with a CD4 count above 200 cells/uL. Neurologists should be aware that atypical presentations of HIV-related neurologic diseases may occur, especially in the context of immune restoration after antiretroviral therapy is initiated (88).
From a historical perspective, opportunistic infections associated with severe immunosuppression were a major cause of HIV-related neurologic complications prior to the current antiretroviral therapy era because patients were not treated until they received an AIDS-defining diagnosis. However, since the advent of combined antiretroviral therapy in 1996 and the subsequent recommendation to treat HIV at the time of diagnosis regardless of the level of immunodeficiency, the incidence of neurologic opportunistic infections has declined from 13.1 per 1000 patient-years in 1996 to 1997 to 1 per 1000 in 2006 to 2007 (136). At present, the most common neurologic complications of HIV are HIV-associated neurocognitive disorder and HIV-associated distal sensory polyneuropathy.
Treatment with antiretroviral therapy is recommended in all patients diagnosed with HIV to prevent neurologic complications. With a few exceptions, two nucleoside/nucleotide reverse transcriptase inhibitors and an integrase strand transfer inhibitor are recommended for most newly diagnosed HIV-infected patients (ie, treatment-naïve) (120). It is important to recognize that, with the widespread use of antiretroviral therapy, life expectancies of people living with HIV are similar to uninfected individuals. Antiretroviral therapy-related toxicities, drug-drug interactions, and neurologic complications associated with immune reconstitution need to be considered when caring for this population. For a detailed discussion of the side effects and neurologic complications of antiretroviral therapy, please refer to the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (47).
This article provides a broad overview of the protean neurologic manifestations and complications encountered in people living with HIV organized by localization and neurologic presentation.
Both primary and secondary causes of headache are more common in people living with HIV than in the general population. In one study, almost half of patients with HIV suffered from chronic migraine, and headache severity was strongly correlated with decreased CD4 cell counts (85). The authors attributed the low frequency of secondary headache in this population to the reduced frequency of opportunistic infections since the introduction of antiretroviral therapy. Nonetheless, a new headache in a patient with HIV should prompt further diagnostic evaluation for secondary causes of headache, particularly when the CD4 count is decreased. Secondary causes of headache in patients with HIV include the following: aseptic meningitis, such as with acute seroconversion syndrome; opportunistic infections (eg, toxoplasmosis, cytomegalovirus, cryptococcus, tuberculosis, histoplasma, coccidioides, varicella-zoster, neurosyphilis); stroke; immune reconstitution inflammatory syndrome; and side effects of antiretroviral therapy (125).
Please refer to the article titled Headache associated with HIV and AIDS for further discussion.
Cognitive dysfunction occurs in 50% or more of people living with HIV and can be a direct result of HIV infection or as a sequela of opportunistic infections; confounding conditions are not uncommon (eg, traumatic brain injury, epilepsy, psychiatric disorders, comorbid alcohol or drug abuse). The spectrum of HIV-associated neurocognitive disorder includes asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia, which are distinguished by patient functional status and neuropsychological testing results. Clinically, patients may demonstrate poor concentration, memory impairment, psychomotor slowing, apathy and social withdrawal independent from depression, decreased libido, irritability, or mental inflexibility (115). Since the introduction of combined antiretroviral therapy in 1996, the prevalence of HIV-associated dementia has decreased; in contrast, the prevalence of milder forms of HIV-associated neurocognitive disorder appears to have increased, especially as patients live longer with HIV. Overall, approximately 30% to 50% of HIV-infected patients have some degree of cognitive impairment directly attributable to HIV (08). Certain antiretroviral therapy, most notably efavirenz, may also contribute to neurocognitive dysfunction in people living with HIV (35). There is no disease-specific treatment for HIV-associated neurocognitive disorder. Management involves optimization of antiretroviral therapy and identification and treatment of reversible comorbid causes of cognitive impairment.
For further discussion, please refer to the article on HIV-associated neurocognitive disorders.
HIV infection is associated with acute, subacute, and chronic meningitis, and the clinical course can help determine the most likely etiology other than HIV itself. Therefore, the first step in evaluating a patient with potential meningitis is to establish a time course of symptoms (139). Meningitis due to HIV itself most often displays a subacute course over 1 to 2 weeks (134). In a study of community acquired-meningitis in people living with HIV, common symptoms were headache, fever, neck stiffness, and photophobia (147). When HIV status is not known, other important diagnostic clues can be identified with a thorough social history that includes travel and potential exposures, past medical history (including immune status and immunizations), and detailed medication history, especially because some medications are also associated with aseptic meningitis (see the article on Drug-induced aseptic meningitis). Physical examination can also provide clues for a specific diagnosis and prognosis, with focal neurologic signs and encephalopathy portending serious consequences that necessitate aggressive diagnostic and treatment approaches.
Meningitis is the most common neurologic manifestation during acute and early HIV infection and can occur in up to 10% of patients during seroconversion. This often occurs as part of an acute mononucleosis-like syndrome that develops 2 to 4 weeks after HIV exposure and lasts 1 to 2 weeks. Other causes of acute or subacute meningitis should be investigated (see the article Diagnosis of CNS infections). A full description of systemic (eg, serology) and CSF testing is beyond the scope of this article (139). Importantly, HIV antibodies may be negative at this early stage, thus, requiring serum HIV viral load testing for diagnosis (02). Other studies, such as CNS imaging, may be indicated depending on the exact circumstances of the clinical presentation and may provide additional important clues about specific diagnosis and prognosis.
Acute or subacute HIV meningitis is usually self-limiting (84; 30); nevertheless, HIV infection requires the initiation of antiretroviral therapy. People living with HIV can also develop chronic, prolonged headache in the setting of CSF pleocytosis (ie, chronic meningitis). In addition to antiretroviral therapy, supportive management of symptoms is important (see the article on Viral meningitis).
The term HIV encephalitis typically refers to the pathological changes (ie, perivascular multinucleated giant cells, microglial nodules, HIV-infected mononuclear phagocytes, astrogliosis, etc.) seen in the AIDS-defining illness of HIV encephalopathy (19), more recently referred to as HIV-associated dementia, the most severe form of HIV-associated neurocognitive disorder (06). For the purposes of this article, HIV encephalitis refers to the type of acute encephalitis that characteristically can be seen in association with numerous infectious agents (146). Acute HIV encephalitis can rarely occur as an initial presentation of HIV infection (110; 89). Symptoms usually include fever, headache, and confusion (aka, encephalopathy). Otherwise, the neurologic examination is usually nonfocal, and brain imaging is unremarkable. Plasma HIV antibody test may be weakly positive, and, again, HIV viral load (mRNA) is important. CSF may show increased cell count and protein or may be only remarkable for the presence of HIV mRNA (ie, CSF viral load). Immediate institution of antiretroviral therapy can lead to clinical improvement and resolution of symptoms, although this may take weeks (110). Acute HIV encephalitis is otherwise uncommon in patients who are virally suppressed.
In treated individuals, the neurologist should be familiar with other causes of encephalitis, such as CNS immune reconstitution inflammatory syndrome, CD8+ T cell encephalitis (hereafter “CD8 encephalitis”), and encephalitis associated with symptomatic CSF escape as well as the rare entity of fulminant encephalopathy with basal ganglia hyperintensities (109). CNS immune reconstitution inflammatory syndrome is discussed later in this article. CD8 encephalitis is usually a rapidly progressive encephalopathy in people living with HIV who are otherwise stable on antiretroviral therapy but with a minor infection or have had a brief antiretroviral therapy interruption (157). Although CD8 encephalitis can be confused with immune reconstitution inflammatory syndrome, CD8 encephalitis does not usually occur after first starting antiretroviral therapy as is typical for immune reconstitution inflammatory syndrome (discussed below).
Symptoms of CD8 encephalitis can include headache, confusion, and other symptoms reflective of specific brain involvement, such as seizures. Plasma HIV load can be undetectable with normal CD4 T cell count, although the condition is believed to be due to CNS viral escape. CSF HIV load is typically high, and CD8+ T cells predominate on flow cytometry. Brain imaging may demonstrate multifocal hyperintensities on T2 or FLAIR with associated edema (contrast-enhancing perivascular lesions) in white and grey matter areas, and there may be raised intracranial pressure. Because the differential diagnosis includes opportunistic infections and neoplasm, brain biopsy may be necessary for definitive tissue diagnosis. Pathology reveals primarily CD8+ lymphocytic, perivascular infiltrates, but there is also substantial reactive gliosis. High-dose steroids may be helpful. Converting antiretroviral therapy to a regimen with higher CNS penetration effectiveness index can also result in clinical improvement (21; 113; 13).
HIV CSF escape. CSF escape is characterized by elevated CSF HIV RNA levels with plasma HIV RNA viral levels below the limits of detection or low but measurable plasma HIV viral loads with CSF HIV RNA levels more than 1 log higher than plasma viral levels in people living with HIV on antiretroviral therapy for at least 6 months (13). CSF escape can be asymptomatic (ie, discovered in the context of research studies); symptomatic (ie, associated with neurologic signs and symptoms due to HIV replication in the CSF); or secondary (ie, associated with another CNS infection like syphilis or varicella-zoster meningitis) (96). With early initiation of antiretroviral therapy, CSF escape is rare: out of 204 people living with HIV, CSF escape was detected in only one patient (73).
Symptomatic CSF escape is uncommon and is usually acute or subacute, although chronic cases (greater than 6 months) were found in 36% of patients in a case series (24). Patients may present with variable neurologic symptoms, including myelitis, meningitis, motor or sensory impairment, imbalance or ataxia, dysarthria, headache, or cognitive dysfunction (which occurs in as many as 50% of patients with chronic CSF escape or very high CSF HIV load) (96; 24). Imaging may demonstrate diffuse confluent, patchy, or focal white matter changes that can involve the cerebellum and may have associated abnormal diffuse pial contrast enhancement (21; 113; 24). CSF studies typically show a lymphocytic pleocytosis with up to 270 cells/uL and an elevated protein up to 400 mg/dL (24). These patients usually have had a CD4 count nadir below 200 at some point, possibly favoring the establishment of a significant CNS HIV reservoir.
Persistent low-level viremia (eg, “plasma blips”) is associated with an increased chance of CSF escape. CSF escape can also be observed in conjunction with suboptimal antiretroviral therapy (eg, inadequate antiretroviral therapy adherence or poor CNS antiretroviral therapy penetration) or viral resistance in the CSF, which can occur independently of viral resistance in the plasma. In the absence of symptoms in CSF escape, no change in antiretroviral therapy may be needed. In symptomatic CNS escape, antiretroviral therapy optimization based on genotype resistance testing of the CSF and the CPE index of each antiretroviral therapy is suggested (21; 113; 13; 96). Although there are no systematic controlled trials to prove efficacy, a CPE index of at least 8 is suggested (97). Antiretroviral therapy optimization usually results in clinical improvement and resolution of MRI and CSF abnormalities, although MRI abnormalities may persist (21; 113; 13). Corticosteroids have also been anecdotally used successfully in association with antiretroviral therapy optimization, particularly in people living with HIV with CD8 encephalitis. Finally, recurrent CSF escape has been reported (95). This was felt to be due to low CPE score of antiretroviral therapy. Intensification of antiretroviral therapy with higher CPE index resulted in sustained improvement of symptoms without recurrence.
People living with HIV are at an increased risk for both ischemic and hemorrhagic stroke compared to the general population due to the direct sequelae of HIV infection, HIV-associated chronic inflammation, higher prevalence of vascular risk factors, opportunistic infections, and side effects of certain antiretroviral therapy.
HIV infection is a risk factor for stroke independent of traditional vascular risk factors (107; 34; 75). Chow and colleagues estimated the unadjusted incidence of ischemic stroke in people living with HIV at 5.27 compared to 3.75 per 1000 person-years in HIV-seronegative controls (34). Approximately 75% of strokes in people living with HIV are ischemic. Large artery atherosclerosis accounts for 13% to 42%, small vessel atherosclerosis 20% to 35%, cardioembolism 3% to 20%, and undetermined etiology 10% to 32% of ischemic strokes in people living with HIV (111; 38; 148; 33; 40). HIV vasculopathy, a form of secondary dolichoectasia, accounts for approximately one-fifth of ischemic stroke in people living with HIV by causing mechanical traction of penetrating arteries or thrombosis due to stagnant flow (71).
Adjusting for known vascular risk factors, uncontrolled viremia and worsening immunodeficiency are associated with an increased risk of ischemic stroke (93; 127; 75). In a large study of 76,835 veterans, HIV RNA levels of greater than 500 copies/mL (HR = 1.36, 95% CI 1.15-1.63) or CD4 count less than 200 cells/mm3 (HR = 1.66, 95% CI 1.30-2.12) increased the stroke risk compared to uninfected veterans (127). Another large cohort study of 24,768 HIV-positive and 257,600 HIV-negative individuals from Kaiser Northern and Southern California demonstrated similar findings. In addition, decreasing levels of CD8 count and increasing HIV-RNA copies were also associated with increased stroke risk (93). In an autopsy study of people living with HIV who suffered ischemic stroke, lower nadir CD4 count and higher CD4 count at the time of death were associated with increased intracranial atherosclerosis compared to matched controls (71). In the same study, HIV vasculopathy was found to be significantly associated with lower CD4 count (71). Taken together, these findings underscore the importance of early antiretroviral therapy treatment with the goal of viremic suppression and immune reconstitution.
HIV infection may also increase the risk of hypertension, thereby further increasing the risk of stroke; however, this effect was only seen in North America and Europe--in Africa and Asia, people living with HIV were at a lower risk of hypertension (42).
Although traditional risk factors typically influence stroke risk in older patients, younger patients may have other contributing factors, such as infection or substance abuse (eg, cocaine). In the setting of HIV, ischemic stroke may result from an underlying opportunistic infection, such as tuberculous meningitis, cryptococcal meningitis, varicella vasculopathy, or tertiary (eg, meningovascular) syphilis (112).
Antiretroviral therapy may also lead to an increase in stroke. The nucleoside reverse transcriptase inhibitor abacavir increases the risk of stroke by an uncertain mechanism (122; 31; 153; 131; 71; 94). Protease inhibitors as a class can increase traditional cardiovascular risk factors by contributing to insulin resistance, diabetes, and hyperlipidemia (154). Treatment with antiretroviral therapy has likely also increased the prevalence of stroke in people living with HIV by extending the overall population life expectancy allowing patients to accrue vascular risk factors.
HIV infection is also a risk factor for intracerebral hemorrhage, with an incidence rate of 2.29 in people living with HIV compared to 1.23 per 1000 person-years in uninfected individuals (32). High baseline viral load is also associated with a threefold increased risk of hemorrhagic stroke (75). Among people living with HIV in the United States admitted to the hospital for any cause, toxoplasmosis, meningitis, and cytomegalovirus encephalitis were all associated with higher odds of hemorrhagic stroke (112).
People living with HIV have a significantly higher risk of seizures than the general population, which is generally attributable to the direct effects of HIV infection or to opportunistic infections. A 2019 systematic review and meta-analysis, including nine studies from the United States, Europe, Asia, and Africa, found both the prevalence and incidence of seizures to be approximately 6% in people living with HIV, of whom 65% had AIDS at the time of first seizure. Seizure recurrence was noted in 63% of people living with HIV. Increased viral load, opportunistic infections, and metabolic derangements were associated with an increased risk of seizures. The most common seizure phenotype was generalized-onset (58%, range: 13% to 94%), followed by focal to bilateral tonic-clonic (23%), focal impaired awareness (16%), and focal aware (10%) (132). Supratherapeutic levels of the antiretroviral therapy efavirenz have been reported to cause seizures in individuals with impaired clearance associated with the CYP2B6 genotype variant (128).
The treatment approach for epilepsy in people living with HIV may need to be adjusted due to recognized interactions between antiseizure medication and antiretroviral therapy. Enzyme-inducing antiseizure medications should be avoided in patients treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors to prevent the loss of virologic suppression or development of treatment-resistant mutations in the HIV genotype. Antiseizure medications that are known to affect the serum concentrations of certain antiretroviral therapies include phenytoin, carbamazepine, oxcarbazepine, phenobarbital, and valproic acid. For instance, phenytoin induces the metabolism of lopinavir/ritonavir, potentially necessitating an increase in the dosage of lopinavir/ritonavir of about 50%. On the other hand, valproic acid inhibits the metabolism of zidovudine, potentially necessitating a decrease in the dosage of zidovudine.
Antiseizure medication dosage may also need to be adjusted in people living with HIV either due to HIV-associated hypoalbuminemia causing increased free levels of protein-bound antiseizure medications or by interaction with antiretroviral therapy. For example, ritonavir/atazanavir inhibits the metabolism of lamotrigine, potentially necessitating an increase in lamotrigine dosage by approximately 50% (15).
It is not clear if antiretroviral therapy dose adjustment is required for other combinations of antiretroviral therapies with antiseizure medications. For instance, efavirenz may decrease carbamazepine and valproic acid levels, ritonavir may decrease valproic acid levels, and lopinavir/ritonavir may decrease phenytoin levels (154); however, the clinical significance of these interactions or need for dose adjustment with these or other combinations of antiretroviral therapy and antiseizure medications is unclear (15). Levetiracetam, lacosamide, gabapentin, and pregabalin have been suggested when treatment of seizures is required. In resource-limited settings where these medications are not readily available and are cost-prohibitive, valproic acid is a treatment option with the caveat that it may lead to markedly increased levels of zidovudine as mentioned above (15; 154; 138). A prior iteration of this article stated that midazolam is contraindicated in people living with HIV on antiretroviral therapy because its effects are unpredictable and can be significantly prolonged; however, the ILAE and AAN concluded that coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (15).
It should be noted that HIV infection, antiretroviral therapy, hepatitis C virus coinfection, and opioid use (common in this population) are risk factors for osteopenia and osteoporosis. As such, treatment with antiseizure medications may further increase the risk of osteoporosis and fracture when individuals require long-term antiseizure medication therapy, and treating physicians should be aware that proper surveillance of bone density should be entertained in this clinical population (154; 138).
Visual impairment in people living with HIV may be due to optic neuropathy, retinal disease, diplopia due to cranial nerve palsies, or abnormal pupillary function. Optic neuropathy has been estimated to be present in about 31% of people living with HIV with neurologic symptoms and appears independent of CD4 count (66). Optic neuropathy can occur due to multiple causes: (1) primary infection of the optic nerve with HIV (identified in 80% of optic nerves on pathological evaluation); (2) opportunistic infections, including syphilis, cytomegalovirus, varicella-zoster virus, cryptococcosis, toxoplasmosis, and tuberculosis; (3) ethambutol used as part of the treatment of tuberculosis; (4) anterior ischemic optic neuropathy in the setting of retinal nerve fiber layer infarctions; or (5) prolonged optic disc edema in the setting of increased intracranial pressure due to opportunistic infection or neoplasm, such as primary CNS lymphoma (123; 66). HIV-associated optic neuropathy can be unilateral or bilateral and anterior or retrobulbar (78). Vision loss is usually bilateral and painless in contrast to individuals with idiopathic demyelinating optic neuritis who typically have unilateral vision loss with associated pain in or behind the eye that is worse with eye movements (78). In a retrospective analysis of 117 patients admitted to a tertiary hospital in South Africa between 2002 and 2012 for optic neuritis, approximately 25% of the patients were infected with HIV (104). Syphilitic and optic neuritis or progressive outer retinal necrosis can have a similar presentation and should be considered in the differential diagnosis of HIV-associated optic neuropathy (156; 61; 106). People living with HIV and suspected optic neuropathy should undergo a complete ophthalmological evaluation, including OCT and formal visual field testing to assess the extent of the deficit as well as neuroimaging and laboratory studies of the serum and CSF to evaluate for secondary causes.
Retinal disease can occur as a result of HIV-mediated microvascular disease or opportunistic infection. Both are correlated with high viral load and low CD4 count. The most common secondary retinopathy causes include cytomegalovirus, herpes, and toxoplasmosis, with cryptococcosis, tuberculosis, pneumocystis, and syphilis occurring less frequently (66).
People living with HIV may also experience abnormalities of extraocular movements. Saccadic intrusions to smooth pursuit are most frequently seen in association with HIV-associated dementia but may be observed even in the absence of other signs of HIV (66). Oculomotor and abducens palsies have been reported, most commonly in the setting of opportunistic infections, such as toxoplasmosis, cryptococcosis, and syphilis. Patients report diplopia, headache, and blurred vision. Bilateral abducens palsies raise concern for elevated intracranial pressure and should prompt further evaluation with fundoscopy and neuroimaging.
Pupillary abnormalities, including light near dissociation and anisocoria, are usually secondary and may occur as a late sequela of syphilis (Argyll Robertson pupil) or by infection or malignancy involving the brainstem or sympathetic chain (66).
Before the advent of combined antiretroviral therapy in 1996, movement disorders were detected in as many as 50% of people living with HIV who had AIDS and were referred to a specialized Neuro-AIDS center (99; 22). However, the overall prevalence of movement disorders prior to the combined antiretroviral therapy era was estimated to be about 2% to 3% (44; 141). Most of these movement disorders were seen in patients with AIDS who most commonly had toxoplasmosis encephalitis, another opportunistic infection, primary CNS lymphoma, HIV-associated neurocognitive disorder, or another AIDS-defining illness. These scenarios, of course, can still commonly occur when there are problems with access to antiretroviral therapy, treatment interruption, or the development of antiretroviral therapy resistance that can lead to AIDS. There are a variety of movement disorders in people living with HIV, including hemiballism, hemichorea, a variety of tremor types, parkinsonism, and, perhaps less commonly, generalized or focal dystonia, myoclonus, tics, and paroxysmal dyskinesias. It is beyond the scope of this article to discuss the recognition or diagnosis of these movement disorders and their specific pharmacological treatments (see the articles: Hemiballism, Tremors, Parkinson disease, Drug-induced parkinsonism, Isolated dystonia, Myoclonus, and Paroxysmal dyskinesias).
The parkinsonism seen in patients with AIDS with HIV-associated neurocognitive disorder is often atypical and may show symmetrical signs of bradykinesia and rigidity, postural instability, and gait disorder. Frequently, there is a lack of resting tremor (141). In the absence of opportunistic CNS infections, this is attributed to HIV infection of the brain and also is often associated with dementia. It may or may not respond to dopaminergic treatments. With the advent of combined antiretroviral therapy, HIV-associated dementia and opportunistic infections were markedly decreased. Consequently, parkinsonism due to opportunistic infections or related to HIV itself has become far less prevalent (46). However, due to an aging population of people living with HIV on antiretroviral therapy, there is concern that parkinsonism or incidental Parkinson disease will increase in prevalence. Valcour and colleagues showed that people living with HIV on antiretroviral therapy can exhibit bradykinesia, postural tremor, and hypomimia (145). Age and HIV status can aggravate these motor problems. A more recent study of people living with HIV with parkinsonism who were receiving antiretroviral therapy showed no difference in response to dopaminergic treatment compared to patients with HIV-negative Parkinson disease (102). Mild cognitive deficits are also common in people living with HIV on antiretroviral therapy who also have parkinsonism (46), but parkinsonian signs, such as bradykinesia, tend to be milder than in patients with HIV-negative Parkinson disease, and tremor is less common and less severe when present (135).
Demyelinating disorders as sequelae of HIV infection are extremely rare and limited to small case reports or case series. Nevertheless, they represent important differential diagnoses of new neurologic symptoms or abnormal neuroimaging in people living with HIV.
Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis associated with HIV has been described at all stages of HIV infection in both adult and pediatric patients (83; 69; 130; 108; 142; 105). Patients are typically described as having only a mildly or moderately decreased CD4 count when presenting neurologic symptoms, and symptoms are responsive to standard acute disseminated encephalomyelitis management with high-dose corticosteroids. However, recurrent symptoms of acute disseminated encephalomyelitis (multiphasic disseminated encephalomyelitis) and patients with a fulminant fatal course have also been reported in people living with HIV and a markedly depleted CD4 count (83; 69; 130; 101; 142; 105). In those individuals who had a fulminant fatal course, autopsy showed multiple, well-demarcated foci of perivenular demyelination disseminated throughout the brain and spinal cord in addition to a severe vacuolar myelopathy (83; 69; 130).
Acute hemorrhagic encephalomyelitis or acute disseminated encephalomyelitis with peripheral nervous system involvement variants have not been described in the context of HIV. CSF analysis can demonstrate a wide range of findings both between patients and within the same patient, from normal to marked elevation of white blood cells up to 500 cells/uL and elevated levels of protein above 100 mg/dL (108; 142; 105).
Neuromyelitis optica spectrum disorder. A neuromyelitis optica spectrum disorder-like syndrome with and without aquaporin-4 receptor IgG has been reported with coexisting HIV infection. CSF oligoclonal bands are usually present in these cases, which is atypical for neuromyelitis optica spectrum disorder in the HIV-seronegative population (16; 59; 124; 43; 140). It is unclear if the presence of oligoclonal bands is confounded by HIV infection, as oligoclonal bands and intrathecal IgG synthesis are frequently found in the CSF of asymptomatic HIV-infected individuals without opportunistic infections (124). Syphilitic meningomyelitis should be considered in the differential of HIV-infected individuals with a neuromyelitis optica spectrum disorder-like syndrome (14).
Multiple sclerosis. The relationship between HIV and multiple sclerosis is complex, with large epidemiological studies finding an inverse correlation between HIV and the risk of developing multiple sclerosis, but several case reports and case series describe people living with HIV who develop a neurologic syndrome clinically and radiographically indistinguishable from multiple sclerosis during any stage of HIV infection (11; 36; 144; 65; 23; 29; 133).
In a study using data from one of the world’s largest linked medical data sets comparing over 21,000 patients who were HIV positive to over 5 million controls, people living with HIV developed multiple sclerosis at less than half the rate of individuals without HIV (rate ratio 0.38) (64; 133). This has been postulated to be directly attributable to HIV, the effects of antiretroviral therapy, or underreporting caused by the diagnostic criteria for multiple sclerosis that recommend exclusion of alternative diagnoses, including chronic infections such as HIV (133).
The cases of “multiple sclerosis-like disease” in people living with HIV resembled multiple sclerosis radiologically, histologically, and clinically at presentation; however, these patients often had a more fulminant, rapidly progressing disease course, and certain cases resembled primary progressive or tumefactive multiple sclerosis (36; 23; 133). Biopsies of the white matter lesions include inflammatory demyelination without identification of JC virus or the characteristic changes of progressive multifocal leukoencephalopathy (36; 65).
Impaired sleep is common among people living with HIV, with approximately 58% of people living with HIV worldwide reporting sleep disturbances compared with approximately 10% of the general population (116; 155). The reason for sleep disturbances differs between these populations. Anxiety is the most important factor predicting poor sleep quality in people living with HIV (117; 28). Insomnia and bothersome vivid dreams are frequent causes of sleep disturbances and were reported in 50.3% and 20.5% of people living with HIV, respectively (121). Among patients reporting poor sleep, psychological disturbances, suspected REM behavior disorder, percentage of sleep time in REM, and nocturia were all more common in people living with HIV than in matched controls (28). Good sleep quality among people living with HIV was associated with strong family and social support (117).
Although sleep-disordered breathing is common among people living with HIV, among patients reporting significantly impaired sleep, sleep-disordered breathing is more frequently the cause of sleep disturbances in patients without HIV than people living with HIV when matched by age, sex, and BMI (27; 28). Snoring and nonrestorative sleep were also more prevalent among patients without HIV reporting poor sleep compared to those living with HIV and reporting poor sleep (28). There was no difference in periodic limb movements between these populations (28).
The relationship between the severity of HIV infection and sleep is complicated. Low CD4 count was associated with longer nightly sleep time but was not associated with severity of insomnia nor prevalence of sleep disturbance (155; 57). Decreased adherence to antiretroviral therapy and poor sleep quality are correlated, though the directionality of this association is unclear (121). Poor sleep quality may also due to the side effects of antiretroviral therapy. Treatment with efavirenz was the second most important factor after anxiety in predicting poor sleep among people living with HIV and has been associated with poor quality of sleep, vivid dreams, and altered sleep architecture, with reduced time in stage 2 sleep and increased time in REM sleep as well as slow-wave sleep (103; 117). Unfortunately, switching from efavirenz-based antiretroviral therapy did not improve objective measures of sleep quality or neurocognitive functioning after 12 weeks (126). Other antiretroviral therapies that can affect sleep include dolutegravir, which can cause insomnia, dizziness, depression, and very rarely suicidal ideation; and rilpivirine, which can cause vivid dreams, nightmares, depression, anxiety, and dissociative symptoms within 2 to 4 weeks of starting treatment (37; 152; 154).
Addressing sleep disorders in this population is critical as poor sleep quality is associated with reduced quality of life in people living with HIV, and the sequelae of sleep disturbances and HIV infection overlap. Both poor sleep quality and HIV infection may significantly impair cognitive function, resulting in HIV-associated neurocognitive disorder (62; 155; 08). Sleep-disordered breathing and HIV both may increase the risk of hypertension (27; 42). Both HIV and sleep disturbances also may impair the immune system (155).
Sleep hygiene training alone or combined with trazodone has been used successfully to reduce sleep disturbances and improve daytime functioning in people living with HIV on methadone maintenance therapy for comorbid opioid dependence (03).
The diagnosis and treatment of sleep disorders are similar to the general population, and this topic is covered in more detail in the article Sleep disorders.
HIV is associated with myelopathy and, rarely, myelitis.
HIV-associated vacuolar myelopathy. HIV-associated vacuolar myelopathy is a late complication of HIV infection in the setting of advanced immunosuppression (ie, AIDS), at one time affecting up to 10% of severely immunosuppressed individuals. This condition has become increasingly uncommon in people living with HIV who are taking antiretroviral therapy, many of whom do not experience severe immunosuppression due to early diagnosis and prompt treatment intervention.
Patients typically present with subacute or chronic corticospinal and posterior column dysfunction, which is most prominent in the legs. Early symptoms may also include urinary urgency and frequency as well as sexual dysfunction. Like a metabolic or nutritional myelopathy, the arms are usually spared because the spinal cord pathology is usually limited to the thoracic spinal cord. However, arm involvement can occur in rare or very advanced cases (80).
Although the exact pathogenic mechanism of vacuolar myelopathy is unknown, some hypothesize impairment of the transmethylation pathway essential to myelin formation and repair (48). Clinically and pathologically, vacuolar myelopathy resembles subacute combined spinal cord degeneration due to B12 deficiency.
MRI is usually normal though it may demonstrate spinal cord atrophy (typically at the level of the thoracic cord) with or without nonspecific intramedullary T2 cord signal and without abnormal enhancement. CSF studies can be normal or demonstrate a mild lymphocytic pleocytosis (fewer than 20 cells/uL), elevated protein, and normal glucose (49). Without prompt antiretroviral therapy initiation and HIV viral load suppression, HIV-associated vacuolar myelopathy may be progressively disabling, resulting in severe paraparesis with loss of sphincter control (70). Prompt therapy may arrest progression with subsequent functional improvement.
Differential diagnosis is broad and may include common entities, such as spondylotic myelopathy, disc disease, and nutritional deficiency of B12 or copper. Several co-infections may be complicated by spinal cord involvement, including syphilis, tuberculosis (ie, Pott disease), or herpesvirus infection (including herpes simplex virus, varicella-zoster virus, and cytomegalovirus). HTLV co-infection may contribute to an anterior cord syndrome with predominate corticospinal dysfunction, sparing the spinothalamic tracts and posterior columns.
HIV-associated myelitis. HIV-associated myelitis is rare. It is preceded by an acute retroviral syndrome, which is then followed by acute to subacute onset weakness and altered sensations in the legs, gait impairment, and difficulty urinating. Thoracic or lower back pain has also been reported. Examination demonstrates leg weakness accompanied by a sensory level hyperreflexia and extensor plantar response (45; 72; 05). Spinal MRI may demonstrate longitudinally extensive cord signal changes, typically in the posterior columns on T2-weighted images without abnormal enhancement (05). A normal spinal cord MRI has also been reported (72). CSF studies typically demonstrate a mild lymphocytic pleocytosis (though levels up to 300 cells/uL), normal or mild elevated protein (less than 100 mg/dL), and normal glucose. IgG index and myelin basic protein can be elevated. Prognosis is favorable, and the disease is typically self-limited (45; 72; 05).
The most common polyneuropathy associated with HIV is related to chronic HIV infection with moderate-to-severe immunodeficiency, known as HIV-associated distal symmetric polyneuropathy. Antiretroviral toxic neuropathy is a drug-related toxic polyneuropathy associated with dideoxynucleoside reverse transcriptase inhibitors. Historically, the dideoxynucleoside reverse transcriptase inhibitors (ie, zalcitabine [ddC], stavudine [d4T], and didanosine [ddI]) known collectively as “d-drugs” were the most neurotoxic. In the current era, medical advancements have resulted in near-discontinuation of the drugs responsible for antiretroviral toxic neuropathy, so antiretroviral toxic neuropathy is rarely encountered unless the patient has a long treatment history and a history of incident neuropathy on exposure to one of these medications. For more information regarding antiretroviral toxic neuropathy, please refer to the article on Nucleoside analogue neuropathies. Less common peripheral neuropathy syndromes include autonomic neuropathy, peripheral neuropathy associated with diffuse infiltrative lymphomatosis syndrome, mononeuritis multiplex or peripheral nervous system vasculitis, and inflammatory demyelinating peripheral neuropathies (including Guillain Barre syndrome as well as chronic inflammatory demyelinating polyneuropathy). For a comprehensive review of HIV-associated peripheral nerve disorders, inclusive of cranial neuropathy, polyradiculopathy, and the amyotrophic lateral sclerosis-like syndrome, readers are referred to the article on Peripheral nerve complications of HIV-1 infection.
Early in the era of antiretroviral therapy, approximately one third of patients with moderate to severe immunodeficiency (CD4 T cell count < 300) had symptomatic polyneuropathy, which represented a combination of HIV-associated distal sensory polyneuropathy and antiretroviral toxic neuropathy. Data suggest symptomatic polyneuropathy impacts 10% of people living with HIV in the current era. Trends in earlier HIV diagnosis and prompt initiation of non-neurotoxic antiretroviral therapy contribute to these trends. Although the pathophysiology is not precisely known, HIV-peripheral neuropathy is likely a consequence of chronic immune activation as opposed to direct viral infection of either peripheral nerve, dorsal root ganglia, or Schwann cells. D-drug neurotoxicity stems from inhibition of the mtDNA gamma polymerase, a key enzyme for mtDNA replication and repair. Antiretroviral toxic neuropathy typically occurs within 1 year of treatment initiation and most commonly within the first few months. Although earlier studies suggested that exposure to protease inhibitors increased the risk of distal sensory polyneuropathy (91; 114), a larger study suggested no link between protease inhibitors and polyneuropathy (53).
HIV-associated distal sensory polyneuropathy typically presents with stocking-distribution sensory symptoms, numbness, and neuropathic pain. Examination reveals minimal distal extensor weakness with decreased or absent ankle reflexes. Peripheral neuropathy may also be symptom-predominant with a normal examination, consistent with “small fiber” pathology. Electrodiagnostic studies typically show generalized length-dependent sensorimotor axonal polyneuropathy but may be normal. Skin biopsy is more sensitive than nerve conduction studies, showing reduced epidermal nerve fiber density. Antiretroviral toxic neuropathy shares similar clinical and electrophysiological features with HIV-peripheral neuropathy; the clinical distinction is based on the timing of symptom onset or worsening related to drug exposure and the patient’s response to dosage reduction or drug withdrawal (09).
Stavudine (d4T) has been associated with acute progressive ascending weakness, similar to Guillain-Barre syndrome, known as HIV-associated neuromuscular weakness syndrome. Neuromuscular symptoms generally present with a systemic illness characterized by nausea, vomiting, abdominal pain, lactic acidosis, and hepatomegaly, which occurs while being treated with or within a few weeks of stopping d4T. Although rare and now exceedingly so with the waning use of d4T, recognition of this HIV-associated neuromuscular weakness syndrome is important so d4T can be stopped and supportive measures started in this potentially life-threatening disorder (79; 92; 154).
When polyneuropathy onset coincides with severe immunodeficiency in an antiretroviral therapy-naïve patient, the high prevalence of HIV-associated distal sensory polyneuropathy makes alternative causes unlikely. Conversely, if polyneuropathy symptoms commence with only mild immunodeficiency (eg, CD4 > 500), HIV-associated distal sensory polyneuropathy is unlikely, and other etiologies should be investigated with testing as recommended by endorsed testing guidelines (54). Worsening neuropathic pain in the setting of stable HIV disease (suppressed viral load, only mildly or moderately immunosuppressed) on non-neurotoxic antiretroviral therapy with suppressed viral load should also prompt thorough evaluation. Commonly used medications that may cause toxic neuropathy include dapsone, metronidazole, trimethoprim/sulfamethoxazole, and isoniazid. Alcohol or intravenous drug (eg, heroin) abuse, malnutrition, vitamin (eg, thiamine, B12) deficiency, renal insufficiency, and disorders of glucose metabolism may all significantly contribute to polyneuropathy risk.
For those with neuropathic pain affecting quality of life or function, treatment options include gabapentinoids, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or topical analgesics, such as capsaicin or lidocaine. Smoked cannabis, cognitive behavioral therapy, and self-hypnosis have also been evaluated in small studies; few clinical trials, however, have proven efficacy in this population (98).
HIV-associated myopathies are rare and have been estimated to effect up to 1% of patients (149). HIV-associated muscle disorders can be classified as: (1) rhabdomyolysis; (2) HIV-associated myopathies; and (3) toxic myopathies. For further discussion of HIV-associated myopathies, the reader is referred to the article on Viral and retroviral myositis.
HIV-associated rhabdomyolysis. HIV-associated rhabdomyolysis (defined by a CK > 1000 IU) has a reported incidence rate of 943 cases per 100,000 person-years, which is several folds higher than rhabdomyolysis associated with statin monotherapy or statin-fibrate combinations (67; 04; 87). Infection or sepsis, compression injury, and drug or medication myotoxicity are common causes, with a multifactorial etiology in up to 33% (25; 87). Ritonavir and cobicistat are potent inhibitors of the cytochrome P450 3A pathways and may increase the risk of rhabdomyolysis when taken with simvastatin, lovastatin, and atorvastatin (26; 58).
HIV-associated myopathy. HIV-associated myopathy often refers to HIV-associated polymyositis, but the spectrum of these myopathies also includes inclusion-body myositis and nemaline rod myopathy. Although all these myopathies are rare, HIV-associated polymyositis is the most common. HIV-associated myopathies can occur at all stages of HIV disease (118; 76). Because HIV-associated polymyositis, inclusion-body myositis, and nemaline rod myopathy are similar clinically and pathologically to the HIV-seronegative population, the reader is directed to the following three articles: Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis; Inclusion-body myositis; and Nemaline myopathy.
It is important to recognize that HIV-associated polymyositis is treatable with immunosuppression, similar to polymyositis without HIV, though data for nonsteroid immunosuppressants are limited. Although HIV associated inclusion-body myopathy has not been shown to respond to treatment intervention (as in the case of sporadic inclusion-body myopathy), case reports have documented improvement of HIV-associated nemaline rod myopathy with prednisone, IVIG, and plasma exchange.
Toxic myopathy. Zidovudine can cause a toxic myopathy presenting with weakness, exercise intolerance, and proximal hip girdle involvement within 6 to 12 months of starting treatment. Creatine kinase levels are normal or mildly elevated. Muscle biopsy is the gold standard for diagnosis and demonstrates ragged red fibers consistent with the recognized mitochondrial toxicity associated with this medication class. Zidovudine-associated toxic myopathy typically resolves within months of stopping the drug (41; 118; 154).
As a class, integrase strand transfer inhibitors are well-tolerated; however, elevations of creatine kinase, rhabdomyolysis, and myopathy or myositis have been reported in patients taking dolutegravir and raltegravir (47).
The incidence of opportunistic neurologic infections in people living with HIV is approximately 1 per 1000 patient-years, with up to 15% of people living with HIV experiencing multiple opportunistic infections (136; 138). For this article, major opportunistic infections, such as toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and cytomegalovirus, will be briefly described. These infections are discussed in other articles, and the interested reader is encouraged to review the more in-depth discussion of each entity. For information regarding tuberculous meningitis, which is not covered in this article, readers are recommended to read the article on Tuberculosis of the CNS. Immune reconstitution inflammatory syndrome has been associated with the initiation of antiretroviral therapy in the context of many of these opportunistic infections and will be discussed herein.
Toxoplasmosis infection constitutes the most common cause of a focal brain lesion with mass effect in patients with AIDS and advanced immunodeficiency (eg, CD8 count below 200 cells/μL). Although primary infection may occur, most patients have reactivation of latent infection due to cellular immunodeficiency. It should be noted that in the general population, the prevalence of toxoplasma-specific antibodies is high, particularly so in tropical areas where seropositivity is noted in over 50% of the population. The incidence of CNS toxoplasmosis has significantly decreased with the early use of antiretroviral therapy and with the practice of prescribing sulfamethoxazole-trimethoprim for primary prophylaxis in the severely immunosuppressed (eg, CD4 < 100 cells/μL and seropositive for toxoplasmosis gondii IgG antibodies).
Cerebral toxoplasmosis typically presents with a spectrum of focal neurologic deficits (referable to the site of the lesion in the central nervous system) though may have a nonspecific presentation of fever, headache, and encephalopathy. New-onset seizure is not uncommon. Contrasted brain MRI typically shows multifocal brain masses with enhancement and vasogenic edema.
The second most common cause of a focal brain mass with mass effect in people living with HIV is primary CNS lymphoma, a high-grade B cell non-Hodgkin lymphoma, and is typically seen with a CD8 count below 50 cells/μL. Although toxoplasmosis tends to present with multifocal lesions that localize to the basal ganglia or grey-white junction, primary CNS lymphoma tends to present with a solitary periventricular lesion. Unfortunately, the number and spatial distribution of lesions do not reliably distinguish these two entities. In general, for the patient with severe immunosuppression and a positive serum toxoplasma IgG, the diagnosis of toxoplasmosis encephalitis is likely. CSF findings in toxoplasmosis encephalitis are relatively nonspecific though T. gondii PCR is specific (albeit insensitive) for diagnosis.
Lumbar puncture serves an important role in distinguishing between toxoplasmosis encephalitis and primary CNS lymphoma, as a positive CSF Epstein-Barr virus PCR would suggest a diagnosis of primary CNS lymphoma. Other entities, including cryptococcoma, syphilitic gumma, tuberculoma, neurocysticercosis, or bacterial abscess may also be considered in the differential diagnosis. Advanced imaging such as MR spectroscopy, thallium single-photon emission computed tomography, or positron emission tomography may also be informative and guide clinical care. A toxoplasmosis encephalitis diagnosis is often made clinically with repeated imaging 10 to 14 days after introduction of toxoplasmosis therapy to evaluate for interval clinical or radiographic improvement. At times, tissue diagnosis is necessary.
Toxoplasmosis is treated with pyrimethamine, sulfadiazine, and folinic acid for 6 weeks. Clindamycin, azithromycin, or atovaquone can be used in sulfa-allergic patients. Acute therapy is followed by maintenance therapy with lower doses of pyrimethamine/sulfadiazine until CD4 is greater than 200 cells/uL to prevent recurrence. As immune reconstitution inflammatory syndrome is a rare phenomenon with this particular intracranial infection, antiretroviral therapy is indicated at the time of toxoplasmosis encephalitis diagnosis and should be delayed for no more than 2 weeks from initiation of toxoplasmosis encephalitis treatment (20).
For further reading, please see the articles on Cerebral toxoplasmosis and Primary CNS lymphoma.
Cryptococcal meningitis is actually a meningoencephalitis stemming from infection by the yeast Cryptococcus neoformans. Cryptococcal disease remains a significant contributor to AIDS-related mortality, and serum CrAg has a prevalence of 6.5% in patients with CD4 less than 100 (60). Cryptococcal meningoencephalitis is classically a late complication of HIV infection, typically with a CD8 count of fewer than 100 cells/μL. Symptoms include headache, malaise, fever, photophobia, or phonophobia as well as nausea or vomiting, which typically evolve over weeks, though at times can present acutely. Patients can also present with encephalopathy, binocular diplopia, or visual disturbance from papilledema in the presence of elevated intracranial pressure.
Diagnosis is based on CSF results with fungal cultures or the presence of cryptococcal antigen as well as positive India ink staining, which reveals the characteristic polysaccharide capsule. A meta-analysis indicates that serum CrAg is sufficient to exclude cryptococcal meningitis, whereas in those who have not been previously treated for disease, cryptococcal Ag in CSF is diagnostic (137). Other causes of chronic meningitis are in the differential, including other fungal infections (such as histoplasmosis or coccidioidomycosis) as well as tuberculous meningitis.
The mainstay of cryptococcal meningitis treatment is induction therapy with liposomal amphotericin B and flucytosine for 2 weeks, followed by fluconazole first at a consolidation dose for 8 weeks, and then a maintenance dose of 200 mg daily is maintained until CD4 is greater than 200. The World Health Organization has published recommendations for treatment in low- and middle-income countries (151). At the time of diagnosis, serial lumbar punctures are utilized to treat elevated opening pressures, noting that elevated intracranial pressure is not adequately treated with medications (eg, mannitol, hypertonic saline, steroids). It is important to recognize that initiation of antiretroviral therapy in patients with cryptococcal meningitis can be complicated by immune reconstitution inflammatory syndrome, leading to paradoxical worsening of neurologic symptoms or rarely death (55; 20). In patients with cryptococcal meningitis, the optimal timing of antiretroviral therapy initiation or re-initiation is debated, but guidelines recommend delaying at least 2 weeks or possibly up to 10 weeks after introduction of therapy for cryptococcal meningitis (55; 20).
For further discussion regarding cryptococcal infection of the CNS, interested readers should refer to the article titled Cryptococcal meningitis.
Progressive multifocal leukoencephalopathy is caused by the JC virus (a polyomavirus), which primarily infects oligodendrocytes in the CNS, though other cell types can be affected (39). Progressive multifocal leukoencephalopathy is typically an opportunistic infection seen in AIDS with a CD8 count of fewer than 200 cells/μL (typically fewer than 100, but a subset of patients may have counts greater than 200), and at the height of the AIDS epidemic affected up to 5% to 8% of people living with HIV. It represents the reactivation of a subclinical or latent infection in the setting of severe immunodeficiency.
Briefly, progressive multifocal leukoencephalopathy is suspected when there is a subacute progression of focal neurologic findings, variably including cognitive, motor, or visual deficits. The diagnosis is usually established through a combination of brain imaging and CSF findings (noninflammatory CSF with positive JC virus PCR) and, on occasion, brain biopsy.
The treatment of progressive multifocal leukoencephalopathy in association with HIV infection is the treatment of underlying impaired cellular immunity with antiretroviral therapy. A number of antiviral agents targeting JC virus have been evaluated, but none have been clearly effective. In the pre-antiretroviral therapy era, progressive multifocal leukoencephalopathy was almost always fatal, with a median survival of only 6 months (and less than 10% of patients surviving more than a year) (10). With antiretroviral therapy, approximately 50% of patients will stabilize. Small studies of checkpoint inhibitors or therapy with JCV-specific T cells suggested the possibility of efficacy, and studies are ongoing (12).
Progressive multifocal leukoencephalopathy is also associated with immune reconstitution inflammatory syndrome. Of the 5% of patients with progressive multifocal leukoencephalopathy, approximately 20% will develop progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome after antiretroviral therapy, typically around 2 months after initiation, though time-course may be longer. Radiographic characteristics include the atypical findings of perivascular enhancement and vasogenic mass effect.
For further reading, please refer to the article titled Progressive multifocal leukoencephalopathy.
Cytomegalovirus infection of the CNS was historically rare (less than 5%) in the pre-antiretroviral therapy era and is even more infrequent in the current treatment era. These syndromes generally represent viral reactivation in the setting of severe immunodeficiency because the majority of patients with HIV have serological evidence of prior cytomegalovirus infection. Patients may have other systemic manifestations of cytomegalovirus reactivation (eg, retinitis, esophagitis, or colitis), though reactivation may be compartmental and isolated to the central nervous system.
In the central nervous system, cytomegalovirus infection generally presents as one of two syndromes: microglial nodular encephalitis or ventriculitis (68). Cytomegalovirus microglial nodular encephalitis is classically a progressive encephalopathy that progresses over weeks. The presentation can be nonspecific, typically without headache or fever, though it may involve focal neurologic symptoms or features of meningitis. A fluctuating altered sensorium is generally observed with variable degrees of cognitive, mood, or personality changes. Cytomegalovirus ventriculitis may show similar clinical features to those of encephalitis but tends to feature symptoms of ataxia and nystagmus as well as cranial neuropathies.
Major diagnostic considerations when evaluating for cytomegalovirus encephalitis include delirium, HIV-associated neurocognitive disorder, and other causes of viral encephalitis. Diagnostic considerations for cytomegalovirus ventriculitis primarily include lymphomatous or varicella-zoster virus-related ventriculitis. CSF abnormalities are variable and may range from normal cell counts to lymphocytic or polymorphonuclear pleocytosis. Total protein is typically elevated, and hypoglycorrhachia is variable. Diagnosis generally relies on CSF cytomegalovirus PCR detection. MRI of the brain is commonly normal with diffuse microglial nodular encephalitis. Ventriculitis may show enhancement or signal abnormalities along the ependymal lining of the lateral ventricles. When high suspicion exists for cytomegalovirus, workup for extra neurologic manifestations should be considered, including dilated eye examination to detect retinitis.
Other cytomegalovirus-related diagnoses in patients with HIV or AIDS include retinitis and polyradiculitis. Cytomegalovirus retinitis is more common than other neurologic infections, typically presenting with complaints of floaters or “flashing lights” in one eye, accounting for up to 25% of AIDS-associated cytomegalovirus disease, and discussion is beyond the scope of this article. Polyradiculitis presents with lower extremity sensory and motor deficits combined with urinary retention, with neurologic examination findings typical for a cauda equina syndrome. CSF shows a polymorphonuclear pleocytosis, which might suggest a bacterial infection though the patient does not have headache. MRI may show cauda equina enhancement, and electrodiagnostic studies may show evidence for lumbosacral polyradiculopathy.
Ganciclovir therapy is the mainstay of treatment, and there are some data to suggest improved outcomes with the combination of ganciclovir and foscarnet (100). Introduction of antiretroviral therapy may prolong survival after cytomegalovirus disease in patients with AIDS.
Interested readers may refer to the article on Acquired human cytomegalovirus for further content on this subject.
Immune reconstitution inflammatory syndrome is a dysregulated CD4+ and CD8+ T cell immune response occurring against an opportunistic pathogen or the host during CD4 count restoration in 15% to 35% of HIV-infected patients, usually within the first 3 to 6 months of starting antiretroviral therapy (82; 17). Risk factors for immune reconstitution inflammatory syndrome include lower CD8 count and a high plasma HIV RNA viral load, although it can occur at any CD4 count (92; 20).
Immune reconstitution inflammatory syndrome is most commonly categorized into paradoxical or unmasked immune reconstitution inflammatory syndrome. Paradoxical immune reconstitution inflammatory syndrome occurs in the presence of a known opportunistic infection that was present before antiretroviral therapy and results in a paradoxical worsening with antiretroviral therapy. Unmasked immune reconstitution inflammatory syndrome occurs when an asymptomatic opportunistic infection is “unmasked” during immune reconstitution (17). Immune reconstitution inflammatory syndrome can also occur without an opportunistic infection (82). Other autoimmune conditions (eg, multiple sclerosis-like illness, Guillain-Barre syndrome, polymyositis, systemic lupus erythematosus, Grave disease) can co-occur with immune reconstitution inflammatory syndrome (82; 92). MRI appearance alone is not diagnostic of immune reconstitution inflammatory syndrome and is disease-specific based on the opportunistic infection present or absent at initial presentation and initial treatment with antiretroviral therapy (82; 92; 17). Defining features of immune reconstitution inflammatory syndrome include: (1) worsening of neurologic status after initiation of antiretroviral therapy; (2) deterioration of new inflammatory changes on neuroimaging; (3) decrease in plasma HIV RNA viral levels of more than 1 log10; (4) symptoms not explained by a newly acquired disease or by the expected course of a previously acquired illness; and (5) histopathology demonstrating T cell infiltration (82). Although mortality in immune reconstitution inflammatory syndrome is rare overall (4.5%), mortality is highest in immune reconstitution inflammatory syndrome affecting the CNS (13% to 75%) (20).
Except in the case of severe, life-threatening immune reconstitution inflammatory syndrome, patients who develop immune reconstitution inflammatory syndrome should continue antiretroviral therapy, and, if identified, the opportunistic infection(s) should be treated. For all patients with immune reconstitution inflammatory syndrome, clinicians should take care to weigh the risks and benefits of corticosteroid treatment, particularly given the high prevalence of comorbid diabetes mellitus, hypertension, and mental health disorders in people living with HIV, which all may be exacerbated by corticosteroid treatment (20). Corticosteroids can be considered in patients who do not have cryptococcal meningitis. Prednisone 1 to 2 mg/kg for 5 to 7 days followed by a 2- to 3-week taper has been suggested for mild immune reconstitution inflammatory syndrome. A loading dose of methylprednisolone 1 gram daily for 3 to 5 days followed by a tapering dose over 2 to 3 weeks can be used for severe edema with impending herniation. Methylprednisolone, prednisone, and dexamethasone can be used interchangeably (17). Prolonged corticosteroid tapers are important because abrupt discontinuation or short tapers of corticosteroids can result in recurrence (82). In cryptococcal meningitis, it has been recommended that corticosteroids should be avoided due to an increased risk of adverse events and disability compared to placebo (20).
The vast majority of cases of HIV infection globally are caused by HIV-1, as opposed to HIV-2, which produces relatively less severe manifestations, such as immunodeficiency and its consequences. HIV-1 targets cell-surface CD4 receptors to infect lymphocytes using the CXCR4 coreceptor and monocyte and macrophage using the CCR5 coreceptor (129). It can also infect CNS cells, such as astrocytes, in a restrictive manner via cell-to-cell contact (90). HIV-1 uses reverse transcriptase to transcribe RNA into DNA, which integrates into the host’s genome as a provirus, which is the primary reason it is difficult to eradicate HIV.
Invasion of the CNS results when HIV-infected monocytes pass through the blood-brain barrier (often described as the “Trojan horse” mechanism) (119). Infection then spreads to other cell types, primarily microglia, with resultant immune activation, inflammation, and secondary neuronal dysfunction due to both HIV itself (eg, Tat) and host response elements (eg, cytokines) that are neurotoxic. A similar relationship exists between HIV-activated macrophages mediating indirect injury to the dorsal root ganglia in the peripheral nervous system, but the mechanisms are incompletely understood (118; 07).
The autoimmune sequelae of HIV infection typically occur early after infection. This is probably related to immune dysregulation from HIV and as a general phenomenon of infections that rarely affect autoimmune diseases. Opportunistic infections (eg, cryptococcal meningitis) and cancer (eg, lymphoma) are the results of immune deficiency; normally the immune system is a powerful deterrent to the development of these conditions.
Both systemic disease severity (ie, plasma HIV RNA viral load and CD4 count) and early CNS invasion play a role in the development of neurologic manifestations in HIV and support the emphasis on early treatment with antiretroviral therapy at the time of diagnosis (86; 77; 120). Data suggesting that macrophage/microglia activation and immune activation persist despite long-term viral suppression on antiretroviral therapy indicate that further studies are required to sort through the ongoing neurologic manifestations seen at the bedside (51; 63).
Pediatric HIV neurology
See Congenital HIV-1 infection.
See Congenital HIV-1 infection.
Approximately 20% to 25% of HIV-infected individuals will require surgery during their illness (52), and HIV-associated neurologic manifestations need to be considered by anesthesiologists. For example, cognitive impairment may have implications for obtaining informed consent. HIV-infected individuals may be sensitive to opioids and benzodiazepines. Interactions between antiretroviral therapy and anesthetic drugs are common. Individuals with neuropathy may experience autonomic instability or make postoperative pain difficulty to treat. Although general anesthesia is safe, the presence of an intracranial mass, cerebral edema, or raised intracranial pressure will influence anesthetic choice (56). Although information is limited, HIV-infection does not appear to increase the postoperative risk for complications or death (56; 01).
Andrew M Tarr MD
Dr. Tarr of Atlanta Veterans Administration and Emory University MS Center has no relevant financial relationships to disclose.See Profile
Taylor B Harrison MD
Dr. Harrison of Emory University School of Medicine and Grady Memorial Hospital has no relevant financial relationships to disclose.See Profile
William R Tyor MD FAAN
Dr. Tyor of Emory University School of Medicine has no relevant financial relationships to disclose.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.See Profile
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