Soon after outbreaks of opportunistic infections (OIs) in Los Angeles among men who have sex with men heralded the HIV/AIDS pandemic in 1981, the nervous system emerged as a major site of clinical involvement [3]. Manifestations included cerebral OIs and neoplasms from severe immunocompromise, peripheral neuropathy, and a dementing illness initially referred to as subacute encephalitis [3–5]. The clinical syndrome, termed AIDS dementia complex (ADC) [4], and its neuropathologic substrate [5] were defined further in 1986. HIV encephalopathy [6] and AIDS-related dementia [7] were other terms for the occasionally static but more characteristically progressive cognitive, motor, and behavioral impairments that characterized the syndrome before cART [4, 6, 7]. Typical early symptoms include apathy, slowed thinking, impaired memory, and gait difficulty; neurological examination might be normal or reveal psychomotor slowing, hyperreflexia (sometimes masked by concomitant distal symmetric polyneuropathy), and pathological reflexes [4, 7]. In untreated patients, these early features often progress over months to mutism, quadriparesis, and incontinence [4]. Occasional patients may present with psychosis or mania [4, 7]. The Memorial Sloan Kettering (MSK) scale for ADC (Table 13.1), a staging system devised for patient care and clinical research in the late 1980s [8], remains in use. Host risk factors for dementia in the pre-cART era included low CD4 count, hemoglobin, or body mass, as well as constitutional symptoms, advancing age, and elevated cerebrospinal fluid (CSF) HIV viral load [9, 10]. Before cART, dementia was common, affecting approximately half of the HIV-infected patients [11].

In 1991, the AIDS Task Force of the American Academy of Neurology (AAN) defined the criteria for HAD and a milder condition, minor cognitive motor disorder (MCMD) [12]. The advent of cART with at least three antiretroviral drugs, in the mid-1990s, dramatically improved the outlook for HIV+ patients with access to treatment. Death rates fell, as did the incidence of HAD along with neurologic and systemic OIs [13, 14]. With improved survival, the prevalence of HAD increased, as did the frequency of less severe degrees of cognitive impairment [9–11, 13]. Progression over months was less common in treated patients, suggesting that cART had beneficial effects on the natural history of HAD, including slowing down the course. Dementia is now seen at higher CD4 counts than in the pre-cART era [13]. Risk factors for cognitive impairment in patients on cART include advancing age, particularly older than 50 years of age, and possibly hepatitis C coinfection [10]. With increasing numbers of older HIV+ patients, due in part to long-term survival on cART, distinguishing HAD and related conditions from age-related neurodegenerative disorders could become a more common clinical problem [15].

In 2007, a working group of the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke revised the AAN research nosology and associated diagnostic criteria, in part reflecting changes in clinical features and epidemiology in the era of cART [16]. This most recent update defined three conditions as comprising the HIV-associated neurocognitive disorders (HANDs): asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-1-associated dementia. The revised criteria emphasize acquired cognitive impairment, assessed by neuropsychological testing when possible, in at least two cognitive domains, typically impaired attention and learning with slowed information processing. The updated HAD criteria usually correspond to MSK stage score of two or greater. Significant functional impairment and the absence of delirium or other evident causes for dementia (including cerebral infection or neoplasm, stroke, other neurologic diseases, or substance abuse) are other key elements. The prevalence of HAND is approximately 50%, with a shift from HAD to milder forms in the era of cART [10, 16].

The differential diagnosis of cognitive impairment in patients with known HIV infection is broad. Substance abuse, psychiatric disorders, toxic-metabolic encephalopathies, neurosyphilis (discussed later in this chapter), and neurodegenerative disorders are considerations throughout the course of HIV disease. At CD4 counts below 200 cells/mm³, cerebral malignancies and OIs are important and life-threatening diagnostic concerns [8–10]. Depression is common in HIV+ patients and can be difficult to distinguish from early HAD. Primary central nervous system (CNS) lymphoma in the setting of HIV classically causes altered mental status with focal cerebral dysfunction or headache, typically evolving over months. The predilection of this B-cell lymphoma for periventricular regions and the corpus callosum [9] means that patients with bifrontal involvement may present primarily with personality change and cognitive impairment with minimal visual or motor dysfunction, at least in the early stages. Progressive multifocal leukoencephalopathy, an infection of oligodendrocytes by JC virus, typically manifests as worsening lateralized visual or motor impairment, evolving over months, consistent with asymmetric hemispheric white matter involvement, or occasionally as progressive brainstem dysfunction, but presentation with dementia has been reported [17]. Cerebral toxoplasmosis is a common cerebral OI in the setting of HIV/AIDS. Most commonly, this protozoal infection presents with headache, fever, focal cerebral dysfunction, impaired alertness, and other features of expanding cerebral mass lesions, although rarer meningoencephalitic forms with unusually bland neuroimaging have resembled HAD [18]. Cryptococcal meningitis, another common cerebral OI in HIV+ patients, is discussed later in this chapter.

Cytomegalovirus (CMV) encephalitis sometimes presents as a rapidly progressive dementia, usually in very advanced AIDS, when CD4 count falls below 50 cells/mm³ [9, 19, 20]. Nearly one-third of the patients with CMV encephalitis and concurrent HIV infection have evidence of brainstem or cerebellar dysfunction [20]. Concomitant myelitis, radiculitis, retinitis, esophagitis, hepatitis, or colitis can also be useful diagnostic clues, since these are other common sites of CMV infection [9, 20]. CSF findings of polymorphonuclear pleocytosis with hypoglycorrhachia, resembling bacterial meningitis, and neuroimaging revealing ventriculitis are also suggestive, although the absence of either or both does not exclude CMV encephalitis. CSF CMV polymerase chain reaction (PCR) is more specific than sensitive for the diagnosis. CMV encephalitis is fatal without treatment but, if caught early, might respond to ganciclovir or foscarnet [9, 20].

It should be emphasized that throughout the HIV/AIDS epidemic, dementia has been reported as the presenting manifestation of previously undiagnosed HIV infection [21, 22]. HIV testing is thus an appropriate part of the evaluation for patients with unexplained cognitive impairment.

HIV entry into the CNS has been demonstrated early in the course of infection, via infected monocytes [9–11, 23]. Occasionally, this is associated with typical aseptic meningitis but more commonly with asymptomatic mild lymphocytic CSF pleocytosis and elevated protein [9–11, 23–25]. Productive infection of neurons has not been demonstrated, suggesting that indirect mechanisms of brain injury, such as chronic inflammation or viral protein neurotoxicity, may underlie the myelin pallor and multinucleated giant cells seen in patients dying with HAD in the pre-cART era [5, 10, 23]. As the epidemiology and natural history of HANDs in the cART era have evolved, so also has the neuropathology, with more prominent inflammation in the brains of treated patients [10].

The diagnostic evaluation for HIV+ patients with cognitive dysfunction should include review of medications and screening for depression and substance use disorders, along with appropriate blood tests for thyroid disease, vitamin B₁₂ deficiency, and neurosyphilis. Neuroimaging, with and without contrast when safe and feasible, to exclude multifocal OIs and malignancies typically reveals cerebral atrophy [9, 10]. MRI is superior to CT (Figure 13.1) in demonstrating symmetric, ill-defined, nonenhancing white matter hyperintensities on T2-weighted images [10], but these are neither necessary nor sufficient for a diagnosis of HAD. CSF protein often is mildly elevated; white cell count depends in part on CD4+ count [24, 25]. Pleocytosis is unusual among patients with CD4 counts below 50 cells/mm³, regardless of treatment status [24]. At higher CD4+ counts, patients not on cART, with or without neurologic symptoms, may demonstrate mildly elevated CSF white count (<30 cells/mm³). Pleocytosis normalizes within months of virologic control of HIV on cART, in concert with CSF HIV viral load falling near or below the limit of detection [11, 24, 25].

Small clinical studies in the pre-cART era demonstrated that zidovudine monotherapy, albeit at doses higher than typically used currently, slowed the progression of dementia [9, 23]. Zidovudine, unlike most other antiretrovirals in use at the time, achieved good CSF levels, generating debate about the degree to which CSF (and, it is assumed, cerebral) penetration is important in treating HAD [9, 10, 23, 26]. In addition to zidovudine, nevirapine and ritonavir-boosted indinavir penetrate well into the CNS, followed by abacavir, emtricitabine, delavirdine, efavirenz, and indinavir; boosted darunavir, fosamprenavir, or lopinavir; and maraviroc and raltegravir [10, 26]. Other antiretroviral drugs do not penetrate the CNS as well [9–11]. Patients who develop HANDs while not on cART should be started on therapy [9–11, 23]; whether patients who develop HANDs while on cART benefit from modifying the regimen toward drugs with good CNS penetration remains uncertain. Controlled trials of adjunctive antioxidant and neuroprotective agents have been disappointing [9, 10].

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is caused by cerebral infection with defective measles virus occurring long after acute measles infection [27–32]. Incidence estimates range from four to nearly 30 SSPE cases per 100 000 measles cases [27]. As a consequence of a preventable childhood infection, SSPE has become quite rare in countries with effective measles vaccination programs, and the diagnosis is easily missed [27, 28]. SSPE is typically a disease of childhood and adolescence, although adult-onset cases have been reported, with symptoms beginning as late as 49 years of age [28, 29].

Acute measles acquired very early in life increases the risk for SSPE, and pregnancy may also be a risk factor [27–29]. Symptoms begin months to decades after acute measles, which might not have been diagnosed, and include cognitive impairment, behavioral and personality changes, visual dysfunction, myoclonus, and seizures, usually developing over months [27, 28]. The myoclonus is typically generalized, without associated loss of consciousness and is common, but not always present [27, 28]. When myoclonus is present, the differential diagnosis includes prion disorders, corticobasal syndrome, dementia with Lewy bodies, hypoxia, thyrotoxic encephalopathy, and progressive myoclonic epilepsies such as mitochondrial cytopathies, Lafora’s disease, neuronal ceroid lipofuscinoses, Unverricht–Lundborg syndrome, and the sialidoses [27]. In the absence of myoclonus, the clinical syndrome suggests a neurodegenerative disorder, making the recognition of SSPE especially challenging [30].

The diagnosis should be considered through middle age in patients with cognitive or behavioral decline, particularly associated with myoclonus. Neuroimaging may be normal in early SSPE. As the disease advances, subcortical and periventricular white matter and basal ganglia abnormalities may be seen, progressing to hemispheric, brainstem, and cerebellar atrophy [27]. EEG may be normal or nonspecifically slow in early disease but typically demonstrates synchronous, stereotyped high-voltage periodic complexes usually associated with myoclonic jerks in midstage SSPE [27]. Routine CSF studies may be entirely normal or show mild lymphocytic pleocytosis and protein elevation, with elevated CSF gamma globulin concentration [27, 28, 30]. Antimeasles antibodies are elevated in CSF and establish the diagnosis, in the appropriate clinical setting and with characteristic EEG abnormalities [27–31]. Brain biopsy might be necessary in rare cases, such as in very early or advanced disease, when EEG may not show periodic complexes [27].

Neuropathologic findings include parenchymal inflammation in hemispheres spreading to brainstem and spinal cord, with demyelination and neuronal and glial viral inclusions [27, 32]. The occipital lobes are often involved in early disease, perhaps accounting for visual symptoms, although retinitis or optic nerve involvement also occurs [27, 32].

Fulminant cases resembling acute viral encephalitis have been reported [29], but the typical course is progression to death over several years [27, 28]. Oral isoprinosine alone or in combination with alpha interferon (intramuscular, intravenous, or intrathecal) or ribavirin (intraventricular or intravenous) might prolong survival, with varying degrees of symptomatic improvement [27]. Myoclonus is managed with benzodiazepines and antiepileptic agents but can be refractory to treatment [27]. Previous concerns that the measles vaccine might cause SSPE have not been realized. Prevention with vaccination remains the best intervention for this devastating infection [27].

Hepatitis C

Seroprevalence rates for antibodies to hepatitis C virus (HCV), indicating exposure to the hepatotropic single-stranded RNA virus, are below 2% in most industrialized nations and higher in Africa (0.8% in Ethiopia to more than 15% in Rwanda and Egypt), Latin America (0.7% in Mexico to 11.2% in Bolivia), and parts of Asia (5.6% in Thailand, 6.2% in Vietnam, 10.7% in Mongolia) [33]. Most infected individuals develop chronic liver disease, which can progress to cirrhosis and hepatocellular carcinoma [33–35]. Extrahepatic disease is common, and neurologic complications include peripheral neuropathy and stroke, in addition to hepatic encephalopathy from portal hypertension [35]. Coinfection with HIV and HCV is common, as both viruses are transmissible by exposure to blood, including injection drug use [33].

Even in the absence of cirrhosis, fatigue and functionally limiting memory impairment are common complaints in early HCV disease [35–37]. Abnormal neuropsychological testing, particularly in attention and executive function, compared to controls has been reported in patients with HCV without cirrhosis in many, but not all, studies [36]. Proton magnetic resonance spectroscopy demonstrated elevated choline to creatine ratio in the basal ganglia of patients with HCV and histologically mild liver disease [37]. Selection of proper testing batteries, control for psychiatric comorbidities, and relevance of abnormal functional imaging are among many methodologic concerns in these studies [35, 36]. In the setting of HIV coinfection, HCV infection was associated with adverse effects on cognitive function in patients with advanced HIV disease [38], but not in the setting of well-controlled HIV infection [39] or hemophilia [40]. Interestingly, HCV is not strictly hepatotropic and can replicate in peripheral blood mononuclear cells [33, 41]. The identification in the brain of macrophages and microglia harboring HCV is reminiscent of the pathogenesis of HAD and related disorders [10, 41]. Treatment for HCV consists of ribavirin with alpha interferon, the latter of which can cause depression or cognitive impairment [36].

Cognitive sequelae of viral encephalitis

Viruses are common causes of acute infectious encephalitis, although extensive diagnostic evaluation often does not reveal the specific pathogen [42]. Herpesviruses, neurotropic double-stranded DNA viruses, are important diagnostic considerations year-round. Herpes simplex virus 1 (HSV-1) accounts for 5–10% of encephalitis cases in the United States [42–44]. Reactivation of latent HSV-1 in trigeminal ganglia most commonly causes labial vesicular lesions known as cold sores and, rarely, spreads proximally to the brain, resulting in HSV-1 encephalitis [44, 45]. In addition to fever, headache, and seizures, common presenting symptoms include behavioral and personality change and aphasia, consistent with involvement of one or both medial temporal lobes or orbitofrontal cortices [44, 45]. High-dose intravenous acyclovir lowered mortality to 28%, compared to 70% in historical controls [46]. Even with treatment, many survivors have persistent neuropsychological impairment including anterograde and retrograde amnesia, anomia, semantic memory deficit, executive dysfunction, mood disorders, and dementia [43–46].

Arbovirus (arthropod-borne virus) infections occur classically as summer outbreaks and are important causes of encephalitis globally. West Nile virus, first isolated from an African patient in 1937, rapidly became endemic in North America after a 1999 outbreak in New York City [47]. The mosquito-borne virus most frequently causes the acute febrile illness known as West Nile fever and, occasionally, West Nile neuroinvasive disease involving the meninges, brain, or anterior horn cells [47, 48]. Impaired function or quality of life was noted 18 months after the acute illness in half or more patients after West Nile infection, even those without neuroinvasive disease [48]. Neuropsychological testing revealed psychomotor slowing [47]. Acute mortality for tick-borne encephalitis, the predominant European arbovirus, is low, but persistently impaired memory is a common long-term complication, with normal cognitive testing in only 10% of survivors and dementia evident in one-third [49].

Data are even more scant for neuropsychological outcomes from other forms of viral encephalitis [45]. Cognitive dysfunction tends to remain stable or improve slowly over time [50].