Keywords

Introduction

The human immunodeficiency virus (HIV) infects both macrophages and CD4+ lymphocytes. Infected macrophages invade the central nervous system (CNS) and may cause direct CNS damage. CD4 lymphocyte depletion causes cellular immune depression, which may condition CNS opportunistic infections. In consequence, neurological manifestations are frequent in HIV-infected patients and tend to occur in advanced stages of HIV infection. Approximately 50 % of acquired immune deficiency syndrome (AIDS) patients will suffer neurological manifestations along the course of the disease [1] even a higher frequency of HIV-associated disorders (more than 75 % of cases) demonstrated in neuropathology studies [2].

After the introduction of HAART in 1996, a drastic decline in the incidence of opportunistic diseases and neurological disorders associated with severe immune depression was noted in developed countries [3, 4]. The prognosis and survival of patients with previously considered fatal diseases, such as progressive multifocal leukoencephalopathy (PML) and primary central nervous system lymphoma (PCNSL), have also substantially improved. Other concerns, however, emerged in the care of HIV-infected patients in the HAART era. The prolonged patient survival results in an increased morbidity due to chronic disorders, with particular relevance for those involving the CNS, including cerebrovascular disease and HIV-associated neurocognitive disorders (HAND). HAART itself is related to new emerging neurological problems that result from the specific neurotoxicity of these drugs and the appearance of neurological immune reconstitution inflammatory syndromes (IRIS). Nowadays, opportunistic CNS lesions present only as the first manifestation of disease, or in patients who do not adhere to treatment or with treatment failure due to drug resistance, or as IRIS.

Classification and Approach to the Patient

The approach to the patient with suspected neurological complications of HIV should consider three different yet complementary ways of classifying these disorders: (a) a pathogenic and etiological classification; (b) a chronologic classification, attending to the different stages of HIV infection regarding immune depression and antiretroviral treatment received; and (c) a neuroanatomical classification of the lesion. From a pathogenic point of view, the neurological disorders presenting in HIV-infected patients may be associated with (1) the infection of the nervous system by the HIV; (2) the disorder of cellular immunity, which facilitates opportunistic infections or tumors and may occasionally favor autoimmune neurological disorders; (3) the immune restoration induced by HAART; and (4) the neurological complications of other systemic diseases associated with the HIV and of the different drugs used in these patients, including the antiretrovirals. The wide spectrum of opportunistic CNS infections reported in AIDS patients may be classified according to the causing microorganism in bacterial (conventional bacteria, mycobacteria, nocardia), fungal, viral, and parasitic infections.

As the specific neurological disorders depend on the immunological status of the patient, they correlate with the stage of systemic HIV infection (Table 15.1). In primary HIV infection, neurological disease may be similar to that of other acute viral infections, presenting as acute encephalitis, aseptic meningitis, or transverse myelitis. In the early stages of HIV infection, including primary infection, autoimmune neurological disorders may occasionally occur. Cases of Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, acute disseminated encephalomyelitis, and multiple sclerosis-like disease have been reported. Opportunistic infections and HIV-associated disorders present almost exclusively in advanced stages of the disease, usually with a CD4+ lymphocyte count under 200/mm3. In these stages, metabolic and toxic disorders are also common because of the frequency of systemic disease and the complexity of treatments received. Patients under HAART may suffer neurological IRISs in addition to the toxic effects of the drugs.

Table 15.1 Pathogenic and chronologic classification of neurological complications of HIV infection
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The neuroanatomical localization of the neurological syndrome presented by the patient will limit the differential diagnosis to the possible etiologies of the syndrome. A further limitation would be facilitated taking into account the stage of HIV infection, other clinical data, and the results of specific complementary studies (Table 15.2). However, the neurological diagnosis in patients with HIV infection is hampered by a number of difficulties. A major problem is that these patients may suffer several simultaneous neurological diseases. Autopsy studies frequently demonstrate more than one concomitant opportunistic disease, together with HIV-associated diseases [2]. In addition, the HIV and some opportunistic infections, such as cytomegalovirus (CMV) or varicella-zoster virus (VZV), may affect simultaneously various levels in the nervous system. Drug toxicity or withdrawal may complicate the picture in patients with illicit drug or alcohol abuse.

Table 15.2 Neuroanatomical and etiological classification of neurological complications of HIV infection
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Encephalic Complications

The encephalic complications of HIV infection may be classified into focal lesions and diffuse encephalopathies (Table 15.2). Among the latter, a key point is whether the patient presents with attention deficit or alteration of the level of consciousness, in which case the patient probably suffers from diffuse infections or toxic–metabolic disorders. Attention and consciousness are preserved in HIV-associated neurocognitive disorders.

Focal lesions include opportunistic infections, primary or metastatic neoplasm, demyelinating lesions, and cerebrovascular diseases. The frequency of opportunistic infections of the CNS and PCNSL has dramatically decreased since the introduction of HAART, and CMV encephalitis is now rarely diagnosed [4, 5].

HIV-Associated Dementia

The HIV invades the SNC soon after primary infection, and inflammatory markers and evidence of neural damage are found in early HIV infection [6, 7]. Patients, however, remain asymptomatic until advanced stages of disease because a significant HIV infection of the CNS occurs only in the setting of severe immune depression [8], and thus the frequency of HIV-associated dementia (HAD) increases with the advance of systemic disease. The mean CD4 cell count in patients with HAD is approximately 100/mm3. In patients with AIDS, the prevalence of dementia is close to 50 % [9], but the characteristic pathological features have been found in 11–90 % of autopsy cases [2, 10]. Risk factors associated with dementia are high plasma HIV RNA level, low CD4 cell count, advanced age, female sex, the use of recreational drugs, and the presence of anemia and constitutional syndrome.

HAD can compromise cognitive, motor, and behavioral disorders. Any of these disorders may be the presenting symptom, and a psychiatric presentation with depression, acute psychosis, or mania is not uncommon. HAD usually begins insidiously, with difficulties in concentration, memory deficits, and psychomotor slowing progressing along weeks or months. The patient shows lack of motivation, apathy, irritability, emotional liability, and abnormal social behavior. These symptoms are frequently attributed to depression. Motor disorders include bradykinesia, incoordination, hypertonia, pyramidalism, and frontal regression signs. In the presence of vacuolar myelopathy, frequently associated with HAD, motor deficits in the legs may be present. HAD has been considered classically as a subcortical dementia. Cortical deficits, such as aphasia, apraxia, and agnosia are rare, but a frontal syndrome is common.

The diagnosis of HAD is clinical. Neuroimaging and CSF studies may support the diagnosis, but are oriented to exclude other neurological disorders. Information from the family or friends of the patient is essential to confirm cognitive or behavioral symptoms. A diagnosis of HAD should be postponed in the case of existing confounding factors, as active drug or alcohol abuse and systemic or neurological opportunistic diseases. Neuropsychological deficits must be confirmed with appropriate tests. To detect minor deficits, tests should explore memory, executive function, and complex attention [11]. The best screening tests are those exploring psychomotor speed (i.e., trail making test). The International HIV Dementia Scale is a rapid test useful for screening and follow-up [12].

Cranial tomography (CT) and magnetic resonance imaging (MRI) may show cerebral atrophy and leukoencephalopathy, which consists in symmetric and confluent areas of hyperintensity in T2 and fluid-attenuated inversion recovery (FLAIR)-weighted MRI sequences (Fig. 15.1). MRI spectroscopy may detect an early reduction in N-acetyl aspartate due neuronal loss, as well as an increase in choline, a marker of gliosis. CSF may show normal findings or nonspecific mild increase in protein concentration or lymphocytes. The presence of markers of immune activation in CSF (increased β2-microglobulin or neopterin) supports the diagnosis. High levels of HIV RNA in CSF correlate with the presence of HIV encephalitis at autopsy [13], but there have been contradictory results regarding its value as a diagnostic test for dementia, especially in patients under HAART. The presence of HIV DNA in monocytes correlates with cognitive impairment, both before and after HAART, and increased levels differentiate patients with and without dementia [14].

Fig. 15.1
figure 1

Leukoencephalopathy of HIV-associated dementia. T2-weighted magnetic resonance imaging

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A more inclusive classification now considered the HIV-associated neurocognitive disorders (HAND) has been recently divided into three categories: (1) HAD; (2) mild neurocognitive impairment (MNI), when cognitive deficits produce mild disability without dementia; and (3) asymptomatic neurocognitive impairment (ANI), when performance in neuropsychological test falls below that of controls, but there are no symptoms or functional impairment noted by the patient or informers [15]. The inclusion of ANI might overestimate the prevalence of HAND, as a percentage of the normal population would enter this category [16].

Survival of HAD patients without treatment is less than 1 year. HAART is the standard therapy for HAD. The neuropsychological performance of HAD patients improves after months under HAART [17]. Maximal improvement occurs between weeks 24 and 36 of therapy, but may continue for more than 1 year [18]. In correlation with clinical improvement, HAART reduces CSF glutamate and other metabolites concentration, which are increased in HAD, lowers CSF HIV viral load, improves leukoencephalopathy in MRI, and reduces metabolic abnormalities of MR spectroscopy. However, many HAD patients improve incompletely or do not improve at all. Controlled trials of coadjutant treatment options for HAD have been disappointing [19].

HIV-Associated Neurocognitive Disorders in the HAART Era

In recent cohorts of patients receiving HAART, HAND was diagnosed in more than 50 % of patients, although fortunately many of them remained asymptomatic [19–23]. Many factors may condition this high prevalence. On the one hand, comorbidities may influence the diagnosis of HAND [21]. Cognitive performance can be influenced by the presence of vascular risk factors (hypertension, dyslipidemia, diabetes, obesity), hepatitis C virus (HCV) coinfection, drug abuse, or patient’s age and educational level [20, 23–25]. On the other hand, the CNS damage caused by the HIV before treatment initiation or before HIV replication is controlled determines the persistence of cognitive deficits. HAND is associated with a lower pretreatment performance [20], a lower CD4 nadir [21, 26], a more advanced CDC stage, and a lower duration of controlled HIV replication [22]. Cerebral atrophy in MRI correlates with data of previous HIV infection, as are nadir CD4 count and duration of the infection [27]. These results highlight the need for early antiviral treatment to prevent HAND, before irreversible neuronal damage is established.

Persistent systemic HIV replication associates with higher frequency of HAND [21, 25, 26], but HAND prevalence is high even in patients with a successful control of HIV replication for years [22]. Markers of inflammation persist in CSF [19] and MRI spectroscopy [29] despite a controlled systemic replication. The presence of intramonocytic HIV DNA in treated patients has been associated with persistent HAND, suggesting a role of infected monocytes in the maintenance of neural injury through immune activation [28]. The possibility of escape replication of HIV within de CNS in patients with controlled systemic replication offers another hypothesis to explain the high prevalence of HAND. Recent reports of patients developing HAD after successful HAART due to CSF viral escape support this concept [30, 31]. In some patients with HAND, a compartmentalization of HIV in the CNS has been demonstrated by genetic differences between plasmatic and CSF viruses, especially in cases with controlled systemic replication and with drugs with low CNS penetration [32]. This may condition a different susceptibility pattern for antiretrovirals and a different macrophage tropism between plasma and CSF viruses. Antiretroviral combinations with a lower global CNS penetration might favor persistent CNS replication and HAND [33]. Indeed, HAART regimes with a higher penetration index give a better control of CNS replication, but contradictory results have been found regarding their effect on neuropsychological performance [18, 21, 29, 34–38]. On the contrary, antiretrovirals with high CNS penetration might have a negative effect on neuropsychological performance [34].

The pattern of cognitive impairment and cerebral atrophy in patients with HIV infection seems to have changed with HAART. In the pre-HAART era, there was a predominant involvement of motor skills, psychomotor speed, and verbal fluency, while in the HAART era, a greater impairment of memory and executive functions have been found [39], which correlates with greater temporal and frontal atrophy and less involvement of basal ganglia in MRI and pathological studies [21, 27]. Persistent inflammation associated with HIV infection might facilitate neurodegenerative disorders in patients with an increasing age [19]. There are some parallels between HAND and Alzheimer disease. In patients with HIV infection, an abnormal metabolism of β-amyloid protein is suggested [40], and APOE e4 allele is associated with HAND and cerebral atrophy [41]. The APOE e4 allele and older age are associated with the presence of amyloid plaques in the brain of HIV-infected patients and the probability of developing HAND [42]. In addition, familial history of dementia predicts HAND [43]. The present criteria for the diagnosis of HAND are not specific for the neural damage caused by the HIV and might not differentiate HAND from other neurodegenerative disorders. CSF analysis can help in the differential diagnosis between HAND and mild Alzheimer disease, because, while both show a decrease in β-amyloid 1-42, tau and phosphorylated tau levels are decreased in the later [40].

In patients with HAART failure, a severe form of diffuse leukoencephalopathy has been reported. Pathological findings are similar to those of HIV encephalitis, with areas of demyelination and axonal damage, and intense perivascular infiltrates of lymphocytes and HIV-infected macrophages [44]. Patients with inadequate control of HIV infection and active cocaine abuse may suffer fulminant HIV encephalitis with predominant basal ganglia involvement in MRI [45].

Focal Brain Lesions

For the evaluation of focal brain lesions, clinical presentation, temporal evolution, and CSF and radiographic features should be considered. Opportunistic infections and tumors are usually present at advanced stages of disease (CD4 under 200/mm3) [3]. The spectrum of diseases that may cause focal lesions is wide. Three diseases constitute the great majority of diseases that contribute to focal lesions: toxoplasma encephalitis (TE), PCNLS, and PML. In patients under HAART PML seems the most frequent cause [3]. The evolution of the diseases is typically in hours or days in TE, days or weeks in PCNSL, and weeks or months in PML. A diagnostic algorithm is proposed in Fig. 15.2. In some patients, the presence of systemic infection might suggest the possible etiology. Ring enhancing lesions on CT or MRI are identical in abscesses caused by different microorganisms and may be difficult to distinguish from tumors. A definite diagnosis will frequently be established only by biopsy. If lumbar puncture is not contraindicated because of mass effect, it is helpful to perform specific CSF studies, such as cultures; polymerase chain reaction (PCR) for toxoplasma, mycobacteria, bacteria, JC virus (JCV), and Epstein–Barr virus (EBV); cytology; or immunophenotyping.

Fig. 15.2
figure 2

Algorithm for the management of HIV-infected patients with focal brain lesions. Cranial tomography (CT) or magnetic resonance imaging (MRI) should be performed in every HIV-infected patient presenting with focal symptoms or signs, seizures, or altered state of consciousness. MRI is more sensitive to detect leukoencephalopathies, encephalitis, or posterior fossa lesions. If CT is normal and symptoms had ictal presentation, an ischemic stroke should be considered and the possible cause specifically investigated. In the presence of a mass lesion, empiric antitoxoplasma therapy is indicated in the case of a positive serology, but also if serology is negative if the patient has not received prophylaxis with cotrimoxazole. Biopsy is indicated if no clinical or radiological improvement is noted after 2 weeks of treatment or the patient has negative serology and received prophylaxis because in this case the probability of toxoplasma encephalitis is negligible. Before brain biopsy, if there is no contraindication for lumbar puncture because of the mass effect, an attempt for specific diagnosis by means of polymerase chain reaction (PCR) and other studies in cerebrospinal fluid (CSF) should be considered. If neuroimaging studies are normal, viral encephalitis must be considered, and CSF PCR for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV) should be performed. In the case of focal lesions suggesting focal leukoencephalopathy, CSF PCR for VZV or JC virus (JCV) may aid the diagnosis of VZV leukoencephalitis or progressive multifocal leukoencephalopathy (PML). If both are negative, brain biopsy is necessary

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TE is the most frequent cause of focal brain lesions in AIDS. It usually results from reactivation of latent infection and, therefore, IgG antibodies against toxoplasma are detected in more than 90 % of cases. Clinical presentation consists in focal neurological deficits or seizures. Lesions most frequently locate at the cortico-subcortical union, but may affect the basal ganglia and, rarely, the brainstem or cerebellum. Multiple lesions are found in more than 50 % of patients. The characteristic lesions on CT are hypodense with perilesional edema and mass effect, with ring or nodular contrast enhancement. However, this pattern is unspecific and may not be present. A target sign highly suggests TE. The high frequency of TE justifies empiric treatment when it is suspected by radiology, even if serology is negative, which allows an ex juvantibus diagnosis. In a patient with negative serology under prophylaxis with cotrimoxazole, the probability of TE is very low, and empiric treatment is not indicated: a prompt brain biopsy should be scheduled [46]. CSF PCR for toxoplasma has high specificity but only 50 % sensitivity. Treatment consists in an induction phase with 2 drugs (pyrimethamine and sulfadiazine, or clindamycin, with folinic acid) for at least 6 weeks. Steroids may be added in the presence of significant mass effect. An indefinite maintenance therapy should be given to avoid relapses. In fact, relapses may occur in 20 % of cases and are related with inadequate maintenance therapy. In patients under HAART with more than 200 CD4/mm3, maintenance therapy can be confidently suspended because the risk of relapse is very low in this setting [47].

PCNSL are diffuse B-cell or immunoblastic lymphomas, associated with the Epstein–Barr virus (EBV) [48]. PCNSL are multicentric in 40 % of patients (up to 72 % in autopsy series). They are most commonly supratentorial and frequently periventricular, and only 10 % locate infratentorial. Spinal and meningeal forms are rare. Most patients present focal neurological deficits. Intracranial hypertension, changes in mental status, and, occasionally, seizures may also occur. CT shows a hypodense, or sometimes hyperdense, lesion, with perilesional edema and mass effect, with ring enhancement after contrast, which can be indistinguishable from TE or other abscesses. Dissemination through the ependimary surface is a very characteristic radiological sign of PCNSL. Single photon emission computed tomography with thallium-201 and positron emission tomography with fluorodeoxyglucose may aid in the diagnosis and are useful for the differentiation between neoplastic and infectious lesions with high sensitivity and specificity. Detection of EBV in CSF by PCR has also shown a high diagnostic value for PCNSL. Radiotherapy is the most frequently employed treatment, along with steroids. Prognosis is fatal in patients without antiretroviral therapy, with a mean survival of 1 month, which can be prolonged to 3 months with radiotherapy or steroids. In patients receiving HAART survival is significantly prolonged, for years, and some complete remissions have been reported [49, 50]. Chemotherapy or combined treatments, as in patients without HIV infection, are options to consider in the era of HAART [50].

PML is a CNS demyelinating disease caused by oligodendrocyte infection by the JCV, a DNA virus of the polyomavirus family [51]. It affects 4 % of AIDS patients. JCV infection is practically universal in adults, and nonpathogenic strains may remain latent in the kidney and other organs [52]. Immune depression may favor replication of pathogenic strains (with rearrangements in the regulatory region of DNA), their hematogenous spread, and CNS infection. Alternatively, brain JCV latent infection may reactivate when immune surveillance fails. JCV binds serotoninergic 5-HT2A and sialic acid receptors for integration in infected cells. Productive infection of neurons by a variant JCV has recently been demonstrated: infection of the granular cells of the cerebellum causes cerebellar syndrome without demyelination, and infection of pyramidal cells causes an acute encephalopathy [53].

PML manifests clinically as a slowly progressive focal deficit along weeks or months. It is often (47 % of cases) the first manifestation of AIDS. The most frequent initial symptoms are limb paresis, cognitive impairment, or visual symptoms. Seizures occur in 18 % of patients, are associated with juxtacortical lesions, and have a good response to antiepileptic drugs [54]. Neuroimaging studies are, in the clinical context, the main clue to suspect the diagnosis [55]. CT shows characteristic hypodense lesions, without mass effect or contrast enhancement, in the periventricular or subcortical white matter. Subcortical lesions display a geographic pattern as a consequence of U fibers involvement. MRI is more sensitive than CT for PML lesions. Lesions are hyperintense in T2- and FLAIR-weighted sequences and hypointense in T1-weighted images (Fig. 15.3). Gadolinium enhancement is exceptional (5–10 % of cases) and, when present, it is mild and peripheral. In diffusion sequences, there is restriction in the active borders of the lesions. A characteristic pattern in MRI spectroscopy may help in the diagnosis of PML: there is reduction of N-acetyl-aspartate and increase in choline, lipids, and myoinositol.

Fig. 15.3
figure 3

Progressive multifocal leukoencephalopathy. T1-weighted magnetic resonance imaging

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CSF is normal or can show mild protein elevation. The demonstration of JCV DNA in CSF has positive and negative predictive value of 88–100 % and 88.5–95 %, respectively, for the diagnosis of PML, although sensitivity is always below 75 % [56]. A negative result, however, does not exclude the diagnosis in 20–30 % of cases, but sensitivity can be increased with repeated CSF studies. In clinical practice, a diagnosis of PML can be established confidently with this technique, which avoids the need for brain biopsy. With clinical–radiological criteria and a positive CSF PCR, the probability of a correct diagnosis reaches 99 % [46]. The confirmation of LMP diagnosis requires demonstration of the characteristic pathological changes and of JCV in biopsy specimens or autopsy.

The differential diagnosis of PML includes other possible causes of leukoencephalopathy in patients with HIV infection. The leukoencephalopathy present in HAD may be confounded with PML. Aside from the clinical differences, the former is isodense in T1-weighted sequences, do not reach juxtacortical regions, and do not involve posterior fossa. VVZ vasculopathy and multiple sclerosis-like disease may have radiological similarities with PML [57]. Other diagnoses to consider are CMV encephalitis, posterior reversible leukoencephalopathy, leukoencephalopathy caused by heroin inhalation, ischemic stroke, and low-grade astrocytomas.

The natural course of PML is fatal within a mean of 4 months [51]. Factors associated with shorter survival are lower CD4 count, brainstem or cerebellar involvement, and high JCV viral load in CSF in quantitative PCR [58, 59]. A short percentage of patients may stabilize or improve spontaneously, with survival for more than 30 months or even complete remission. They have a higher CD4 count, some of them over 300/mm3, and show frequently contrast enhancement due to inflammatory infiltrates [60].

Since the introduction of HAART, the prognosis of PML has improved drastically. More than 50 % improve or stabilize clinically, and the disease remains inactive after 1-year follow-up. MRI lesions also improve or stabilize in the majority of PML patients with HAART. Prolonged survival associates with restoration of the specific T-cell response against JCV [61, 62] and reduction or negativization of JCV load [58, 63]. However, efficacy of HAART is limited, since one-third of treated patients die due to progression of the lesions and half of survivors do not show significant neurological improvement [63]. A 3-year survival of only 27 % has been reported despite HAART [64]. PML is the AIDS-defining disease with higher mortality in the HAART era, after non-Hodgkin lymphoma [65]. No specific treatment for PML has shown efficacy in randomized studies [66]. Cidofovir, mefloquine, and mirtazapine have been reported to improve LMP in some patients, but their efficacy has not been proven.

Multiple infections can cause brain abscess in AIDS patients. Tuberculous granuloma or abscess and nocardia abscess should be considered (Fig. 15.4). Fungal granulomas or abscesses are uncommon and include those caused by aspergillus, mucor, histoplasma, cryptococcus, and candida. Cases of syphilitic gumma and cysticercosis have been reported in patients with HIV infection. Brain tumors may be secondary to Kaposi’s sarcoma, systemic lymphoma, or other solid tumors, whose incidence are increased in HIV infection. Primary brain tumors, such as gliomas, seem also increased in these patients. Demyelinating diseases, either a multiple sclerosis-like disease or acute disseminated encephalomyelitis, have been reported in primary infection and early stages of HIV infection, but may occur also in advanced stages.

Fig. 15.4
figure 4

Posterior fossa tuberculous abscess. Cranial computed tomography after intravenous contrast, showing a hypodense lesion, with ring enhancement and mass effect

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Encephalitis Caused by Herpesviruses

CMV is the most common herpesvirus causing neurological disease in AIDS patients. Risk for CMV diseases parallels the immune suppression and is maximal with CD4 counts below 50/mm3. Median CD4 count in patients with CMV encephalitis is 20/mm3 (range 2–94) [67]. CNS involvement by CMV usually takes place in the context of systemic CMV infection, particularly retinitis, and encephalitis frequently develops despite maintenance therapy against CMV. An impressive reduction in the frequency of CMV disease, including CNS disease, followed the introduction of HAART, and, nowadays, it has practically disappeared in developed countries.

Two clinicopathologic forms of CMV encephalitis can be distinguished, as extremes of a spectrum where mixed forms are common: ventriculoencephalitis and diffuse micronodular encephalitis [67, 68]. In ventriculoencephalitis, there is destruction of the ependymal layer and necrosis of periventricular parenchyma. The most frequent clinical presentations are acute or subacute confusional state or depressed consciousness. Half of the patients present focal symptoms or signs, frequently revealing brainstem involvement (nystagmus, vertigo, ataxia, or cranial nerve palsy). Paraparesis may reflect associated polyradiculitis. In diffuse micronodular encephalitis, widespread microglial nodes and cytomegalic cells in gray matter suggest hematogenous dissemination. This condition presents as a subacute dementia difficult to differentiate from HAD. Confusion, hyponatremia, or focal brainstem symptoms may help in the diagnosis. This diagnosis should be considered in patients with systemic CMV disease presenting with cognitive impairment.

MRI has low sensitivity for CMV encephalitis and frequently has no specific findings. The most characteristic finding is periventricular contrast enhancement, with or without hydrocephalus. Cases of encephalitis presenting with progressive focal enhancing mass lesion have been reported [69]. CSF may show normal findings or pleocytosis. Detection of CMV DNA in CSF by PCR is the diagnostic test of choice for neurological CMV disease, with a reported sensitivity of 82–92 % and specificity of 94–99 % [56, 70].

CMV CNS disease is usually fatal in a few weeks. Mean survival of ventriculoencephalitis from the first symptom is 42 days [67]. Antiviral drugs against CMV are not effective in most cases, but a combined regimen with foscarnet and ganciclovir may produce clinical improvement or stabilization in a high proportion of cases [71], until immune reconstitution with HAART.

Herpes simplex virus (HSV) encephalitis in AIDS patients can show identical presentation as that of immunocompetent patients [72] or can present with atypical clinical or pathological presentations due to immune suppression. While HSV-2 encephalitis is rare in immunocompetent patients, it has been reported frequently in HIV-infected patients [73]. Concomitant HSV-1 or HSV-2 and CMV encephalitis may also occur [73]. The demonstration of HSV DNA in CSF by PCR has high diagnostic value for HSV encephalitis [73]. Acyclovir is the treatment of choice, although resistant strains may cause disease in AIDS. A bad response is the rule in cases with severe immune depression, usually associated with CMV encephalitis [73].

A wide spectrum of neurological complications of VZV has been described in patients with HIV infection, including encephalitis (or leukoencephalitis), ventriculoencephalitis, myelitis, aseptic meningitis, polyradiculitis, optic neuritis, and other cranial neuritis [74, 75]. The risk of herpes zoster complications increases with immune depression. They can present months after cutaneous lesions or even without them. VZV encephalitis or leukoencephalitis is considered to represent actually a vasculopathy caused by the virus [76]. Small artery vasculopathy produces demyelination or necrotizing leukoencephalitis with a multifocal distribution and sometimes with hemorrhages; large artery vasculopathy causes cerebral infarction. This condition manifests clinically with a progressive encephalopathy with variable impairment of consciousness and focal signs, which may take a chronic course. Sometimes the encephalitis is limited to the brainstem. Demyelinating lesions, mimicking those of PML, can be seen in CT or MRI. The association of multiple ischemic and hemorrhagic lesions is highly suggestive of VZV vasculopathy. Cerebral angiography may show arterial narrowing indicative of vasculitis. CSF usually contains high proteins without pleocytosis. Demonstration of VZV DNA in CSF may be useful for the diagnosis of VZV neurological complications. Intrathecal synthesis of IgG antibodies against VZV is more sensitive than PCR for the diagnosis [76]. Treatment with acyclovir may improve VZV encephalitis. Steroids are indicated as coadjutant therapy for vasculitis.

Stroke in Patients with HIV Infection

The frequency of stroke is highly increased in AIDS patients compared to an age-matched population. Patients with HIV infection may suffer a stroke due to a wide spectrum of mechanisms and etiologies [77–79]. Ischemic stroke may be caused by infections, most of them associated with immune depression, such as vasculitis associated with opportunistic meningitis (bacterial, including tuberculous, cryptococcal, or candidal), VZV, or CMV infection. Meningovascular syphilis should also be considered. Cardioembolic stroke may be related to AIDS-related cardiomyopathy, nonbacterial thrombotic endocarditis, and, particularly, infectious endocarditis in intravenous drug users. Between hematological causes, the high frequency of antiphospholipid antibodies and protein S deficit should be borne in mind, although it is sometimes difficult to establish a causal relationship. Acute stroke may occur also in the context of disseminated intravascular coagulation. Atherothrombotic stroke is also common, especially in older patients [78]. HIV per se may cause large vessel vasculopathy, sometimes with formation or large aneurysms, which may be the cause of up to 20 % of strokes in these patients [79]. In many cases stroke cause cannot be finally demonstrated.

In recent years, there has been concern about a possible risk of accelerated atherosclerosis associated with HAART, particularly with protease inhibitors, which may cause metabolic syndrome, with dyslipidemia and insulin resistance. The risk increases with the time of HAART exposure, but also with the presence of vascular risk factors [80]. The incidence of ischemic stroke in HAART-treated patients is also increased with respect the general population [81], and a substantial rise in patients hospitalized for stroke with coexisting HIV infection has been noticed in the United States [82]. However, the causes of the stroke in these patients are also multiple, and as yet it is not been shown that HAART increases the frequency of atherothrombotic strokes [78, 81].

Meningitis

Causes of meningitis among HIV-infected patients are multiple, including viral, bacterial, and fungal infections, together with carcinomatous meningitis. Clinical and CSF findings may be similar in all types of meningitis in HIV-infected patients. In some patients, CSF analysis can be entirely normal. Therefore, an exhaustive processing of CSF samples covering all the possible etiologies is warranted in cases with suspected meningitis. However, the low diagnostic yield of CSF microbiological studies forces empirical treatment in many patients. Cryptococcus and Mycobacterium tuberculosis meningitis are the most frequent etiological agents of meningitis in these patients. Aseptic lymphocytic meningitis may be caused by the HIV and herpesviruses, particularly VZV. The incidence of conventional bacterial meningitis is highly increased in comparison with the general population, even in the HAART era, and carries out a worse prognosis [83]. Streptococcus pneumoniae is the most frequent agent. Listeria meningitis may be increased in HIV-infected patients. Staphylococcus aureus causes meningitis in intravenous drug users, sometimes associated with endocarditis. Meningitis due to Candida spp. has been reported in HIV-infected patients usually in the presence of other predisposing factors, such as intravenous drug use and previous antibiotics [84].

The clinical manifestations of tuberculous meningitis are similar in patients with and without HIV infection [85]. Presentation is with subacute or chronic (occasionally acute) meningeal syndrome with fever, headache, and frequently altered mental status. Cranial nerve involvement is common, and focal neurological symptoms may be the consequence of vasculitic infarctions or granulomas. Most patients have extraneurological tuberculosis and 50 % have lung infiltrates. CT and MRI may reveal hydrocephalus, meningeal enhancement, and, occasionally, granulomas. CSF contains a variable pleocytosis, which is usually lymphocytic, but sometimes polymorphonuclear, elevated proteins and low levels of glucose. Sensitivity of the Ziehl-auramine stain is low (20 %), as is the yield of CSF cultures for mycobacteria. Adenosine deaminase activity in CSF has been considered useful in the early diagnosis of tuberculous meningitis, but in HIV-infected patients has low sensitivity and specificity [86]. CSF PCR for M. tuberculosis in CSF may aid in the diagnosis because of its high sensitivity and specificity. Meningitis caused by opportunistic mycobacteria is rare.

Cryptococcal meningitis may be indistinguishable from tuberculous meningitis on clinical grounds or in CSF findings [87]. A characteristic finding in MRI is the presence of hyperintensities in T2-weighted sequences in the basal ganglia caused by dilatation of the Virchow–Robin spaces. CSF India ink can demonstrate the fungal capsule in 75 % of cases. Cryptococcal antigen is positive in 90–100 % of patients in CSF and in 75–99 % in serum, always with high specificity. Treatment of choice is amphotericin B associated with 5-fluocytosine. A maintenance therapy with fluconazole is mandatory because of the high risk of relapse. In patients under HAART, maintenance therapy can be suppressed after 3 months with CD4 over 100/mm3 and undetectable HIV viral load [47].

Myelopathies

Myelopathies affecting patients with HIV infection are best classified in segmentary myelopathies, which tend to present with an acute or subacute course, and diffuse myelopathies, usually with a progressive chronic or subacute presentation, as is the case with vacuolar myelopathy.

Vacuolar myelopathy is the most common cause of myelopathy in these patients [88]. It has been found in 50 % of autopsies of AIDS patients, although only one-fourth of them were evident clinically. Pathological anomalies predominantly involve the lateral and dorsal columns of dorsal region, resembling subacute combined degeneration. It presents clinically as slowly progressive (along weeks or months) and symmetric spastic paraparesis. Gait ataxia or sensory symptoms are also common presentations. Sphincter symptoms are late. HAD is present in 60 % of the patients. Neurological exam reveals that vibration and position senses are more severely affected than pain or light touch. There are symmetric pyramidal signs, but hyperreflexia might be absent in the case of associated peripheral neuropathy. Vacuolar myelopathy progresses slowly to spastic paraplegia. Diagnosis is mainly clinical, after other possible causes of myelopathy are excluded by means of spinal MRI and CSF studies. MRI shows atrophy of the spine and, occasionally, hyperintensities in the lateral or dorsal columns. There is no specific treatment. There have been reports of patients who improved after HAART. The other chronic diffuse myelopathy to consider in patients with HIV infection is tropical spastic paraparesis caused by HTLV-I, particularly in patients from countries were this infection is prevalent. Contrary to what happens with vacuolar myelopathy, this disease does not occur necessarily in patients with significant immune depression [89].

Among the segmentary myelopathies, viruses are the most frequent causes. HIV may cause transverse myelitis during primary infection. VZV myelitis develops more frequently in immunocompromised patients [90]. Weakness progresses in weeks, but may show a chronic course over several months. MRI may be normal or show spinal hyperintensities in T2-weighted sequences, which may enhance after gadolinium. CSF may also be normal or demonstrate a variable inflammatory response. CMV can cause necrotizing myelopathy, which may be associated with encephalitis or polyradiculitis. The HSV-1 and more frequently the HSV-2 in association with genital herpes are other possible causes of myelopathy. Concomitant HSV-2 and CMV myelopathy has also been reported. Other causes of segmentary myelopathies are toxoplasmosis, tuberculous granuloma, epidural tumor or abscess, and vascular lesions due to syphilis or disseminated intravascular coagulation. Primary intramedullary tumors, as gliomas or lymphomas, are rare.

Neuropathies

Peripheral neuropathy is very common in HIV infection. In the pre-HAART era, the prevalence of symptomatic neuropathy was 35 %, while 20 % had asymptomatic neuropathy [91]. A similar prevalence has been found in HAART-treated patients, despite controlled HIV infection [92]. For the clinical management of patients with suspected neuropathy, it is useful to classify neuropathies according to the clinical and electrophysiological pattern [93]. We will consider four groups: demyelinating neuropathies, axonal polyradiculopathies, mononeuritis multiplex, and distal symmetric polyneuropathy.

Distal symmetric polyneuropathy is the most frequent pattern. It is an axonal predominantly sensory polyneuropathy, caused most commonly by the HIV itself and by antiretroviral toxicity [93]. These two etiologies are practically indistinguishable from the clinical or electrophysiological point of view. Other causes of predominantly sensory distal neuropathy in these patients are alcoholism, malnutrition and vitamin deficits, diabetes, and uremia. A clinical picture similar to distal sensory polyneuropathy may occur with CMV nerve infection. HIV-associated distal sensory polyneuropathy characteristically presents with symmetric distal painful paresthesias and affects mainly the legs. Only occasionally a motor deficit exists. Examination may disclose hypesthesia with a stocking and glove distribution and distal hyporeflexia. Treatment is only symptomatic. Tricyclic antidepressants and antiepileptic drugs as gabapentin and lamotrigine are widely used, but unfortunately only topic capsaicin and cannabis have demonstrated efficacy in controlled studies [93]. Antiretroviral toxic neuropathy is caused by the nucleoside reverse transcriptase inhibitors didanosine, zalcitabine, and stavudine. Combined therapy has a synergistic toxic effect. It affects between 15 and 30 % of treated patients. They cause a sensitive, dose-dependent, distal axonal neuropathy. Treatment consists in drug suppression and symptomatic treatment as used for VIH-associated neuropathy. Other drugs used in HIV-infected patients may cause toxic neuropathy: vincristine, isoniazid, dapsone, metronidazole, and thalidomide. Autonomic nervous system dysfunction can be demonstrated in a high percentage of HIV-infected patients in advanced stages, frequently in association with distal neuropathy, but it is rarely symptomatic.

Demyelinating inflammatory neuropathies are an uncommon cause of neuropathy in HIV-infected patients. Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy in HIV-infected patients have the same clinical, electrophysiological, and pathological characteristics as in uninfected patients [94]. CSF may contain mild pleocytosis, but not in all cases. Both present in patients without significative immune depression or in primary HIV infection.

Acute lumbosacral polyradiculitis, or cauda equina syndrome, is a well-defined clinical syndrome in AIDS patients with multiple causes [95, 96]. Most cases are caused by CMV infection. Tuberculosis is the second most frequent cause. Other reported etiologies are VZV and HSV, often associated with myelitis, cryptococcal or bacterial meningitis, syphilis, and meningeal lymphomatosis. All these causes have similar clinical presentation and CSF findings. CMV polyradiculitis presents with acute or subacute progressive leg weakness, often accompanied with paresthesias and radicular pain and urinary retention. Encephalopathic symptoms are frequent in final stages due to associated encephalitis. CSF contains variable pleocytosis, which may be polymorphonuclear in the most typical cases, increased proteins, and normal or low glucose. CSF viral cultures have low yield, but CSF PCR for CMV is useful for diagnosis. Lumbar MRI is needed to exclude other causes of cauda equina syndrome. It may show normal results or demonstrate contrast enhancement in the roots and conus medullaris. This disease is fatal in most untreated cases. Treatment with ganciclovir or foscarnet has been successful in many patients. The most important factor for treatment response is early institution of therapy [97]. Therefore, rapid initiation of empirical antiviral treatment is mandatory when the disease is suspected.

Mononeuritis multiplex in HIV-infected patients is due mainly to two causes: the HIV itself and CMV infection. Less common causes are cryoglobulinemia associated with HCV, peripheral nerve infiltration by lymphoma, and diffuse infiltrative lymphocytosis syndrome. Mononeuritis multiplex associated with HIV is caused by peripheral nerve vasculitis and presents in early stages, whereas CMV neuropathy presents in severely immunocompromised patients [98]. The latter is a multifocal sensory and motor neuropathy with a subacute or chronic course, which often presents with patchy areas of dysesthesia and paresthesia. CSF is usually normal. It may improve with ganciclovir or foscarnet.

Myopathies

Two myopathies, difficult to differentiate form each other, may present in HIV-infected patients. One is HIV-associated myopathy and the other is AZT myopathy. HIV-associated myopathy may present at any moment in the course of HIV infection [99]. Clinical and pathological findings are similar to those of polymyositis. The patient experiences symmetric limb weakness, with a predominantly proximal distribution, progressing in months. Patients improve with steroids. AZT myopathy has a similar clinical presentation, but has a distinctive pathological pattern [100]. It improves after suppression of AZT. The probable cause of this myopathy is mitochondrial dysfunction caused by the drug, although mitochondrial anomalies have been found also in untreated HIV-infected patients. Cases of severe rhabdomyolysis caused by other antiretroviral drugs, such as didanosine and raltegravir, have been reported. Other causes of myopathy in HIV-infected patients include focal myositis caused by toxoplasma and pyomyositis of diverse etiologies, frequently associated with venous puncture in drug addicts.

Neurosyphilis and HIV

Neurosyphilis may occur in any stage of HIV infection. However, the prevalence is higher than in patients without HIV infection and greater in patients with CD4 counts under 350/mm3 [101]. In HIV-infected patients, neurosyphilis appears mainly in early stages of the syphilitic infection. For this reason, some authors have recommended CSF analysis in every patient with syphilis and HIV infection. However, CSF analysis is not considered necessary in cases of primary, secondary, or early latent syphilis, if neurological, visual, or auditory symptoms are not present. In HIV-infected patients, neurosyphilis may be asymptomatic or present the usual range of presentations in the general population that include lymphocytic meningitis, cranial neuropathies (VIII nerve), optic neuropathy, meningovascular syphilis, meningomyelitis, meningoradiculitis, cerebral gummas, general paresis, or tabes dorsalis. Some difficulties for the diagnosis of neurosyphilis may be present in these patients. CSF pleocytosis is one of the clues for the diagnosis of neurosyphilis, but it is common in HIV infection. Occasionally non-treponemal tests for syphilis, VDRL (Venereal Disease Research Laboratory) and RPR (rapid plasma reagin), are negative in CSF. Treatment is the same as for patients without HIV infection. Reports of HIV-infected patients correctly treated for primary syphilis who had meningovascular relapse have induced some authors to recommend treating with doses for neurosyphilis every HIV-infected patient with syphilis.

Neurological Complications Associated with HAART

Neurological Immune Reconstitution Inflammatory Syndromes

Following the initiation of HAART, there is a rapid fall in plasma levels of HIV RNA and an increase in T lymphocytes, accompanied by significant functional improvement. Due to the restoration of the capability to develop an inflammatory response against infectious and noninfectious antigens, some patients may suffer clinical deterioration. This phenomenon is designated as immune reconstitution inflammatory syndrome (IRIS) [102]. Some autoimmune diseases presenting after initiation of HAART may be considered part of this entity. IRIS may represent the debut of a previously unknown disease (unmasking IRIS) or a paradoxical clinical deterioration of a known disease (paradoxical IRIS) after the beginning of HAART. IRIS affects between 15 and 35 % of patients receiving HAART, and 1 % suffer neurological IRIS [102, 103]. Risk factors for IRIS are a higher immune depression before HAART and a more rapid immunological response. IRIS usually presents in the first weeks or months of therapy, but may be retarded for more than 1 year. Recognizing this clinical entity is essential for the appropriate management of the patient, without compromising antiretroviral or anti-infective treatment.

IRIS presents in 30 % of all patients with a diagnosis of tuberculosis who initiate HAART, and 12 % of them may be neurological syndromes [104]. Intracranial tuberculomas, meningitis, or myeloradiculitis may appear or deteriorate, after a mean of 14–43 days. Steroids improve the inflammation and clinical course. In patients with a diagnosis of tuberculosis, HAART initiation must be retarded until several weeks of antituberculous drugs have been completed. IRIS may present in 17 % of cryptococcal meningitis [105]. Early initiation of HAART after the diagnosis of cryptococcal meningitis has a high risk of IRIS, and therefore, it is recommended retarding several weeks the beginning of HAART [106]. Latent meningitis may be unmasked. In addition to the clinical deterioration of the patient, there is increased inflammatory reaction in CSF and meningeal enhancement in neuroimaging studies, and granulomas may appear. Patients may improve with steroids or spontaneously.

PML may also present as IRIS or suffer paradoxical deterioration after HAART [107–109]. PML presenting as IRIS constitute up to 20 % of all recent PML cases. After the clinical deterioration produced by IRIS, the patient may improve spontaneously, but occasionally the course is fatal. Thus, while effective HAART initiated early is essential for the improvement of PML patients, this treatment may result in death for some patients. A case of fatal inflammatory PML has presented after more than 2 years of HAART [110]. Global mortality of PML patients with or without IRIS is similar, but patients with paradoxical IRIS have higher mortality than those with unmasking IRIS. In neuroimaging studies the inflammatory component can be demonstrated as contrast enhancement of the lesions in 60 % of cases (Fig. 15.5). CSF may also show inflammatory signs, something unusual in PML. CSF PCR for JCV is frequently negative because the host immune response can control JCV replication. PML IRIS may improve after HAART suppression or with steroids [109].

Fig. 15.5
figure 5

Contrast enhancement in a patient with progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome

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The incidence of herpes zoster increases up to five times in patients with HAART. Most cases (86 %) present between the second and fourth months of treatment [111]. Zoster may be a manifestation of IRIS related to an increase in CD8 T cells, which may be involved in VZV reactivation [111]. VZV myelitis and encephalitis has also been reported as IRIS [102]. Other neurological IRIS reported are associated with TE, Candida meningitis, CMV ventriculoencephalitis, and primary cerebral lymphomatoid granulomatosis [102, 112]. The HIV itself might be the triggering antigen of a neurological IRIS, causing encephalitis with multiple enhancing lesions and CD8 lymphocyte infiltration in pathological studies [113, 114]. Chronic form of CNS-IRIS might be an important component of HAND [102].

After the initiation of HAART, the possible appearance of autoreactive T cells might trigger autoimmune diseases, such as Guillain–Barré syndrome and demyelinating leukoencephalopathies [102].

Neuromuscular Weakness Associated with HIV

Patients undergoing HAART may present a syndrome of acute or subacute neuromuscular weakness associated with lactic acidosis [115]. In most cases, an axonal neuropathy is demonstrated in electrophysiological and pathological studies, but some patients have a myopathy (15 %) or both. This picture resembles axonal Guillain–Barré syndrome. One-third of patients have sensory symptoms, and some have cranial nerve involvement. Hyperlactacidemia causes systemic symptoms, vomiting, and abdominal pain. Mortality of this syndrome is 13 %. It has been related to nucleoside reverse transcriptase inhibitors, particularly stavudine, the antiretrovirals most frequently associated with lactic acidosis. The pathogenesis is not known, but it is considered to be probably caused by mitochondrial dysfunction.