**4. HIV-associated neurological HIV disease**

#### **4.1. Aseptic meningitis**

#### *4.1.1. Introduction*

Vacuolar myelopathy

**2.2. Secondary conditions**

Narcotic overdose

**2.** Psychiatric disorders

Drug toxicity

combined [4].

Hypoxic encephalopathies

Nucleoside neuropathies Zidovudine myopathy

Reactive anxiety, depression

Cerebrovascular complication

Nutritional and metabolic disorders

**3. Epidemiology of neurological HIV disease**

and Latin America has 1.6 million infected people [5].

There are two principal subtypes of HIV, namely HIV-1 and HIV-2:

Studies on the prevalence of HIV among neurologic patients are sparse. The most often quoted study is the CDC study of 195,000 patients in 20 acute-care US hospitals, which found a seroprevalence of 0–13%. This was highly correlated with the seroprevalence among all patients in the hospitals [2]. The study data was difficult to interpret as almost two-thirds of the HIV patients were previously undiagnosed. In a hospital-based study that audited HIV manifestations in medical inpatients in South Africa, the frequency of neurological involvement was 75%, with 11% pure neurological disease, and 64% neurological and non-neurological disease

The paucity of this type of data is in stark contrast to established data on the global prevalence of HIV from the Joint United Nations Programme on HIV/AIDS (UNAIDS). In 2016, the WHO estimated that 36.7 million people worldwide are infected with HIV. Sub-Saharan Africa bears the brunt of the HIV epidemic with 25.5 million infected individuals (a prevalence of 6% and 69% of all persons with HIV globally). Asia and the Pacific have 5.1 million infected people,

HIV-1, the predominant subtype is spread worldwide. HIV-2 was found predominantly in West Africa with scattered cases reported in the Americas and Western Europe. Both are associated with the clinical development of progressive immunological impairment with some differences in incubation and transmission properties. HIV-1 is the major cause of AIDS in humans [6].

HIV myopathy

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**1.** Metabolic

**3.** Other

Aseptic meningitis is a clinicopathological syndrome, and the cardinal symptoms of which are headache, fever, and meningism. Pathologically, it is characterized by serous, nonpyogenic inflammation of the meninges. The defining cerebrospinal fluid (CSF) findings include a mononuclear pleocytosis, normal, or mildly raised protein and normal glucose levels [1]. Aseptic meningitis occurs with an annual incidence rate of 11–27 cases per 100,000 population. The causes are mainly viral infections. Of these, enteroviruses (Echo and Coxsackie) make up 80% of cases followed by mumps, HSV-2, lymphocytic choriomeningitis, and adenovirus. Uncommon causes include infectious mononucleosis, cytomegalovirus (CMV), leptospirosis, HSV-1, mycoplasma, arboviruses (in epidemics mainly in the United States and Europe) and rarely during the icteric phase of infectious hepatitis. In the majority of instances, a causative agent cannot be established (exceptions include enteroviruses, mycoplasma, leptospirosis, and Lyme borreliosis) [1]. The aseptic meningitis in most of these conditions is a self-limiting illness and rarely is of sufficient severity to produce pathological changes in the brain that can be visualized with imaging modalities (CT or MRI).

It is important to recognize that an aseptic meningitis syndrome can occur in the course of other infectious and noninfectious inflammatory granulomatous and vasculitic and autoimmune illnesses. This is well described with respect to partially treated bacterial meningitis, so-called neighborhood infections, fungal, mycobacterial, spirochetal, and parasitic meningitis, malignant meningitis, and other noninfectious inflammatory diseases such as sarcoidosis, Behçet's disease, Wegener's granulomatosis, and granulomatous angiitis of the nervous system [1, 2].

#### *4.1.2. Aseptic meningitis in HIV*

Aseptic meningitis in HIV may be caused by HIV itself or by an opportunistic viral infection (CMV and JCV), mycobacterial infection, noninfectious inflammatory processes (immune reconstitution inflammatory syndrome, IRIS) or CNS neoplasia (lymphoma) [2]. In terms of direct infection, HIV has been identified in the CSF by polymerase chain reaction (PCR) or viral culture techniques throughout the course of HIV infection, and especially during late stage disease. Often despite extensive investigations, the causative infection or agent is not identified. In these latter situations, the aseptic meningitis is presumed to be due to HIV itself.

understood. Peripheral blood-infected monocytes carry HIV to the blood brain barrier and induce a macrophage tropism of tissue invasion. This HIV tropism for macrophages is determined by the V3 domain of the viral envelope glycoprotein. The infected macrophage releases adhesion molecules (intracellular or VCAMs), which cause adherence of the infected macrophage to the vascular endothelium. This triggers an immunological reaction involving inflammatory cytokines as well as matrix metalloproteinases that result in trafficking into the nervous system compartment. HIV may also penetrate the brain as free viral particles when there is a disrupted blood brain barrier. The subsequent events after invasion or trafficking are largely immunological and include activation of various cytokines with macrophage proliferation, microglial infection, and

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Meningeal inflammation occurs as a result of HIV breaching the meningeal blood-CSF barrier or from autoimmune processes causing an inflammatory response. Meningeal invasion occurs by hematogenous spread or via neurotropic mechanisms. Meningeal irritation pro-

The illness takes typically a biphasic course with initial nonspecific constitutional symptoms then followed by the classical features usually associated with meningitis, namely, headache, malaise, fever, neck stiffness, rigors, photophobia, nausea, and vomiting. Skin rash like the eruptions of varicella zoster (VZV) may appear concurrently. Other less common manifestations are cranial neuropathies, confusion, decreased level of consciousness and seizures.

As described above, an aseptic meningitis syndrome is suspected when the CSF profile of a moderately raised protein with predominantly lymphocytic pleocytosis is identified. The crucial investigation is therefore CSF analysis. The subsequent investigations on the spinal fluid are performed to exclude conditions that mimic aseptic meningitis and in some instances to

The typical CSF profile in aseptic meningitis is that of a lymphocytic pleocytosis of less

and negative bacterial antigen tests. Early CSF analysis may reveal a neutrophil predominance. An important differential diagnosis of this CSF constellation is partially treated bacterial meningitis especially in the presence of a history of recent antimicrobial therapy. Latex agglutination tests for bacterial antigens may be helpful in this setting. Aseptic meningitis

, normal or mildly elevated protein, normal glucose concentration,

identify specific viral etiologies. In this regard, the following studies are useful:

Biochemistry, microscopy, and cellular counts Gram stain, bacterial culture, and sensitivity

India ink and cryptococcal antigen

Specific and nonspecific syphilis serology

PCR for HSV, VZV, Epstein-Barr virus (EBV), and CMV

other processes that constitute so-called neurotropism and neurovirulence.

duces reflex neck stiffness and causes headache and cranial nerve lesions.

*4.1.5. Clinical presentation*

*4.1.6. Investigations*

Acid-fast bacilli

than 500 cells per mm<sup>3</sup>

HIV-associated aseptic meningitis occurs in several different settings: at the time of seroconversion, during the course of the disease, and with highly active antiretroviral treatment (HAART) where it can be an IRIS-related manifestation [2, 3].

The aseptic meningitis in these HIV-related settings presents as an acute self-limiting illness (often with a cranial neuropathy, e.g., facial nerve palsy), an acute symptomatic meningitis or a chronic asymptomatic meningitis. Pleocytosis or elevated CSF protein has been described in almost two-thirds of asymptomatic HIV seropositive persons [2].

#### *4.1.3. Epidemiology*

Aseptic meningitis is the second commonest type of meningitis in HIV positive patients, the commonest being cryptococcal meningitis, which is described to affect between 5 and 7% of patients with AIDS [3].

The incidence or prevalence of aseptic meningitis in HIV cannot be accurately determined because it is most often asymptomatic (up to two-thirds of patients) and rarely symptomatic. Frequencies of 0.5–1% have been reported. No gender, ethnic, geographical, or clade-related differences have been described. The non-HIV conditions that can manifest as aseptic meningitis include cryptococcal meningitis, tuberculous meningitis, parasitic meningitis, and CNS neoplasms (lymphoma). Progressive multifocal leukoencephalopathy (PML) caused by JC virus can also mimic the CSF findings of an aseptic meningitis syndrome [2]. The relative frequencies with which these occur are related to the prevalence of infections in the environment and in this regard geographical and clade related differences have been described. Cryptococcal meningitis occurs with frequencies of 6% in South Africa (clade C), 3% in India (clade C), 1% in the United States (clade B), 1% in Brazil (clade B), 7% in Uganda (clades A and D), and 2% in Thailand (clade E). Tuberculous meningitis, on the other hand, occurs in 6% of HIV-infected South Africans, 3% of Indians, 1% of US citizens, 1% of Brazilians, 7% of Ugandans, and in 2% of Thai HIV-infected patients [4]. The frequencies of CMV and the other opportunistic pathogens causing HIV-associated aseptic meningitis are not well documented. The non-HIV viral infections described above that cause an aseptic meningitis syndrome have not been systematically studied in HIV-infected patients.

#### *4.1.4. Pathophysiology*

HIV enters the nervous system at any stage of infection in particular during the primary viremia that accompanies seroconversion. The mechanisms by which this process occurs are now better understood. Peripheral blood-infected monocytes carry HIV to the blood brain barrier and induce a macrophage tropism of tissue invasion. This HIV tropism for macrophages is determined by the V3 domain of the viral envelope glycoprotein. The infected macrophage releases adhesion molecules (intracellular or VCAMs), which cause adherence of the infected macrophage to the vascular endothelium. This triggers an immunological reaction involving inflammatory cytokines as well as matrix metalloproteinases that result in trafficking into the nervous system compartment. HIV may also penetrate the brain as free viral particles when there is a disrupted blood brain barrier. The subsequent events after invasion or trafficking are largely immunological and include activation of various cytokines with macrophage proliferation, microglial infection, and other processes that constitute so-called neurotropism and neurovirulence.

Meningeal inflammation occurs as a result of HIV breaching the meningeal blood-CSF barrier or from autoimmune processes causing an inflammatory response. Meningeal invasion occurs by hematogenous spread or via neurotropic mechanisms. Meningeal irritation produces reflex neck stiffness and causes headache and cranial nerve lesions.

#### *4.1.5. Clinical presentation*

*4.1.2. Aseptic meningitis in HIV*

126 Advances in HIV and AIDS Control

*4.1.3. Epidemiology*

patients with AIDS [3].

*4.1.4. Pathophysiology*

Aseptic meningitis in HIV may be caused by HIV itself or by an opportunistic viral infection (CMV and JCV), mycobacterial infection, noninfectious inflammatory processes (immune reconstitution inflammatory syndrome, IRIS) or CNS neoplasia (lymphoma) [2]. In terms of direct infection, HIV has been identified in the CSF by polymerase chain reaction (PCR) or viral culture techniques throughout the course of HIV infection, and especially during late stage disease. Often despite extensive investigations, the causative infection or agent is not identified. In these latter situations, the aseptic meningitis is presumed to be due to HIV itself. HIV-associated aseptic meningitis occurs in several different settings: at the time of seroconversion, during the course of the disease, and with highly active antiretroviral treatment

The aseptic meningitis in these HIV-related settings presents as an acute self-limiting illness (often with a cranial neuropathy, e.g., facial nerve palsy), an acute symptomatic meningitis or a chronic asymptomatic meningitis. Pleocytosis or elevated CSF protein has been described in

Aseptic meningitis is the second commonest type of meningitis in HIV positive patients, the commonest being cryptococcal meningitis, which is described to affect between 5 and 7% of

The incidence or prevalence of aseptic meningitis in HIV cannot be accurately determined because it is most often asymptomatic (up to two-thirds of patients) and rarely symptomatic. Frequencies of 0.5–1% have been reported. No gender, ethnic, geographical, or clade-related differences have been described. The non-HIV conditions that can manifest as aseptic meningitis include cryptococcal meningitis, tuberculous meningitis, parasitic meningitis, and CNS neoplasms (lymphoma). Progressive multifocal leukoencephalopathy (PML) caused by JC virus can also mimic the CSF findings of an aseptic meningitis syndrome [2]. The relative frequencies with which these occur are related to the prevalence of infections in the environment and in this regard geographical and clade related differences have been described. Cryptococcal meningitis occurs with frequencies of 6% in South Africa (clade C), 3% in India (clade C), 1% in the United States (clade B), 1% in Brazil (clade B), 7% in Uganda (clades A and D), and 2% in Thailand (clade E). Tuberculous meningitis, on the other hand, occurs in 6% of HIV-infected South Africans, 3% of Indians, 1% of US citizens, 1% of Brazilians, 7% of Ugandans, and in 2% of Thai HIV-infected patients [4]. The frequencies of CMV and the other opportunistic pathogens causing HIV-associated aseptic meningitis are not well documented. The non-HIV viral infections described above that cause an aseptic meningitis syndrome have

HIV enters the nervous system at any stage of infection in particular during the primary viremia that accompanies seroconversion. The mechanisms by which this process occurs are now better

(HAART) where it can be an IRIS-related manifestation [2, 3].

almost two-thirds of asymptomatic HIV seropositive persons [2].

not been systematically studied in HIV-infected patients.

The illness takes typically a biphasic course with initial nonspecific constitutional symptoms then followed by the classical features usually associated with meningitis, namely, headache, malaise, fever, neck stiffness, rigors, photophobia, nausea, and vomiting. Skin rash like the eruptions of varicella zoster (VZV) may appear concurrently. Other less common manifestations are cranial neuropathies, confusion, decreased level of consciousness and seizures.

#### *4.1.6. Investigations*

As described above, an aseptic meningitis syndrome is suspected when the CSF profile of a moderately raised protein with predominantly lymphocytic pleocytosis is identified. The crucial investigation is therefore CSF analysis. The subsequent investigations on the spinal fluid are performed to exclude conditions that mimic aseptic meningitis and in some instances to identify specific viral etiologies. In this regard, the following studies are useful:

Biochemistry, microscopy, and cellular counts Gram stain, bacterial culture, and sensitivity Acid-fast bacilli India ink and cryptococcal antigen Specific and nonspecific syphilis serology PCR for HSV, VZV, Epstein-Barr virus (EBV), and CMV

The typical CSF profile in aseptic meningitis is that of a lymphocytic pleocytosis of less than 500 cells per mm<sup>3</sup> , normal or mildly elevated protein, normal glucose concentration, and negative bacterial antigen tests. Early CSF analysis may reveal a neutrophil predominance. An important differential diagnosis of this CSF constellation is partially treated bacterial meningitis especially in the presence of a history of recent antimicrobial therapy. Latex agglutination tests for bacterial antigens may be helpful in this setting. Aseptic meningitis due to noninfectious inflammatory diseases like sarcoid, Behçet's disease, uveo-meningeal syndromes usually have a more complicated course and always must be considered because they may respond to specific treatments [2, 3].

severe HIV associated dementia (HAD) cognitive deficits [10]. The cardinal manifestations

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The HIV epidemic can be described in three phases. The first of these is the illness prior to the introduction of antiretrovirals, followed by the era of monotherapy with zidovudine (AZT), and now more recently, the era of highly active antiretroviral therapy (HAART) or combina-

Before the introduction of antiretrovirals dementia was a common manifestation of late disease occurring in over 50% of AIDS patients prior to death. That phase was characterized by a rapid turnover of prevalent dementia cases due to high incidence rates combined with high mortality rates resulting from AIDS-related complications (opportunistic infections and neoplasms). With the availability of monotherapy like zidovudine dementia rates and overall mortality decreased, but prolonged survival and incomplete recovery of prevalent cases has led to a relative increase of patients with the milder forms of HIV neurocognitive impairment (MCMD and NPI). This phenomenon has been enhanced more recently during the current

This scenario however only applies to the developed regions mainly of North America and Europe, where HAART is the standard of management. These regions are largely dominated

Clade C virus is responsible for an estimated 50% of infections globally and associated with the epidemics in Sub-Saharan Africa, and parts of Asia, particularly India and China. How the different clades in different populations may influence the pathological and clinical spectrum of HIV infection is poorly documented [4]. Relatively little data is available on HIVrelated neurocognitive impairment from non-clade B regions. In these developing regions, HIV neurocognitive deficits were either poorly documented or thought to be a minor problem compared to the overwhelming burden of opportunistic infections. The apparently low prevalence of dementia was explained by possible under-diagnosis and underreporting, short life expectancy and short survival of HIV infected patients due to fatal opportunistic infections. Subsequent research has found the frequency to be higher than previously suspected with reported figures of 38% in South Africa (clade C), up to 35% in India (clade C), and 31% in Uganda (clades A and D), indicating that the influence of clade subtype on the spectrum of

HIV enters the brain during the initial viremia following infection. This occurs through infected macrophage/monocyte lineage cells crossing the blood–brain barrier, the so-called

In the brain parenchyma, mainly monocyte-derived cells (microglia and macrophages), and to a lesser extent astrocytes, can be infected by HIV. Penetration of microglial cells is via the cellular surface CD4 receptor in conjunction with the chemokine receptors CCR5 and CCR3

are a triad of cognitive, behavioral, and motor dysfunction.

cognitive dysfunction is probably minimal if at all [4, 11].

"Trojan horse" mechanism or directly across the blood brain barrier [3].

**5.2. Epidemiology**

era of HAART.

by the clade B strain of HIV-1.

**5.3. Pathophysiology**

tion antiretroviral therapy (cART).

#### *4.1.7. Imaging*

CT or MRI may help to exclude suspected structural disease like parameningeal infectious foci, but is generally not necessary. A Chest X-ray may be indicated when tuberculosis is suspected as an underlying cause of aseptic meningitis.

#### *4.1.8. Treatment*

Management is symptomatic (fluids, analgesics, anti-inflammatories, antipyretics, antiemetics) with hospitalization often not required. If bacterial or partially treated bacterial meningitis is suspected, empiric antibiotics should be commenced. Acyclovir is used for HSV-1 or HSV-2, or severe EBV and VZV infections; antiretrovirals can be considered for HIV. Corticosteroids are not recommended because of their inhibitory effect on immune responses [1].

Hyponatremia as a consequence of infection-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) needs to be recognized and managed.

#### *4.1.9. Prognosis*

The outcome following aseptic viral meningitis is generally excellent with full recovery in 5–14 days after onset of symptoms. Rarely headaches, lightheadedness, and fatigue may persist for longer in some patients. The natural history of aseptic meningitis is determined by the natural history of the HIV infection and its effects on immunity. It is not clear whether the aseptic meningitis syndrome in HIV is a prelude to dementia, CNS neoplasia, or focal brain lesions [1, 2].
