Chapter 29 - HIV peripheral neuropathy

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Abstract

Peripheral neuropathies are the most common neurological manifestations occurring in HIV-infected individuals. Distal symmetrical sensory neuropathy is the most common form encountered today and is one of the few that are specific to HIV infection or its treatment. The wide variety of other neuropathies is akin to the neuropathies seen in the general population and should be managed accordingly.

In the pre-ART era, neuropathies were categorized according to the CD4 count and HIV viral load. In the early stages of HIV infection when CD4 count is high, the inflammatory demyelinating neuropathies predominate and in the late stages with the decline of CD4 count opportunistic infection-related neuropathies prevail.

That scenario has changed with the present almost universal use of ART (antiretroviral therapy). Hence, HIV-associated peripheral neuropathies are better classified according to their clinical presentations: distal symmetrical polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathies, mononeuropathies multiplex and cranial neuropathies, autonomic neuropathy, lumbosacral polyradiculomyelopathy, and amyotrophic lateral sclerosis (ALS)-like motor neuropathy.

Treated with ART, HIV-infected individuals are living longer and are at a higher risk of metabolic and age-related complications; moreover they are also prone to the potentially neurotoxic effects of ART.

There are no epidemiological data regarding the incidence and prevalence of the peripheral neuropathies. In the pre-ART era, most data were from case reports, series of patients, and pooled autopsy data. At that time the histopathological evidence of neuropathies in autopsy series was almost 100%.

In large prospective cohorts presently being evaluated, it has been found that 57% of HIV-infected individuals have distal symmetrical sensory neuropathy and 38% have neuropathic pain. It is now clear that distal symmetrical sensory neuropathy is caused predominantly by the ART’s neurotoxic effect but may also be caused by the HIV itself.

With a sizeable morbidity, the neuropathic pain caused by distal symmetrical sensory neuropathy is very difficult to manage; it is often necessary to change the ART regimen before deciding upon the putative role of HIV infection itself. If the change does not improve the pain, there are few options available; the most common drugs used for neuropathic pain are usually not effective. One is left with cannabis, which cannot be recommended as routine therapy, recombinant human nerve growth factor, which is unavailable, and topical capsaicin with its side-effects.

Much has been done to and learned from HIV infection in humans; HIV-infected individuals, treated with ART, are now dying mostly from cardiovascular disease and non-AIDS-related cancers. It hence behooves us to find new approaches to mitigate the residual neurological morbidity that still impacts the quality of life of that population.

Introduction

The human immunodeficiency virus (HIV) epidemic has leveled off in the last 10 years. In 2009, an estimated 2.6 million people became newly infected with HIV. This number is nearly one-fifth (19%) fewer than the 3.1 million people who were newly infected in 1999, and more than one-fifth (21%) fewer than the estimated 3.2 million in 1997, the year in which annual new infections peaked. (UNAIDS report on the global AIDS epidemics: http://www.unaids.org/globalreport/Global_report.htm).

In 33 countries, the incidence of HIV fell by more than 25% between 2001 and 2009; 22 of these countries are in sub-Saharan Africa. In sub-Saharan Africa, where the majority of new HIV infections continue to occur, an estimated 1.8 million people became infected in 2009; this is considerably lower than the estimated 2.2 million people in sub-Saharan Africa who were newly infected with HIV in 2001. This trend reflects a combination of factors, including the impact of HIV prevention efforts and the natural course of HIV epidemics (UNAIDS report on the global AIDS epidemics: http://www.unaids.org/globalreport/Global_report.htm). UNAIDS estimates that there were 33.3 million people living with HIV at the end of 2009 compared with 26.2 million in 1999  a 27% increase. Although the annual number of new HIV infections has been steadily declining since the late 1990s, this decrease is offset by the reduction in AIDS-related deaths due to the significant improvements in antiretroviral therapy (ART) over the past few years. According to the Centers for Disease Control and Prevention (CDC), an estimated 1 to 1.18 million people in the USA are living with HIV/AIDS. Approximately 24% to 27% of these people are undiagnosed and unaware of their HIV infection. The 2006 CDC report showed that, in the USA, 73% of new infections were in males, 45% were in African Americans, and 53% were in men who have sex with men (MSM). Among females, the predominant HIV transmission category was high-risk heterosexual contact, which accounted for 80% of new infections. Of the new infections that were diagnosed in 2006, at least 20 000 per year were due to transmission of HIV from persons unaware of their infection (Centers for Disease Control and Prevention, 2008).

The Centers for Disease Control and Prevention (CDC) classification system for HIV-infected adolescents and adults was published in 1992 and is still current. This system categorizes people on the basis of clinical conditions associated with HIV infection and CD4 T-cell lymphocyte counts. Three ranges of CD4 lymphocyte counts and the presence of specific HIV-related conditions define a total of nine mutually exclusive categories.

The extensive dysfunction of the immune system caused by the human immunodeficiency viruses 1 (HIV-1) and 2 (HIV-2) is generally progressive, and once an individual manifests an advanced clinical condition, he/she no longer goes back to a previous category even with the improvements that result from treatment.

The three CD4 T-lymphocyte categories are defined as follows:

  • Category 1: greater than or equal to 500 cells/mL

  • Category 2: 200–499 cells/μL

  • Category 3: less than 200 cells/μL

Category A consists of one or more of the conditions listed below in an adolescent or adult (greater than or equal to 13 years) with documented HIV infection. Conditions listed in Categories B and C must not have occurred.

Category A:

  • Asymptomatic HIV infection

  • Persistent generalized lymphadenopathy

  • Acute (primary) HIV infection with accompanying illness or history of acute HIV infection

Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among the conditions listed in clinical Category C and that meet at least one of the following criteria: (a) the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (b) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples of conditions in clinical Category B include but are not limited to the following:

Category B

  • Bacillary angiomatosis

  • Candidiasis, oropharyngeal (thrush)

  • Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

  • Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

  • Constitutional symptoms, such as fever (38.5 °C) or diarrhea lasting for more than 1 month

  • Hairy leukoplakia, oral

  • Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome

  • Idiopathic thrombocytopenic purpura

  • Listeriosis

  • Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

  • Peripheral neuropathy

Category C includes the clinical conditions listed in the AIDS surveillance case definition (below). For classification purposes, once a Category C condition has occurred, the person will remain in Category C.

Category C:

  • Candidiasis of bronchi, trachea, or lungs

  • Candidiasis, esophageal

  • Cervical cancer, invasive

  • Coccidioidomycosis, disseminated or extrapulmonary

  • Cryptococcosis, extrapulmonary

  • Cryptosporidiosis, chronic intestinal (greater than 1 month’s duration)

  • Cytomegalovirus disease (other than liver, spleen, or nodes)

  • Cytomegalovirus retinitis (with loss of vision)

  • Encephalopathy, HIV-related

  • Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis

  • Histoplasmosis, disseminated or extrapulmonary

  • Isosporiasis, chronic intestinal (greater than 1 month's duration)

  • Kaposi sarcoma

  • Lymphoma, Burkitt's (or equivalent term)

  • Lymphoma, immunoblastic (or equivalent term)

  • Lymphoma, primary, of brain

  • Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

  • Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

  • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

  • Pneumocystis carinii pneumonia

  • Pneumonia, recurrent

  • Progressive multifocal leukoencephalopathy

  • Salmonella septicemia, recurrent

  • Toxoplasmosis of brain

  • Wasting syndrome due to HIV

These classifications were extracted from the 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults (Castro et al., 1992).

Hence, all patients with a peripheral neuropathy will be classified as at least B1.

Section snippets

Epidemiology of the peripheral neuropathies

Peripheral neuropathies have been documented since the very early reports of the disease and the isolation of HIV in the human nervous system (Snider et al., 1983, Ho et al., 1985, Levy et al., 1985). In a muscle pathology study performed in 1986, we encountered indirect evidence of motor peripheral neuropathy in 62% of 50 HIV-positive patients (Gabbai et al., 1990).

The prevalence of peripheral neuropathies in HIV-positive individuals is high and is most likely the most common neurological

Clinical presentations

Here, we will deal with the following HIV-related peripheral neuropathies, according to their clinical presentations (Table 29.1):

  • Distal symmetrical polyneuropathy

    • Distal sensory neuropathy

    • Distal symmetric sensory-motor polyneuropathy

    • Immune reconstitution inflammatory syndrome (IRIS)

    • Diffuse infiltrative lymphocytosis syndrome (DILS)

AIDP and CIDP

AIDP and CIDP occurring in HIV-positive patients are clinically and electrophysiologically indistinguishable from those occurring in HIV-negative individuals (Hughes and Cornblath, 2005, Gorson et al., 2010). In an early pathological study (pre-ART), it was found that nerves from patients with CIDP and DSPN showed similar degrees of demyelination and axonal degeneration, but inflammation was more intense in CIDP. Immunohistochemical staining identified the majority of inflammatory cells as T

Mononeuropathies, mononeuropathies multiplex, and cranial neuropathies

Cytomegalovirus was one of the leading causes of mononeuropathies and multiple mononeuropathies in the pre-ART era. It was a serious disease that occurred mainly in the final stages of AIDS; even so, some patients responded to gancyclovir (Said et al., 1991) (Fig. 29.2, Fig. 29.3).

Multiple mononeuropathies associated with HIV disease continue to occur more frequently late in the course of the illness among those who have gone untreated or have developed multidrug resistance. These

Herpes zoster

The incidence of herpes zoster (HZ) was higher in the pre-ART era than it currently is. In a population study of 716 HIV-positive patients from 1994 to 2003, 93 developed 103 episodes of HZ neuropathy. In that study, it was also found that a low baseline CD4 lymphocyte count was the most significant risk factor associated with the development of HZ, and HZ was associated with increased risk for HIV progression but not mortality (Hung et al., 2005).

A cranial neuropathy presenting as an isolated

Autonomic neuropathy

The prevalence of autonomic neuropathy in HIV-infected individuals is not known, but early reports suggest that it was not rare in the pre-ART era. Autonomic neuropathy was more severe in advanced disease than in earlier disease states. Autonomic neuropathy was also more prevalent in concomitant intravenous heroin users (Cohen and Laudenslager, 1989, Freeman et al., 1990, Cohen et al., 1991, Ruttimann et al., 1991, Villa et al., 1992).

Gluck et al. (2000) found evidence of pupillary neuropathy

Lumbosacral polyradiculomyelopathy

In the pre-ART era, lumbosacral polyradiculomyelopathies were relatively common and carried important morbidity. They usually start with back and leg pain that commonly evolves to paraplegia, sphincteric disturbances, and important anesthesia up to the mid-thoracic level. In severe cases, the disease extends to the upper extremities and cranial nerves.

Lumbosacral polyradiculomyelopathy is a clinical syndrome with different etiologies and variable clinical outcome, but the most frequent etiology

Amyotrophic lateral sclerosis-like motor neuropathy

ALS-like syndromes are rare in HIV-positive patients; only two (0.15%) out of 1330 patients with HIV-1 infection associated with neurological manifestations had features of ALS-like syndrome without other manifestations of HIV-1 infection (Nalini et al., 2009). There are no more than 25 cases of ALS or ALS-like disease reported in HIV-seropositive individuals. The first description of ALS-like motor neuropathy was in 1985 when Hoffman et al. (1985) described the isolation of HIV from the plasma

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