Understanding and Managing Peripheral Neuropathy

Winter/Spring 2010

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Understanding and Managing Peripheral Neuropathy
Peripheral neuropathy is the most common neurological disorder in people with HIV infection. It can be a major source of pain and discomfort and a limiting factor in antiretroviral treatment. Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the overall incidence of neurological complications of HIV -- such as HIV-associated dementia and central nervous system opportunistic infections -- has decreased; however, rates of peripheral nervous system complications remain high.

There are numerous current treatment options for peripheral neuropathy and many new candidates under investigation. Appropriate treatment can improve functioning and quality of life for individuals with this common condition.

A Snapshot of the Nervous System

The nervous system enables humans to process and respond to external and internal information. It is comprised of two major components: the central nervous system (CNS) and the peripheral nervous system (PNS).


The CNS includes the brain and spinal cord, which are both enclosed in bone (the skull and the vertebrae) and surrounded by cerebrospinal fluid (CSF). The PNS consists of spinal nerves (originating from the spinal cord) and cranial nerves (originating from the brain), as well as ganglia, which are groups of nerve cells located outside of the CNS. Spinal nerves have a motor nerve root and sensory nerve root, which meet to form a single nerve.

The PNS transmits information to the CNS through afferent nerves, which primarily pass along sensory information, and from the CNS through efferent nerves, which primarily deliver motor commands (for example, the command to contract a muscle). There are more than 100 billion nerve cells in the PNS.

Functionally, the PNS is organized into two divisions: the somatic nervous system and the autonomic nervous system. The somatic nervous system controls receipt of sensory signals and voluntary movements. The autonomic nervous system controls internal bodily functions that do not require conscious effort, such as breathing and the contraction of the heart muscle.

Nerve cells, or neurons, have a large cell body and an axon that extends from the cell body to send signals to other nerve cells. Branches called dendrites receive signals from other neurons. Some axons are surrounded by cells containing myelin, a soft, fatty material that forms a protective sheath. The myelin sheath serves as insulation so that signals can be transmitted more quickly through the neurons.

Clinical Features of Peripheral Neuropathy

Peripheral neuropathy is one of many neurological conditions that can affect people with HIV, and it is the most common peripheral nervous system complication associated with HIV disease and antiretroviral treatment. (For more on CNS manifestations, see "HIV and the Brain," BETA, Summer/Fall 2009.)

The type of peripheral neuropathy most often seen in HIV positive people -- more specifically called distal symmetric polyneuropathy (DSPN) -- is characterized by pain and paresthesias (abnormal sensations such as numbness, tingling, pricking, burning, or creeping). Symptoms typically start in the toes and progress over a period of weeks to months, slowly moving upward to involve the lower limbs up to the knees. The upper extremities are rarely involved at early stages. As its name suggests, the condition typically affects both sides of the body.

Other manifestations of DSPN include allodynia (a pain response to a normally non-painful stimulus like gentle touch), severe burning pain, or a "pins and needles" sensation. The pain associated with DSPN can be mild to severe and even debilitating, and may interfere with walking and other activities of daily living.

Development of DSPN

Two types of DSPN are recognized in the context of HIV disease: DSPN related to HIV infection itself and DSPN related to antiretroviral therapy. In some individuals, both HIV itself and antiretroviral drugs play a role.

HIV-related and treatment-related DSPN are impossible to distinguish clinically; however, DSPN associated with use of the "d-drugs" or dideoxynucleosides -- ddI (didanosine; Videx), d4T (stavudine; Zerit), and ddC (zalcitabine; Hivid, withdrawn from the U.S. market in 2005) -- usually occurs within the first year of treatment. If an individual tolerates early exposure to these agents, it is unlikely that d-drug-related DSPN will develop with prolonged use.

DSPN is the result of damage to axons or loss of their protective myelin sheaths (known as demyelination), but HIV does not directly infect nerve cells. Instead, HIV infection leads to immune activation and production of inflammatory chemicals called cytokines that cause axon damage. In addition, the gp120 envelope protein of the virus causes neuron apoptosis (cell death). Slowly, axons degenerate and are lost, starting with the nerve cells farthest from the CNS.

DPSN caused by antiretroviral drugs is thought to be due to impaired mitochondrial function. Mitochondria are structures within a cell that produce energy and are involved in other crucial cell functions. Different nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are associated with varying degrees of mitochondrial toxicity, with ddC causing the most damage, followed by d4T, ddI, and AZT (zidovudine; Retrovir). The remaining drugs in this class -- 3TC (lamivudine; Epivir), emtricitabine (Emtriva), abacavir (Ziagen), and tenofovir (Viread) -- are less likely to interfere with mitochondrial function.

Other types of antiretroviral drugs, including non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, and entry inhibitors, are less likely to cause mitochondrial toxicity.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.

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