A variety of neurologic diseases have been associated with human immunodeficiency virus (HIV) infection either as a direct result of the virus itself (e.g., HIV-associated dementia and HIV-related painful distal polyneuropathy) or as a result of opportunistic infections or neoplasm. HIV-related neuropathies are one of the most common neurologic complications of HIV infection. There are a variety of neuropathies in patients with HIV and can be broadly classified into: (i) distal symmetric polyneuropathy (DSP), (ii) mononeuropathy multiplex, (iii) acute and chronic inflammatory demyelinating polyneuropathies, (iv) lumbosacral polyradiculopathy, (v) diffuse infiltrative lymphocytosis syndrome (DILS), (vi) autonomic neuropathy, mononeuropathies, (vii) herpes zoster radiculitis, and (viii) sensory ganglioneuritis. DSP represents the most common form of neuropathy seen in patients with HIV and affects about 30% of patients and pathologic findings of DSP occurring in almost all patients with advanced immunodeficiency at autopsy. But with highly active antiretroviral treatment (HAART), the incidence of DSP appears to be decreasing compared to the pre-HAART era. But some studies show a substantial increase in the prevalence of DSP and this may be related to an increased longevity of patients and neurotoxic effects of some antiretroviral drugs. Antiretroviral toxic neuropathy (ATN) occurs with the di-deoxnucleoside group of drugs (DDI: didanosine; DDC : zalcitabine) and is thought to be the direct neurotoxic effect of the drugs. Clinically the two forms are indistinguishable and present in a length dependent axonal polyneuropathy. DSP and ATN cause devastating complications and related to poor treatment compliance. The objective of this review is to update the current knowledge in the two main forms of neuropathy in HIV infection and we believe that physicians practicing in the highly HIV prevalent areas (Sub-Saharan Africa and other developing countries) need to look for these complications in their HIV patients and manage them accordingly.
Keywords: Acquired immune deficiency, human immunodeficiency virus, neuropathy.
Human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS) is a global pandemic, with cases reported from virtually every country. By the end of 2006, nearly 40 million children and adults worldwide were living with HIV and/or AIDS, almost two-thirds (63%) of whom are in sub-Saharan Africa; 50% of cases are women. In addition, an estimated 2.5 million children younger than age 15 are living with HIV/AIDS.  According to the Joint United Nations Program on HIV/AIDS (UNAIDS), in 2006 alone there were an estimated 4.3 million new cases of infection worldwide (>14,000 new infections each day) and 3 million deaths from AIDS, making it the fourth leading cause of mortality worldwide.  The 2.1 million AIDS-related deaths in sub-Saharan Africa represent, therefore, 72% of global AIDS deaths. 
Africa’s HIV epidemics are following divergent trends.  There is evidence of diminishing or stable HIV spreads in most east African and west African countries, along with sings of growing number of patients with new infections. Provision of antiretroviral therapy has expanded dramatically in sub-Saharan Africa: more than 1 million people were receiving antiretroviral treatment by June 2006; a tenfold increase since December 2003.  For this reason, clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection. The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasm.
Peripheral neuropathies are the most common neurologic complication in patients with HIV/AIDS with an estimated incidence of nearly one-third of all people with HIV/AIDS. For patients with HIV/AIDS, peripheral neuropathy can be caused by the virus itself, by certain drugs used in the treatment of HIV/AIDS or other complications, or as a result of opportunistic infections (e.g., cytomegalovirus, candidiasis, herpes virus, and tuberculosis).
Neuropathy could also result from other additional associated causes, such as heavy alcohol consumption and vitamin deficiency. For this reason, there are many types of peripheral neuropathies seen in HIV patients; only a few appear to be HIV specific, that is, they are not seen in other populations [Table 1].
There appeared to be a link between the type of neuropathy and the stage of HIV infection. The most common peripheral neuropathy in HIV-infected individuals is HIV-associated distal sensory polyneuropathy (DSP), affecting about 30% of adults and children with AIDS.  HIV-associated sensory neuropathies that are a sequela of HIV are known as DSP, whereas the sensory neuropathies that result from treatment with neurotoxic drugs are known as antiretroviral drug-induced toxic neuropathies (ATN). Sharing similar clinical features, these two forms of HIV sensory neuropathies are difficult to distinguish and the following discussion is mainly on these two forms of HIV-related neuropathies as they are more or less related to the virus itself or its treatment. Sensory neuropathy not only affects the quality of life, but also is frequently under-treated, even by expert HIV providers. Increasingly, the occurrence of HIV-associated sensory neuropathy limits the choice of highly active antiretroviral treatment (HAART) regimens by excluding the use of dideoxynucleosides.
Studies from Africa, where the majority of HIV-infected people are living, have also shown a higher rate of neuropathy. Wong et al. reported that 51% of HIV-positive patients have painful sensory neuropathy and neurologic signs of aberrant nerve function were seen in 38%.  Parry et al. also reported a higher rate of HIV neuropathy from Zimbabwe. The prevalence of peripheral neuropathy was 44%: subclinical neuropathy accounted for 56%, acute inflammatory demyelinating polyneuropathy (AIDP) for 15%, and (DSP) for 22% of cases of neuropathy. 
The involvement of the peripheral nervous system in HIV infection has been one of the most challenging aspects of the AIDS epidemic. Only few studies have examined the HIV-associated neuropathies and nearly nothing is being done in Africa. We have, therefore, summarized the present knowledge of HIV-associated neuropathy and give – whenever possible – special reference to its occurrence in Africa.
While the incidence of HIV-associated DSP is decreasing, the prevalence of DSP in patients with AIDS appears to be rising as a result of prolonged survival rates and use of HAART.  As the degree of immunosuppression increases, the risk of DSP increases and nearly all patients will have evidence of pathologic involvement of the peripheral nerves at autopsy. ,,,, In the pre-HAART era, DSN usually occurred in the setting of advanced immunosuppression. Barohn et al. , for example, explored the relationship between immunologic competence and nerve function, and found out that the mean CD4 count was 113/µL.  In addition to immunosuppression, the level of HIV viremia also correlated with the development of DSPN and the severity of symptoms. ,, In the Multicenter AIDS Cohort Study, the risk of DSP was increased 2.3-fold in patients with an HIV RNA level >10,000 copies/mL at baseline.  Other factors associated with DSPN include aging, host factors such as diabetes, the nadir CD4 count, nutritional deficiencies, mitochondrial polymorphisms, and the use of didanosine, stavudine, and nevirapine. ,,,,
When we see the effect of HAART on natural history of DSP, the incidence of HIV-associated DSP appears to have decreased compared to pre-HAART cohorts, suggesting that effective suppression of HIV itself may have a beneficial effect on peripheral nerve function. ,,,, As an example, Lichtenstein et al., in a large cohort of 2515 HIV-infected patients showed that certain drugs (didanosine, stavudine, nevirapine, and certain protease inhibitors) were associated with the development of DSP in the first year of use.  However, patients who did not develop DSP in the first year of HAART had a decreased risk of developing this complication with continued drug exposure. These data suggest that immune restoration, or viral suppression of HIV, led to a decreased risk of DSP.
Other studies suggest an increase in prevalence of DSP; this may be related to increased longevity of patients in the post-HAART era combined with continued exposure to antiretroviral therapies with intrinsic mitochondrial toxicity. ,,,, Reports of the incidence of sensory neuropathy have shown substantially higher rates of sensory neuropathy with double dideoxynucleoside regimens (i.e., ddI/d4T) particularly when used in combination with hydroxyurea.  Thus, with AZT : azidothymidin – containing regimens, the incidence of sensory neuropathy is approximately 7%, with d4T 8%, while the incidence rises to 20% with ddI (enteric-coated) + d4T, 21% with ddI + d4T, and 26% with ddI + d4T + hydroxyurea.
These higher incidence rates with double dideoxynucleosides, and particularly with hydroxyurea-containing regimens, underscore the need for the careful screening of individuals for pre-existing neuropathy prior to initiation of these regimens, and regular monitoring of neuropathic symptoms.
The pathology of HIV sensory neuropathy and toxic sensory neuropathy involves loss of distal sensory nerve fibers (i.e., axonal degeneration) in contrast to inflammatory demyelinating peripheral neuropathies, such as Guillain-Barre syndrome, which affect only the myelin sheath. There is prominent macrophage activation, both within the dorsal root ganglia and in a multifocal pattern along the peripheral nerve. Interestingly, although about 30% of individuals with HIV/AIDS will develop the symptoms of sensory neuropathy, axonal degeneration is almost universal at autopsy.
There is a preferential loss of small, unmyelinated nerve fibers in HIV sensory neuropathy and evidence of neuronal and axonal degeneration, both within the dorsal root ganglia (where the cell bodies of the sensory neurons reside) and along the peripherally directed axons. Punch skin biopsy has been shown to be a sensitive and reliable technique to demonstrate damage within small unmyelinated nerve fibers terminating within the epidermis. Typically reduced density and nerve fiber swellings are noted in both HIV-associated sensory neuropathy and nucleoside toxic sensory neuropathies.
Keswani and colleagues showed that HIV-1 envelope protein gp120 could induce indirect neuronal injury through the Schwann cells.  When dorsal root ganglion (DRG) sensory neurons and Schwann cells, in a co-culture paradigm, were exposed to chemokine receptor CXCR4, tropic gp120, or (monogamous CXCR4 ligand stromal-derived factor) (SDF-1[alpha]), there was an up-regulation of regulated upon activation, normal T cell expressed and secreted (RANTES) by the Schwann cells through the chemokine receptor CXCR4. Schwann cell secreted RANTES bound to the chemokine receptor CCR5 on the neurons and induced up-regulation of tumor necrosis factor-[alpha] (TNF-[alpha]) in neurons. This up-regulation of TNF-[alpha] resulted in a classical apoptotic neuronal death in sensory neurons. Axonal degeneration was partially blocked by a specific caspase inhibitor, but it was not clear if this effect was a direct action on the mechanism underlying axonal degeneration or it was an indirect effect due to the apoptotic death of the neuronal body.
For many years, antiretroviral toxic neuropathy (ATN) has been attributed to mitochondrial toxicity due to inhibition of the mitochondrial DNA polymerase-[gamma]. Several lines of evidence, however, argue against this as the sole mechanism of NRTI: nucleoside reverse transcriptase inhibitor neurotoxicity. For example, zidovudine is a potent inhibitor of mitochondrial DNA polymerase-[gamma], but does not cause neuropathy in HIV patients. Second, exposure to NRTIs correlates with mitochondrial DNA content in the subcutaneous fat biopsies but not to the incidence or severity of neuropathy.  In their in vitro study, Keswani and colleagues showed that NRTIs that cause neuropathy in HIV patients cause direct mitochondrial toxicity through inhibition of the mitochondrial transmembrane potential differential.  This leads to energy failure and subsequent axonal degeneration and nonapoptotic cell death in DRG of sensory neurons. This effect is not preventable by a specific caspase inhibitor, suggesting that the classical apoptotic pathway is not involved in NRTI neurotoxicity.
The clinical features of HIV sensory neuropathy and dideoxynucleoside toxicity overlap. Both present as a length-dependent sensory neuropathy (i.e., feet affected first) manifested by pain in the soles of the feet in over 60% of individuals (“burning feet”) and paresthesia in 40%. The spread of sensory symptoms usually occurs over weeks to months and usually occurs symmetrically in the lower extremities. Weakness is almost never a presenting symptom. Neurologic examination shows abnormal sensory thresholds in up to 85% of individuals and reduced or absent ankle reflexes in up to 96%. While joint position remains relatively normal, vibratory thresholds are increased in the feet. Pain and temperature sensations are reduced in a stocking and glove distribution. The presence of brisk knee reflexes in patients with sensory loss raises the possibility of coexistent myelopathy, while the presence of proximal weakness or diffuse areflexia should prompt consideration of acquired inflammatory demyelinating polyradiculoneuropathy, such as Guillain-Barre syndrome. Motor findings are uncommon, with only a third of patients having distal weakness and usually restricted to intrinsic foot muscles.
In practical terms, the definition of dideoxynucleoside toxic sensory neuropathy is made when the neuropathic symptoms develop while an individual is on a dideoxynucleoside-containing regimen. About half of all individuals presenting with sensory neuropathy in the context of HIV/AIDS will have other contributing factors, mostly dideoxynucleoside toxicity or other systemic medical conditions, including diabetes mellitus and alcohol use. 
The diagnosis of peripheral neuropathy syndromes in HIV-infected patients is based mainly upon the clinical picture and physical examination. Laboratory evaluation in DSP has been relatively unrevealing. Appropriate blood studies are needed to exclude other potential causes of neuropathy including diabetes mellitus, vitamin deficiencies, hereditary factors, alcoholism, and other associated infectious agents such as CMV and Lyme disease [Table 2]. Although these laboratory tests are considered routine in the evaluation of DSP, they are usually unremarkable in HIV-related or drug-induced polyneuropathy.
In complex situations, cerebrospinal fluid (CSF) analysis, electrodiagnostic studies and sural nerve biopsy may be helpful. Spinal fluid is mostly acellular, but protein may be slightly elevated in a small proportion of patients. The presence of CSF pleocytosis should raise the possibility of concurrent CNS infection. The electrophysiological findings show predominantly axonal neuropathy. Both sensory and motor axons are involved.
Treatment of human immunodeficiencey virus-associated and dideoxynucleoside-associated toxic sensory neuropathy
Treatment options for HIV-related and drug-induced DSP are limited and often challenging to practicing physicians particularly in the prevailing situation in the developing world where access to ART is limited and changing regimens may be difficult when one develops side effects like neuropathy from the use of toxic drugs. In such situations, it is recommended to continue with the drugs if patient is responding immunologically and clinically.
Unfortunately, there are no agreed upon interventions for the treatment of DSP and one should take in to consideration the following:
The effect of HAART on the severity of DSP is unclear, although there is some evidence showing improved quantitative sensory measures in patients responding to HAART. If a potentially neurotoxic drug is being used, such as stavudine (d4T), or didanosine (ddI), it should be discontinued whenever possible. There may be a “coasting phenomenon” where the neuropathy worsens for 1-6 weeks following reduction in the dose of a nucleoside analogue. ,,, Gradual improvement then occurs; the time to recovery depends upon the dose and varies from 3 to 19 weeks.
Since dideoxynucleoside analogs are thought to cause peripheral neuropathy through the disruption of mitochondrial metabolism, there has been interest in using amino acid supplements needed for oxidative pathways.
The current treatment of DSP is primarily symptomatic. There is considerable variability in the therapeutic strategies in painful DSP [Table 3]. The guidelines of the World Health Organization “analgesic ladder” serve as a helpful approach to painful DSP. The guidelines suggest starting with nonopioid analgesics, such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory agents in patients with mild pain. Adjuvant agents such as antidepressants or anticonvulsants may provide added benefit. Increasing levels of pain call for a mild opioid combination (e.g., paracetamol and codeine) with an adjuvant. For severe pain, a strong opioid or long-lasting opioid agonist (e.g., methadone, long-acting morphine, or fentanyl) may be considered.
Distal symmetric polyneuropathy and acute ATN are common forms of neuropathy seen in patients with HIV infection in sub-Saharan African countries. DSP occurs in all stages of HIV infection, but particularly in the advanced stages, and is present in about 30% of patients. Antiretroviral combination using D4T + ddI can enhance this phenomenon in a context of nutritional deficiencies and frequent infections. There does appear to be a significant association between plasma HIV-1 RNA and the severity of neuropathy. This fits with prevailing theories that advanced HIV disease is associated with immune dysregulation and macrophage activation within the peripheral nervous system, leading to neuropathic damage. We have to be aware of these peripheral nerve symptoms in all HIV-infected patients since it substantially affects our drug selection and treatment compliance in the HIV population. Therefore, timely diagnosis and rational therapeutic intervention may result in the arrest and reversal of neuropathic deficit, relief in neuropathic pain, and improvement in disability and quality of life in HIV-1 as well as AIDS patients.
[Table 1], [Table 2], [Table 3]