Neuropathy means damage to the nerves. The nervous system consists of the central nervous system (CNS), which is comprised of the brain and the spinal cord, and the peripheral nervous system (PNS), which consists of the nerves connecting the CNS to the organs and muscles.

Damage to the nerves in the PNS is termed peripheral neuropathy. As this normally affects the nerves that control the senses, such as touch and pain, it if often termed 'sensory neuropathy'. However, the PNS includes the autonomic nervous system which controls body functions such as blood flow to internal organs, emptying of the stomach and bladder. Damage to these nerves is called autonomic neuropathy.

Epidemiology of neuropathy in HIV

Studies in people with symptomatic HIV infection have reported that about a third develop peripheral neuropathy. A recent study has shown that 51% of untreated HIV-positive patients in Uganda have peripheral neuropathy, while another study found that each year 8% of people with a CD4 count below 100 cells/mm³ developed peripheral neuropathy. About a third of adults and children with AIDS experience peripheral neuropathy at some point, although children may experience less severe symptoms.

Peripheral neuropathy is more common among injecting drug users (IDUs) than in the general population. Consequently HIV-infected IDUs may be more likely to experience neuropathy, particularly if they are taking nucleoside analogue reverse transcriptase inhibitor (NRTI), since these drugs can cause peripheral neuropathy as a side-effect (Berger 1999).

In the era of antiretroviral therapy, people with certain risk factors who are taking anti-HIV therapy may be at greater risk of peripheral neuropathy. Risk factors include:

• Having a CD4 cell count below 100 cells/mm³.

• A history of an AIDS-defining condition.

• A history of peripheral neuropathy.

• High alcohol consumption.

• Use of other neurotoxic drugs.

• Nutritional deficiencies.

Causes

People with HIV can experience neuropathy due to the direct effects of HIV on the nervous system, at any stage of infection, or because of opportunistic infections and tumours which affect the nervous system. Autonomic neuropathy in particular may be a direct effect of HIV (Neild 1998). Neuropathy can also be caused by prescription drugs including some anti-HIV drugs, recreational drugs and alcoholism. Neuropathy is a recognised complication of diabetes, but it is not in itself an AIDS-defining condition.

Neuropathy is a common side-effect of the anti-HIV drugs ddI (didanosine, Videx / VidexEC), d4T (stavudine, Zerit) and ddC (zalcitabine, Hivid). It is not associated with the other NRTIs, nor with protease inhibitors or non-nucleoside reverse transcriptase inhibitors. The addition of hydroxycarbamide (Hydrea) to ddI and d4T may enhance the antiviral effectiveness of these drugs and increase the risk of peripheral neuropathy. Recently, NRTI-related neuropathy has been linked to other class-specific side-effects thought to be caused by damaged to the mitochondria in human cells (Brew 2001; Dalaskas 2001; Rabing Christensen 2004). See Lactic acidosis in Symptoms and illnesses: A to Z of illnesses for further details.

Drugs used to treat many HIV-related conditions and opportunistic illnesses may also cause neuropathy including isoniazid, vincristine (Oncovin), lithium carbonate (Camolit / Liskonum / Priadel), dapsone, metronidazole (Flagyl / Flagyl S / Metrolyl), pyridoxine (vitamin B₆), thalidomide, cytomegalovirus infection and syphilis. Other possible causes of these symptoms include alcohol and some recreational drugs such as heroin, cocaine, or amphetamines.

It seems that these different causes of neuropathy can interact. People with mild neuropathy symptoms often find that they intensify after they start taking treatments such as ddI.

Neuropathy has been associated with a deficiency of the B vitamins, especially vitamin B₁₂.

Factors associated with the development of peripheral neuropathy in a large cohort of HIV-infected patients include older age, diabetes and white race. The risk of peripheral neuropathy is elevated associated with the first year of treatment with drugs such as ddI, but long-term exposure to anti-HIV drugs reduces the risk (Lichtenstein 2003).

Symptoms

The major symptom of neuropathy is pain, which can range from tingling discomfort through to burning sensations and a super-sensitivity to touch. This extreme sensitivity can be so severe that just wearing shoes or socks or lying under bedclothes can be unbearable. These symptoms are usually symmetrical, affecting both sides of the body equally.

Symptoms often start at the soles of the feet and gradually get higher. Many people only complain when the symptoms reach the ankles. Rarely, people experience similar symptoms in their fingers and hands.

The symptoms of autonomic neuropathy can include dizziness, diarrhoea and sexual impotence.

Diagnosis

Peripheral neuropathy can be diagnosed on the basis of the symptoms, especially abnormal sensations in the feet and reduced or absent ankle reflexes, and the results of standard neurological tests. Electromyography (EMG), in which the electrical activity of a muscle is measured through electrodes, and nerve conduction studies may also be used to detect nerve problems.

Testing lactate levels in the blood has been proposed a way of determining whether neuropathy is caused by HIV itself or by the nucleoside class of drugs (Brew 2001). High lactate has been associated with NRTI-mediated neuropathy.

Standard treatment

There are a number of treatments which have some effectiveness against neuropathy.

If the neuropathy is caused by a drug such as ddI, the symptoms usually occur after a few weeks on the drug. Depending on the severity of the neuropathy and other treatments available, a person experiencing neuropathy may be advised to stop or to reduce the dosage of the offending drug immediately. If a person continues on the drug, nerve damage may worsen and become irreversible. Symptoms may continue for a few weeks even after the treatment has been discontinued, and then gradually abate. People who stop taking drug therapies because of neuropathy often find that they can later resume treatment at a lower dose without problems.

The main purpose of treating neuropathy is to relieve symptoms. In mild cases where the symptoms are not affecting daily life, standard painkillers such as ibuprofen may be all that is necessary.

If the symptoms are starting to be disruptive, tricyclic antidepressants such as amitriptyline, nortriptyline (Allegron), doxepin (Sinequan) and desipramine may help, starting at low doses. These drugs can take a couple of weeks to show any effects, and may cause side-effects of dry mouth, difficulty urinating, high blood pressure and drowsiness. These should be used with caution in people with dementia, as they can cause confusion and hallucinations.

People with severe symptoms may require stronger pain killers such as methadone or injections of fentanyl (Actiq / Durogesic).

The anti-convulsants phenytoin (Epinutin) and carbamazepine (Tegretol) used to treat epilepsy can be useful, especially if the pain is coming in brief bursts. A small trial of an anti-convulsant called lamotrigine (Lamictal) commonly used for epilepsy has shown promising results, although it commonly causes rash and occasionally the serious condition Stevens-Johnson syndrome.

Experimental treatments

Many people with HIV report that acupuncture helps relieve the pain of neuropathy. However a trial in the United States found that neither a standardized acupuncture regimen nor amitriptyline were effective at reducing pain due to neuropathy (Shlay 1998) when compared with a placebo.

There is evidence that mexiletine (Mexitil) 10mg/kg per day does not reduce symptoms of neuropathy despite one uncontrolled trial which suggested that mexiletine had benefit. Topical capsaicin (Axsain / Zacin) has also been reported to help. An experimental drug, oxcarbazapine (Trileptal), is available on a named patient basis.

Anecdotal reports from the United States suggest that a non-steroidal anti-inflammatory cream called diclofenac (Voltaren Emulgel) may relieve HIV-related neuropathy. Sold over the counter in Europe, it is generally used to treat aching joints and muscles. A pilot study of a cream containing the drug lidocaine has found that 75% of 27 participants reported moderate or substantial pain relief. Further clinical trials using lidocaine cream may be conducted (Dorfman 1999).

Other experimental drugs include gabapentin (Neurontin), which has been studied as a treatment for neuropathy associated with diabetes, and memantine (Ebixa), a drug approved for treating Parkinsons disease. A small placebo-controlled trial of gabapentin has shown modest effects of the drug in reducing pain and increasing sleep quality in patients with HIV-associated sensory neuropathy, but side-effects can include sleepiness (Hahn 2004).

A drug called flecainide (Tambocor), used to treat cancer-related neuropathic pain, has shown some effectiveness in a trial of HIV-infected people. A trial of a drug called prouridine is being planned in the United States. Researchers are also investigating a drug called nimodipine (Nimotop) for heart-related neurological problems.

Recombinant human nerve growth factor (NGF) has also been used to treat HIV-related and diabetic peripheral neuropathy. One study of 270 people with HIV-associated neuropathy, found that NGF reduced pain and improved sensitivity (McArthur 2000). However, another study found NGF alleviated symptoms of neuropathy but provided no evidence of improvement using neurological measurements (Schifitto 2001). Following disappointing results in treating diabetic neuropathy, Genentech have ceased development of NGF (Apfel 2002).

Administration of low doses of the hormone erythropoietin has been reported to prevent the nerve damage due to HIV infection and treatment with ddC (Keswani 2004).

Role of nutritional supplements

There is considerable interest in L-acetyl carnitine (LAC) as a treatment for neuropathy associated with the NRTIs ddI and d4T. LAC is a natural amino acid that is related to L-carnitine. A recent study has shown that LAC can reverse the loss of nerve fibres from the skin and improve the symptoms of peripheral neuropathy after six months of treatment (Hart 2004). The mechanism of action of this treatment is not known, although it may reduce mitochondrial DNA damage by a direct antioxidant effect, or by promoting the metabolism of fatty acids and glucose.

Research into diabetic neuropathy has suggested that supplements of γ-linolenic acid (GLA), α-lipoic acid, magnesium and chromium may help relieve pain due to neuropathy, although few of these supplements have been tested among people with HIV-related neuropathy. Supplementation with vitamins B₁ and B₂ has also been explored as a way of relieving symptoms of mitochondrial toxicity. There is anecdotal evidence that nutrients may prevent the onset of neuropathy among people with HIV, although this has not been proven in clinical trials (Kaiser 2004).

Vitamin B₁₂ deficiency is a cause of neuropathy and many people with HIV have such a deficiency, which may cause symptoms such as fatigue, poor memory and low levels of red blood cells. A full B complex supplement may be taken to relieve vitamin B₁₂ deficiency although overdosing of vitamin B₆ may cause nerve damage.

Research

Hahn (2004) carried out a multicentre, prospective, randomised, double-blind placebo-controlled study of gabapentin in 26 patients with HIV sensory neuropathy. 15 patients received gabapentin at 400mg per day before being increased to 1200mg per day over 2 weeks. This dose was maintained or increased to 2400mg per day if not beneficial. There was a significant decrease in pain score in the gabapentin group (-44%) but not the placebo group (n = 11; -30%). Sleep interference score decreased in the gabapentin group (-49%) but not the placebo group (-12%). Somnolescence was reported in 80% of the gabapentin group.

Hart (2004) treated 21 patients with NRTI-associated distal symmetric polyneuropathy with 1500mg L-acetyl carnitine (LAC) twice daily. Median baseline CD4 cell count was 286 cells/mm³ and 40% has VLs <400 copies/ml. 8 started the study with grade 1 neuropathy, 10 with grade 2 and 3 with grade 3. Skin biopsies were taken from the leg at baseline and at months 6 and 12 and stained with antibodies for nerve fibres. Innervation of the epidermis increased by 34% and 101% after 6 and 12 months. In the dermis, it increased by 65%, and around the sweat glands by 75% after 6 months. Nerve fibre density approached normal levels after 6 months. The greatest increase was in small sensory nerve fibres, with 100% increase in the epidermis (p = 0.006) and 133% in the dermis (p < 0.001). Neuropathic pain improved in 76% of patients. No side-effects of LAC were experienced.

Lichtenstein (2003) reported on factors associated with risk of peripheral neuropathy from data collected in the HOPS cohort. 490 of 2178 (22.5%) were diagnosed with peripheral neuropathy. In the logistic regression analysis, significant non-drug factors associated with peripheral neuropathy were: age >40 years (odds ratio 1.28; p<0.001); diabetes mellitus (OR 1.71; p=0.012); white race (OR 1.26; p=0.033); lowest ever CD4+ T-cell count <50 cells/mm³; (OR 1.75; p<0.001); lowest ever CD4 count 50-199 cells/mm³ (OR 1.60; p<0.001); viral load >10000 copies/ml (OR 1.57; p<0.001). Use of any three nucleoside analogues or four protease inhibitors was associated with peripheral neuropathy in the short term (OR>1.5), long-term use was protective against peripheral neuropathy ( OR<0.34).

Simpson (2002) studied 236 HIV-infected people with distal neuropathy enrolled in a randomised, placebo-controlled study. Higher viral load was associated with increased pain and reduced sensory ability.

Reliquet (2001) studied the incidence, evolution and predictive factors of peripheral neuropathy among 65 HIV-infected taking d4T or ddI. They had previously taken AZT or ddC. 6/16 sent for systematic electromyographic examination showed nerve conduction abnormalities at baseline, with worsening of abnormalities in 1 person at week 24. In total, 7/59 assessable patients (11.8%) exhibited grade 2-3 neuropathy, with a median time of occurrence of 17 weeks. Peripheral neuropathy resolved rapidly after stopping d4T in all cases. CD4 count, HIV viral load, stage of disease and d4T dose did not predict those who developed neuropathy.

Berger (1999) investigated 212 injecting drug users (IDUs) for peripheral neuropathy (PN). The rate of PN among HIV-negative IDUs was 24.5% (3-4 times the rate of PN in the general population) and 32.1% among HIV-positive IDUs.

Scarpini (1997) treated 16 HIV-infected people with painful distal symmetrical neuropathy with acetyl-L-carnitine (0.5-1 gr per day either intramuscularly or intravenously for 3 weeks). 10 people (62.5%) reported an improvement of symptoms, 5 people (31.25%) had no change and one patient worsened.

Schifitto (2001) reported that symptoms of pain improved in 200 people with HIV-associated distal sensory polyneuropathy (DSP) who were treated with neurotrophin nerve growth factor (NGF) for 48 weeks in an open-label study. However, there was no improvement as measured by neurologic examination, quantitative sensory testing, and epidermal nerve fiber density.

McArthur (2000) reported interim results of ACTG 291, a placebo controlled randomised study of recombinant human nerve growth factor. 270 people were randomised to receive either placebo, 0.1mcg/kg rNGF or 0.3 mcg rNGF subcutaneously three times a week for 18 weeks. Improvement in neuropathy was measured by self-administered questionnaire, neurological exam and interview with investigator. The most significant decline in pain occurred in the 0.3mcg group. The only reported adverse event was injection site pain, most frequent in the higher dose group (48% vs 25%).

Shlay (1998) studied acupuncture and amitriptyline in 250 people with HIV-associated peripheral neuropathy. Participants were randomised to standard acupuncture points for peripheral neuropathy or control points, or to amitriptyline or placebo. The trial lasted 14 weeks and participants kept diaries documenting their level of pain (none, weak, mild, moderate, strong, extreme). There were no significant differences in the quality of life nor the neurological results of the acupuncture group vs the control points groups. However, at 14 weeks, the acupuncture group had slightly higher levels of pain relief although after full analysis this was not statistically significant. Similarly, both the amitriptyline and placebo groups improved and there were no statistical differences between the two groups. The authors speculated that the reasons the acupuncture arm was not superior to the control points could be: first, that the control point did have some beneficial effect and thus was not a true placebo; second, that the standardised approach to acupuncture did not allow practitioners to individualise therapy and thus undermined the effectiveness of the acupuncture.

In an unpublished study, Dejard found that mexiletine (10mg/kg/day by mouth) relieved the symptoms but not the signs of neuropathy in 16 patients with chronic painful diabetic neuropathy. Mexiletine is a congener of lidocaine currently used as a treatment for ventricular arrhythmias.

Kemper (1998) conducted a double-blind placebo controlled trial in which 22 participants received either mexiletine (300mg/day escalating to 600mg/day during the first 2 weeks) or placebo for 6 weeks, and then after a 1 week wash-out 16 crossed over to the other therapy for 6 weeks. There was no significant difference in pain between the arms, assessed by a visual analogue score (VAS) card returned daily by mail. 5 people (31%) receiving mexiletine reported less pain, compared with 5 (31%) placebo recipients. 39% of people on the drug had adverse events which led to dose limitations.

Doob (1991) reported on the use of Peptide T as a palliative treatment for HIV-related peripheral neuropathy. 9/27 patients given Peptide T (10mg by subcutaneous injection every day) had symptoms of peripheral neuropathy. All these patients experienced either complete or subjectively significant resolution of pain as early as two days after treatment initiation. Numbness and sensory loss were unchanged but improvements in two patients with ataxia were noted. Recurrence of pain occurred in two patients whose doses were reduced to 2.5mg every day and alleviated when the dose was increased to 5mg/day. Symptoms returned within one week of cessation of treatment. There were no reported side effects.

Cameron (1999) tested flecainide (an antiarrhythmic agent) as a treatment for neuropathic pain in people with HIV. Flecainide was given twice daily: at 50mg for 4 days, 100mg for 4 days and then 150mg for a week. Improvements in pain, discomfort and mood were reported although results were not statistically significant. All participants developed other AIDS related complications possibly affecting results.

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