HIV-Associated Distal Painful Sensorimotor Polyneuropathy 

A distal painful sensorimotor polyneuropathy is the most common type of HIV-1 associated peripheral neuropathy.^{[1, 2, 3]} It usually develops during late HIV infection; it is rare in otherwise healthy seropositive patients. HIV-associated distal painful neuropathy is a progressive disease unless secondary causes, such as neurotoxic drugs or vitamin deficiencies, can be eliminated.

More than one pathophysiologic mechanism likely exists. HIV may act directly by infecting dorsal root ganglion neurons. These neurons may also be injured by locally infiltrating activated macrophages that secrete neurotoxic cytokines or other metabolites.

Several studies from the highly active antiretroviral therapy (HAART) era show a lack of association between distal painful sensorimotor polyneuropathy and the degree of immunosuppression, including low CD4 counts and high HIV viral load.

Distal epidermal denervation has been shown to be associated with distal painful sensorimotor polyneuropathy.^[4] Other factors may be involved, including nutritional and vitamin deficiencies (eg, vitamin B-12).^[5]

Since the advent of HAART (eg, didanosine, stavudine, zalcitabine, and, rarely, lamivudine), antiretroviral toxic neuropathy (ATN) has been recognized, which occurs in up to 60% of patients and likely results from mitochondrial dysfunction.

Distal painful sensorimotor polyneuropathy is clinically apparent in 10-30% of patients with AIDS. Subclinical forms occur in many more patients who are HIV positive. It is found at autopsy in almost 100% of patients with AIDS. The prevalence of distal painful sensorimotor polyneuropathy continues to rise because of increased life expectancy in the HAART era.^{[6, 7]}

Distal painful sensorimotor polyneuropathy is more prevalent in males than in females and more common in persons older than 50 years.^[8] It rarely occurs in children.

Patients with distal painful sensorimotor polyneuropathy can be asymptomatic, or they may present with the following:

• Painful feet (including soles) that are sensitive to light touch
• Distal numbness
• Distal weakness in the more advanced stage
• Autonomic symptoms referable to urogenital and intestinal function

The physical examination should show the following:

• Panmodal distal sensory loss
• Mild distal weakness
• Hyporeflexia or areflexia
• Symmetric presentation
• Autonomic signs (often can be elicited by careful evaluation)

The differential diagnosis of distal painful sensorimotor polyneuropathy includes the following:

• Acute Inflammatory Demyelinating Polyradiculoneuropathy
• Chronic Inflammatory Demyelinating Polyradiculoneuropathy
• Diabetic Neuropathy
• HIV-Associated Multiple Mononeuropathies
• Nutritional Neuropathy
• Toxic Neuropathy
• Uremic Neuropathy
• Vitamin B-12 Associated Neurological Diseases

Other problems to be considered include the following:

• Other HIV-related neuropathies (differentiated by HIV-associated distal painful sensory neuropathy's slower progression)
• Alcoholic neuropathy
• Metabolic neuropathy
• Paraneoplastic neuropathy
• Paraneoplastic sensory neuropathy
• Paraproteinemic neuropathy
• Cytomegalovirus (CMV)–related mononeuropathy
• Human T-cell leukemia virus type 2 (HTLV-2)–related neuropathy
• Vasculitic neuropathy

Distal painful sensorimotor polyneuropathy is a diagnosis of exclusion. All other secondary causes of distal sensorimotor polyneuropathy must be excluded. Skin punch biopsy for assessment of epidermal nerve fiber density is valuable for diagnosis and prediction of future neuropathy.^[9]

Consider the following in the peripheral neuropathy workup, depending on the specific clinical situation:

• HIV RNA viral load
• Complete blood cell count
• Fasting blood sugar and 2-hour glucose tolerance test
• Hemoglobin A1C
• Antinuclear antibody screen
• Extractable nuclear antibody screen
• Erythrocyte sedimentation rate
• Renal function test
• Paraproteinemia workup
• Angiotensin-converting enzyme level
• Lyme serology
• Thyroid function tests
• Hepatitis workup
• Vitamin B-12 and folic acid levels

In patients with B-12 levels below 350 pg/mL, homocysteine and methylmalonic acid levels are more sensitive indicators of a deficiency. Intrinsic factor or parietal cell antibody testing and a Schilling test may be indicated.

Cerebrospinal fluid analysis may show mildly elevated protein or mild pleocytosis.

Electromyography/nerve conduction studies may indicate the following:

• Symmetric features
• Sensory findings predominant over motor abnormalities
• Greater involvement of lower extremities than upper extremities
• Distal axonal degeneration
• Significantly reduced sensory and motor amplitudes
• Normal to mildly reduced sensory and motor conduction velocities
• Normal to mildly increased sensory and motor distal latencies

Histologic findings include the following:

• Axonal degeneration
• Some demyelination
• Prominent perivascular infiltration by T-lymphocytes and macrophages
• Mild loss of dorsal root ganglion neurons, some found to harbor HIV by in situ polymerase chain reaction (PCR)
• Occasional gracile tract degeneration
• Reduced mtDNA in subcutaneous fat
• Reduced HIV-RNA viral load

The intraepidermal nerve fiber density correlates inversely with the likelihood of neuropathic symptoms.

Treatment options fall into 2 groups: causal and symptomatic. In causal treatment, avoid neurotoxic medications, if possible. Carnitine supplementation may be effective in patients with antiretroviral toxic neuropathy.^[10] Correct vitamin B-12 and folate deficiency. Consider thiamine replacement if the patient is malnourished.

Treatment of HIV-associated distal painful sensorimotor polyneuropathy currently focuses on management of neuropathic pain. Five main classes of agents are used: anticonvulsants, antidepressants, analgesics, topical treatments, and alternative therapies.

Unfortunately, evidence supporting the use of these agents in HIV-related cases is limited. With several of these agents, controlled studies have found them to be well tolerated but not significantly more effective than placebo.

Anticonvulsants

Gabapentin was found to be more effective than placebo in reducing pain and sleep interference in patients with painful HIV-associated sensory neuropathies.^[11] Gabapentin is well tolerated, with a wide dose range. Drug levels are not available, indicated, or meaningful.

Lamotrigine was well tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy.^[12] It was not significantly better than placebo in patients not receiving neurotoxic antiretroviral therapy.

Pregabalin and duloxetine have shown success in diabetic neuropathy. In a study by Simpson et al, however, pregabalin did not show a statistically significant improvement in pain compared with placebo for painful HIV-associated neuropathy.^[13]

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are widely used for painful paresthesias. Nevertheless, 2 older randomized, controlled trials found that amitriptyline was not significantly more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.^[14]

While dosages of various TCAs are similar, drugs in this category vary in their sedative properties. Amitriptyline can be used if the patient suffers from insomnia, while nortriptyline and desipramine are better choices when sedation becomes a problem.

Topical anesthetics

These agents are used to induce localized analgesia. Capsaicin and transdermal lidocaine have been used. A controlled trial of a high-concentration capsaicin dermal patch found that a single application was safe and provided at least 12 weeks of pain reduction; mean pain reduction was 22.8% during weeks 2-12, as compared with a 10.7% reduction for controls.^[15] A randomized controlled trial of 5% lidocaine gel found that it was well tolerated but no more effective than placebo.^[16]

Alternative therapies

In a phase II, double-blind, placebo-controlled, crossover trial by Ellis et al, smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain from HIV-associated distal painful sensorimotor polyneuropathy.^[17] Regulatory concerns limit the utility of this approach.