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, 4]} 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 co-existant causes, such as neurotoxic drugs or vitamin deficiencies, can be eliminated. ^[5] HIV-associated distal sensorimotor polyneuropathy is the most common neurologic complication of HIV infection. ^{[6, 7]} It must be distinguished from neuropathy associated with neurotoxic anti-retroviral agents.

Small fiber neuropathy typically involves distal degeneration of small or unmyelinated nerve fibers. The pattern of neuropathy is different for polyneuropathy caused by direct HIV infection, which affects all fibers, compared with that induced by antiretroviral treatment, which affects small fibers. ^[8]

Autonomic dysfunction is common in HIV infection and is associated with distal symmetric polyneuropathy. ^[9]

More than one pathophysiologic mechanism likely exists. HIV may act directly by infecting dorsal root ganglion neurons. However, there may also be an indirect mechanism where neurons are injured by infiltrating macrophages, which release proinflammatory chemokines and free radicals. ^[10]

Since the advent of HAART, several studies have shown a lack of association between distal painful sensorimotor polyneuropathy and the degree of immunosuppression, including CD4 counts and viral load. Several HAART medications may be toxic to mitochondria by inhibiting mitochondrial DNA polymerase. ^{[11, 12, 13]}  The latest 2013 WHO guidelines have sought to phase out d4T therapy in underdeveloped countries as first-line treatment. 

Distal epidermal denervation has been shown to be associated with distal painful sensorimotor polyneuropathy. ^[14] Other factors may be involved, including nutritional and vitamin deficiencies (eg, vitamin B-12). ^[15]

In the Goullee 2016 study, HIV-associated sensory neuropathy was found to be the most common neurological condition associated with HIV, affecting up to 50% of HIV individuals. A  study by Smyth showed the prevalence of HIV-SN was 42% among patients at an outpatient clinic in Australia; 92% of patients with sensory neuropathy were on ARVs. In a predominately female HIV-1 population (69.8%) in Cameroon the prevalence of HIV-SN was 96.9%. In this outpatient clinic 83.9% of patients were diagnosed with sensory neuropathy prior to initiating highly active antiretroviral therapy (HAART) while 16.3% developed symptoms while on HAART (Luma). In a cohort of treatment-naïve patients, 22.6% had PN without pain, whereas 4.6% had symptomatic painful neuropathy; in the majority, PN persisted despite effective control of HIV with ARV therapy (Evans). The risk of developing PN is higher for patients with advanced HIV infection (Evans). The annual incidence of DSP among patients with CD4 counts of < 200 cells/µL is 7%. In two studies from the 1980s, 30% of patients hospitalized with advanced AIDS had DSP in the absence of ARV therapy (McArthur). Although a risk factor, as discussed above, Smyth cites studies that suggest that in the post-cART-era, neither CD4 count nor viral load correlate with the incidence of PN. ^[16]  Other risk factors include diabetes, height, statin use, d4T exposure, and substance abuse. ^{[17, 18, 19, 20, 21, 22, 23]}

 

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

Physical findings include:

• 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:

• 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

• Alcoholic neuropathy

• Metabolic neuropathy

• Paraneoplastic neuropathies

• Paraproteinemic neuropathy

• Cytomegalovirus (CMV)–related mononeuropathies

• Human T-cell leukemia virus type 2 (HTLV-2)–related neuropathy

• Vasculitic neuropathy

Distal painful sensorimotor polyneuropathy is a diagnosis of exclusion. Skin punch biopsy for epidermal nerve fiber density is a valuable tool. ^[24] Scales have been developed to measure the degree of neuropathy. Total neuropathy score (TNS) uses the neurologic exam and nerve conductions studies. The brief peripheral neuropathy screen (BPNS) is based on lower extremity symptoms, ankle reflexes, and vibration sense. ^[14]  A modified TNS replaces nerve conduction testing with autonomic indices. ^[25]

Consider the following in the workup:

• 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 may be indicated.

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

Electromyography/nerve conduction features include:

• 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

• Variable 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.

There are no FDA-approved treatments. Treatment options fall into 2 groups: causal and symptomatic. In causal treatment, avoid neurotoxic medications, if possible. Carnitine supplementation may be effective in antiretroviral toxic neuropathy. ^[26] 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 pain management. As in other painful neuropathies drugs from several classes can be used alone or in combination.

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. ^[27]  It is usually 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, but not in patients not receiving such drugs. ^[28]

Pregabalin and duloxetine have shown success in diabetic neuropathy. In a study by Simpson et al, however, pregabalin did not significantly improve pain compared with placebo for painful HIV-associated neuropathy. ^[29]

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are widely used for painful paresthesias. Nevertheless, amitriptyline was not significantly more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy. ^[30]

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

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. ^[31]

Repeated NGX-4010, a capsaicin 8% dermal patch, treatments were generally well tolerated and resulted in consistent reductions in HIV distal sensory polyneuropathy–associated pain. ^[32]  In patients that respond to the high-dose patch, relief begins within days and typically lasts on average for 5 months. ^[33]

A randomized controlled trial of 5% lidocaine gel found that it was well tolerated but no more effective than placebo. ^[34]

Alternative therapies

In a phase II, double-blind, placebo-controlled, crossover trial by Ellis et al, adjunctive smoked cannabis was generally well tolerated and effective for refractory pain from HIV-associated distal painful sensorimotor polyneuropathy. ^[35] Regulatory concerns limit the utility of this approach in many parts of the world.

Brief hypnosis may have a role in painful HIV distal sensory polyneuropathy. ^[36]

Acupuncture and moxibustion reduced symptoms in a small sample. ^[20]  Lower extremity night splints also reduce pain. ^{[37, 38]}