HIV-Associated Distal Painful Sensorimotor Polyneuropathy

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Overview

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.

Pathophysiology

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]

Epidemiology

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]

 

Clinical Presentation

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

Physical findings include:

Differential Diagnosis

The differential diagnosis of distal painful sensorimotor polyneuropathy includes:

Other problems to be considered include the following:

Diagnostic Testing

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:

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:

Histologic Findings

Histologic findings include the following:

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

Causal and Symptomatic Treatments

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]

What is HIV-associated distal painful sensorimotor polyneuropathy?What is the pathophysiology of HIV-associated distal painful sensorimotor polyneuropathy?What is the prevalence of HIV-associated distal painful sensorimotor polyneuropathy?What are the signs and symptoms of HIV-associated distal painful sensorimotor polyneuropathy?Which physical findings are characteristic of HIV-associated distal painful sensorimotor polyneuropathy?Which conditions are included in the differential diagnoses of HIV-associated distal painful sensorimotor polyneuropathy?What is the diagnostic testing for HIV-associated distal painful sensorimotor polyneuropathy?How is HIV-associated distal painful sensorimotor polyneuropathy diagnosed?Which findings on EMG are characteristic of HIV-associated distal painful sensorimotor polyneuropathy?Which histologic findings are characteristic of HIV-associated distal painful sensorimotor polyneuropathy?How is HIV-associated distal painful sensorimotor polyneuropathy treated?What is the efficacy of anticonvulsants in the treatment of HIV-associated distal painful sensorimotor polyneuropathy?What is the efficacy of tricyclic antidepressants (TCAs) in the treatment of HIV-associated distal painful sensorimotor polyneuropathy?What is the efficacy of topical anesthetics in the treatment of HIV-associated distal painful sensorimotor polyneuropathy?What is the role of alternative therapies in the treatment of HIV-associated distal painful sensorimotor polyneuropathy?

Author

Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, National MS Society Multiple Sclerosis Center and Hereditary Neuropathy Foundation Center of Excellence, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Erik Z Krause, DO, Resident Physician, Department of Neurology, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Nothing to disclose.

Chief Editor

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM, Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health

Disclosure: Nothing to disclose.

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