HIV-Associated Distal Painful Sensorimotor Polyneuropathy

Updated: Aug 08, 2019

Author: Florian P Thomas, MD, PhD, MA, MS; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM

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]

Presentation

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)

Differential Diagnosis

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

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:

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

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.

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]

Questions & Answers

Overview

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

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Erik Z Krause, DO Assistant Professor, Department of Neurology, Dell Medical School, The University of Texas at Austin; Movement Disorder Specialist, Department of Neurology, Ascension Seton Brain and Spine Institute

Erik Z Krause, DO is a member of the following medical societies: American Academy of Neurology, American Osteopathic Association

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

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

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

Cornblath DR, McArthur JC. Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology. 1988 May. 38(5):794-6. [QxMD MEDLINE Link].
de Gans J, Portegies P. Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg. 1989. 91(3):199-219. [QxMD MEDLINE Link].
Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency virus-associated peripheral neuropathies. Mayo Clin Proc. 2006 Feb. 81(2):213-9. [QxMD MEDLINE Link].
Adem KS, Janakiraman B, Gebremeskel BF, Chala MB, Gelaw AY, Alemu K. Epidemiology and factors associated with peripheral neuropathy among HIV infected patients in Gondar, Ethiopia: A cross-sectional study. PLoS One. 2019. 14 (1):e0211354. [QxMD MEDLINE Link]. [Full Text].
Aziz-Donnelly A, Harrison TB. Update of HIV-Associated Sensory Neuropathies. Curr Treat Options Neurol. 2017 Aug 31. 19 (10):36. [QxMD MEDLINE Link].
Prior DE, Song N, Cohen JA. Neuromuscular diseases associated with Human Immunodeficiency Virus infection. J Neurol Sci. 2018 Apr 15. 387:27-36. [QxMD MEDLINE Link].
Kaku M, Simpson DM. Neuromuscular complications of HIV infection. Handb Clin Neurol. 2018. 152:201-212. [QxMD MEDLINE Link].
Kokotis P, Schmelz M, Papadimas GK, et al. Polyneuropathy induced by HIV disease and antiretroviral therapy. Clin Neurophysiol. 2013 Jan. 124(1):176-82. [QxMD MEDLINE Link].
Centner CM, Bateman KJ, Heckmann JM. Manifestations of HIV infection in the peripheral nervous system. Lancet Neurol. 2013 Mar. 12(3):295-309. [QxMD MEDLINE Link].
Hao S. The Molecular and Pharmacological Mechanisms of HIV-Related Neuropathic Pain. Curr Neuropharmacol. 2013 Sep. 11 (5):499-512. [QxMD MEDLINE Link].
Cooley TP, Kunches LM, Saunders CA, Ritter JK, Perkins CJ, McLaren C, et al. Once-daily administration of 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial. N Engl J Med. 1990 May 10. 322 (19):1340-5. [QxMD MEDLINE Link].
Wright E, Brew B, Arayawichanont A, Robertson K, Samintharapanya K, et al. Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region. Neurology. 2008 Jul 1. 71 (1):50-6. [QxMD MEDLINE Link].
Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med. 1995 May. 1 (5):417-22. [QxMD MEDLINE Link].
Simpson DM, Kitch D, Evans SR, et al. HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology. 2006 Jun 13. 66(11):1679-87. [QxMD MEDLINE Link].
Simpson DM, Olney RK. Peripheral neuropathies associated with human immunodeficiency virus infection. Neurol Clin. 1992 Aug. 10(3):685-711. [QxMD MEDLINE Link].
Primary care of veterans with HIV. U.S. Department of Veterans Affairs. Available at https://www.hiv.va.gov/pdf/pcm-manual.pdf. 2019 Jan 01; Accessed: August 04, 2019.
Morgello S, Estanislao L, Simpson D, et al. HIV-associated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: the Manhattan HIV Brain Bank. Arch Neurol. 2004 Apr. 61(4):546-51. [QxMD MEDLINE Link].
Cherry CL, Skolasky RL, Lal L, Creighton J, Hauer P, Raman SP, et al. Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort. Neurology. 2006 Mar 28. 66 (6):867-73. [QxMD MEDLINE Link].
Evans SR, Ellis RJ, Chen H, Yeh TM, Lee AJ, Schifitto G, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011 Apr 24. 25 (7):919-28. [QxMD MEDLINE Link].
Anastasi JK, Capili B, McMahon DJ, Scully C. Acu/Moxa for distal sensory peripheral neuropathy in HIV: a randomized control pilot study. J Assoc Nurses AIDS Care. 2013 May-Jun. 24 (3):268-75. [QxMD MEDLINE Link].
Chen H, Clifford DB, Deng L, Wu K, Lee AJ, Bosch RJ, et al. Peripheral neuropathy in ART-experienced patients: prevalence and risk factors. J Neurovirol. 2013 Dec. 19 (6):557-64. [QxMD MEDLINE Link].
Holzinger ER, Hulgan T, Ellis RJ, Samuels DC, Ritchie MD, et al. Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. J Neurovirol. 2012 Dec. 18 (6):511-20. [QxMD MEDLINE Link].
Robinson-Papp J, Gelman BB, Grant I, Singer E, Gensler G, Morgello S, et al. Substance abuse increases the risk of neuropathy in an HIV-infected cohort. Muscle Nerve. 2012 Apr. 45 (4):471-6. [QxMD MEDLINE Link].
Cornblath DR, Hoke A. Recent advances in HIV neuropathy. Curr Opin Neurol. 2006. 5:446-50. [QxMD MEDLINE Link].
Robinson-Papp J, Sharma S, Simpson DM, Morgello S. Autonomic dysfunction is common in HIV and associated with distal symmetric polyneuropathy. J Neurovirol. 2013 Apr. 19 (2):172-80. [QxMD MEDLINE Link].
Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 2004 Jul 23. 18(11):1549-60. [QxMD MEDLINE Link].
Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004 Oct. 251(10):1260-6. [QxMD MEDLINE Link].
Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology. 2003 May 13. 60(9):1508-14. [QxMD MEDLINE Link].
Simpson DM, Schifitto G, Clifford DB, et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology. 2010 Feb 2. 74(5):413-20. [QxMD MEDLINE Link]. [Full Text].
Shlay JC, Chaloner K, Max MB, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA. 1998 Nov 11. 280(18):1590-5. [QxMD MEDLINE Link].
Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008 Jun 10. 70(24):2305-13. [QxMD MEDLINE Link].
Simpson DM, Brown S, Tobias JK, Vanhove GF. NGX-4010, a Capsaicin 8% Dermal Patch, for the Treatment of Painful HIV-associated Distal Sensory Polyneuropathy: Results of a 52-Week Open-Label Study. Clin J Pain. 2013 Feb 26. [QxMD MEDLINE Link].
Mou J, Paillard F, Turnbull B, Trudeau J, Stoker M, Katz NP. Qutenza (capsaicin) 8% patch onset and duration of response and effects of multiple treatments in neuropathic pain patients. Clin J Pain. 2014 Apr. 30 (4):286-94. [QxMD MEDLINE Link].
Estanislao L, Carter K, McArthur J, et al. A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr. 2004 Dec 15. 37(5):1584-6. [QxMD MEDLINE Link].
Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009 Feb. 34(3):672-80. [QxMD MEDLINE Link].
Dorfman D, George MC, Schnur J, Simpson DM, Davidson G, Montgomery G. Hypnosis for Treatment of HIV Neuropathic Pain: A Preliminary Report. Pain Med. 2013 Jul. 14(7):1048-56. [QxMD MEDLINE Link].
Sandoval R, Runft B, Roddey T. Pilot study: does lower extremity night splinting assist in the management of painful peripheral neuropathy in the HIV/AIDS population?. J Int Assoc Physicians AIDS Care (Chic). 2010 Nov-Dec. 9 (6):368-81. [QxMD MEDLINE Link].
Sandoval R, Roddey T, Giordano TP, Mitchell K, Kelley C. Randomized Trial of Lower Extremity Splinting to Manage Neuropathic Pain and Sleep Disturbances in People Living with HIV/AIDS. J Int Assoc Provid AIDS Care. 2013 Dec 30. [QxMD MEDLINE Link].
Geraci AP, Simpson DM. Neurological manifestations of HIV-1 infection in the HAART era. Compr Ther. 2001 Fall. 27 (3):232-41. [QxMD MEDLINE Link].
Maschke M, Kastrup O, Esser S, et al. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry. 2000 Sep. 69(3):376-80. [QxMD MEDLINE Link].
Watters MR, Poff PW, Shiramizu BT, et al. Symptomatic distal sensory polyneuropathy in HIV after age 50. Neurology. 2004 Apr 27. 62(8):1378-83. [QxMD MEDLINE Link].
Peters RP, Van Ramshorst MS, Struthers HE, McIntyre JA. Clinical assessment of peripheral neuropathy in HIV-infected children on antiretroviral therapy in rural South Africa. Eur J Pediatr. 2014 Sep. 173 (9):1245-8. [QxMD MEDLINE Link].
Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology. 1999 Feb. 52 (3):607-13. [QxMD MEDLINE Link].
Kume K, Ikeda K, Kamada M, Touge T, Deguchi K, Masaki T. [Successful treatment of HIV-associated chronic inflammatory demyelinating polyneuropathy by early initiation of highly active anti-retroviral therapy]. Rinsho Shinkeigaku. 2013. 53(5):362-6. [QxMD MEDLINE Link].
Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009 Dec. 40(6):1043-53. [QxMD MEDLINE Link].
Wang SX, Ho EL, Grill M, Lee E, Peterson J, Robertson K, et al. Peripheral neuropathy in primary HIV infection associates with systemic and central nervous system immune activation. J Acquir Immune Defic Syndr. 2014 Jul 1. 66 (3):303-10. [QxMD MEDLINE Link].