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Peripheral Neuropathy

Primary Care of Veterans with HIV

Neurology, Psychiatry, and Pain

April 2009

Contents

Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.

Key Points

  • HIV-associated peripheral sensory neuropathy (HIV-SN) includes distal sensory polyneuropathy (DSP) and ARV toxic neuropathy.
  • Patients typically present with bilateral tingling, numbness, or neuropathic pain starting in their toes and spreading proximally; the pain frequently is described as burning or aching and is worse on the soles.
  • For a very simple and brief evaluation: Ask about distal numbness and check ankle reflexes. Screening for numbness and delayed or absent ankle reflexes has the highest sensitivity and specificity among the clinical evaluation tools.
  • Treat suspected ARV toxic neuropathy by withdrawing the offending drug, if possible.
  • Treat the pain of HIV-SN with analgesics, anticonvulsants, and topical medication; if severe, treat with long-acting narcotics.

Background

  • HIV-SN is a "dying-back" neuropathy, affecting the most distal fibers first, involving myelinated and unmyelinated axons of all sizes. On pathologic examination, this pattern of loss is indistinguishable from other toxic neuropathies.
  • Patients typically present with bilateral tingling, numbness, or neuropathic pain that starts in the toes and spreads proximally; the pain frequently is described as burning or aching and is worse on the soles. It also may be described as shocklike or knifelike.
  • HIV-SN includes:
    • DSP caused by HIV infection itself
    • ARV toxic neuropathy resulting from exposure to ARVs, particularly d4T, ddI, and ddC (the "dNRTIs" or "d-drugs"). The onset can occur as early as 9 weeks after starting the offending agent.
  • DSP is thought to be related to chronic immune activation, leading to macrophage overproduction of proinflammatory cytokines and chemokines in the peripheral nervous system.
  • ARV toxic neuropathy is thought to be associated with mitochondrial toxicities of the dNRTIs.
  • Many other drugs and conditions may cause peripheral neuropathy (PN) or compound the condition.

Veterans with HIV*

Peripheral neuropathy: 19%

*Veterans in the VA HIV Clinical Case Registry in care in 2007 who had an ICD-9 code corresponding to this condition

Epidemiology

  • A recent study 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.
  • The risk of PN is higher for patients with advanced HIV infection.
    • 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 ART.
    • The prevalence is lower among patients with less-advanced HIV disease.

Prevention

Prevention and early intervention are vitally important in avoiding or reversing symptoms of neuropathy.

  • Initiate ART according to usual guidelines to avoid increased risk of HIV-SN resulting from advanced HIV disease.
  • Avoid ARVs (particularly d4T and ddI) associated with neurotoxicity.
  • If possible, avoid non-ARV medications that may cause PN.
  • Avoid treatment regimens that have additive neurotoxicity (eg, ddI for a patient who is receiving isoniazid).
  • With patients who develop ARV toxic neuropathy, discontinue the causative ARV if a reasonable substitution can be made.

Evaluation

DSP and ARV toxic neuropathy are clinically indistinguishable, although the timing of symptom onset may help to differentiate the etiology.

Risk factors
  • Increasing age
  • Exposure to d4T, ddI, or ddC
  • Advanced untreated HIV (low CD4 count nadir, high HIV RNA)
  • Alcohol use
  • Nutritional deficiencies (eg, vitamin B12)
  • Other neurotoxic medications, eg:
    • Dapsone
    • Hydroxyurea
    • Metronidazole
    • Vincristine
    • Thalidomide
    • Isoniazid
    • Linezolid
    • Ribavirin
  • Diabetes, impaired glucose tolerance

Screening

Quick Screen

Ask about distal numbness and check ankle reflexes.

  • Use the ACTG Brief Peripheral Neuropathy Screen (BPNS). This is a validated screening tool for scaling the degree of PN. It includes subjective and objective information, and takes <10 minutes to administer.
  • HIV-SN can be diagnosed when a patient exhibits ≥1 symptom specified in the BPNS and 1 of the following: diminished ankle reflexes, reduced vibration sense at the first toe.
  • Serial assessment of BPNS scores allows tracking of symptom severity and response to treatment.
History
  • Ask about numbness, pain, location/distribution of symptoms, character or quality of pain, other neurologic symptoms, duration, exposure to dNRTIs and other neurotoxic drugs.
  • Numbness has a sensitivity of 86% and a specificity of 81% for the clinical diagnosis of HIV-SN. Asking about numbness has greater sensitivity for the diagnosis of HIV-SN than asking about pain.
Physical examination
  • Perform a thorough neurologic examination.
  • Characteristics of HIV-SN:
    • Reduced or absent ankle Achilles tendon reflexes; this has a sensitivity of 84% and a specificity of 98% for HIV-SN.
    • Distal sensory loss (temporal progression: loss of vibratory sense occurs first, followed by loss of temperature sensation, followed by pain).
    • Findings usually are bilateral and symmetric.
Differential diagnosis
  • Alcohol toxicity
  • Non-ARV medication toxicity
  • Nutritional deficiency (eg, vitamin B12)
  • Diabetes, impaired glucose tolerance
  • Hypothyroidism
  • Other HIV-associated neuropathies, including:
    • Inflammatory demyelinating polyradiculoneuropathy
    • Cauda equina syndrome
    • Neuromuscular weakness syndrome
    • Diffuse infiltrative lymphocytosis syndrome (DILS)
    • Autonomic neuropathy
    • Mononeuritis
    • Polyradiculitis
  • Cryoglobulinemia (especially in hepatitis C virus-infected patients)
  • Syphilis
  • Herpes zoster radiculitis
  • Plantar fasciitis, musculoskeletal conditions, tarsal or carpal tunnel compression
  • Note: Patients with foot pain or numbness may have ≥1 source of symptoms.
Findings that suggest a different diagnosis
  • Prominent weakness (consider inflammatory demyelinating polyneuropathies, HIV-associated neuromuscular weakness syndrome, especially with d4T use - check lactic acid levels)
  • Neuropathy in the hands more so than in the feet (consider carpal tunnel syndrome)
  • Proximal features (consider inflammatory demyelinating polyneuropathies)
  • Marked asymmetry (consider mononeuritis multiplex, especially with foot drop)
  • Sphincter dysfunction (consider progressive polyradiculoneuropathy, especially caused by cytomegalovirus)
  • Cranial nerve involvement (consider progressive polyradiculoneuropathy)
  • Tenderness or deformity in plantar foot or joints (consider plantar fasciitis, gout)
Laboratory evaluationScreen for:
  • Diabetes (fasting glucose; consider HbA1c)
  • Vitamin B12 deficiency (check B12 level; if low, check methylmalonic acid levels and intrinsic factor antibody titers)
  • Hypothyroidism (TSH, T4)
  • Syphilis (RPR or VDRL)
  • Renal failure (serum creatinine, blood urea nitrogen; consider serum protein electrophoresis)
  • Hepatitis C (HCV IgG/PCR)
Further evaluation
  • Electromyography and nerve conduction velocity studies are not needed unless the symptoms are complex or there are atypical findings.
  • Sensory threshold testing is used primarily in research settings.
  • Punch biopsy for pathologic evaluation of epidermal nerve density may be useful in differentiating HIV-SN and other causes.
  • Consider referral of patients to neurologist or podiatrist if the diagnosis is unclear.

Management

  • Goals: relieve pain, halt progression of symptoms.
  • Patients taking neurotoxic medications: discontinue these if possible.
  • Patients not on ART: consider initiation, if low CD4 cell count or high HIV viral load.
  • Pharmacologic treatment often is multimodal, involving several types of medications.
    • Consider starting with an anticonvulsant such as gabapentin or pregabalin and titrating to effect.
    • Add or use antidepressants, especially for patients with comorbid depression.
    • Add or use topical agents for patients who cannot tolerate systemic pain medications.
    • For breakthrough pain, add topical agents or NSAIDs.
    • For severe or recalcitrant symptoms, consider adding a long-acting opioid.

When to Refer

Refer to a pain specialist or neurologist if symptoms are not controlled with initial trials of medication.

Table 1. Pharmacologic Interventions
InterventionComments

(Print table)

Pharmacologic
Discontinuation of offending drug (eg, switching from dNRTIs, avoiding combinations with additive neurotoxicity)
  • Differentiate DSP and ARV toxic neuropathy by timing of symptom onset.
  • Prompt discontinuation of a neurotoxic medication may prevent progression of symptoms, and may allow reversal of symptoms.
  • Before discontinuing an offending drug, carefully weigh risks and potential benefits.
  • Consider dosage reduction of d4T, if discontinuation is not possible.
  • With ARV toxic neuropathy caused by a dNRTI, symptoms often improve within 3 months (though they may be permanent).
Initiation of ART
  • Avoid dNRTIs
  • Initiation of ART can improve non-ARV-associated DSP for patients with advanced HIV who have uncontrolled viremia and low CD4 counts.
Medications
(for dosages and additional information, see Pain Medications)
Mild analgesics
  • Acetaminophen
  • NSAIDs
  • Use as first-line therapy for mild symptoms.
  • Can use in combination with tricyclic antidepressants (TCAs), anticonvulsants, and topical adjuncts.
  • Avoid use or limit dosages for patients with underlying liver or renal disease.
Anticonvulsants
  • Gabapentin
  • Pregabalin
  • Lamotrigine
  • Gabapentin: considered first-line for its tolerability.
  • Pregabalin: sometimes better tolerated than gabapentin. Little evidence of efficacy for HIV-SN.
  • Lamotrigine: has shown the greatest efficacy in clinical trials for HIV-SN.
  • To discontinue these agents, taper slowly over course of ≥7 days.
Antidepressants: TCAs and others
  • Amitriptyline
  • Nortriptyline
  • Other potential agents include venlafaxine and duloxetine; these have shown limited efficacy or are inadequately studied in people with HIV infection
  • Consider for patients with comorbid depression.
  • Small studies have shown limited or negative results with antidepressants.
  • Monitor serum TCA levels to avoid cardiotoxicity at higher dosage levels.
Potential ARV Interactions
  • Drug interactions: RTV and other PIs may increase the level of TCAs; start at low dosage, increase slowly.
Topical anesthetics
  • Capsaicin patch or cream
  • Lidocaine patch
  • A single capsaicin patch application can provide some degree of pain relief for up to 12 weeks.
  • Topical lidocaine has not shown significant benefit over placebo, and is expensive. Consider brief trial for patients with incomplete pain relief on other therapies.
Opiate analgesics
  • Long-acting narcotics preferred:
    • Transdermal fentanyl
    • Long-acting morphine
    • Methadone
    • Long-acting oxycodone
  • For moderate to severe HIV-SN with an inadequate response to the therapies listed above.
  • Titrate carefully. (For more information, see Pain Medications.)
  • Methadone: acts on NMDA receptors; may give adjunctive benefit. Caution: start at low dosage and titrate slowly because of its long half-life; consult with pharmacist.
  • Transdermal fentanyl is appropriate only for patients already on stable dosage of other opiates: start at equianalgesic (or lower) dosage.

ACTG Brief Peripheral Neuropathy Screen (BPNS)

NIAID Adult AIDS Clinical Trials Group

1. Elicit Subjective Symptoms

Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) to 10 (most severe) for right and left feet and legs. Enter the score for each symptom in the columns marked R (right lower limb) and L (left lower limb). If a symptom has been present in the past, but not since the last visit, enter "00 - Currently Absent." If the symptom has never been present, enter "11 - Always Been Normal."

Always Been NormalCurrently AbsentMild ←→ Severe
110001020304050607080910
SymptomsRL
a. Pain, aching, or burning in feet, legs
b."Pins and needles" in feet, legs
c. Numbness (lack of feeling) in feet, legs

2. Grade Subjective Symptoms

Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy score. If all severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."

Subjective Sensory Neuropathy Score (based on highest severity rating)

01 - 03 = grade of 1
04 - 06 = grade of 2
07 - 10 = grade of 3
11 or 00 = grade of 0

RL
  

3. Evaluate Perception of Vibration

Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place the vibrating tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she can recognize the vibration or "buzzing" quality of the tuning fork. Again, compress the ends of the tuning fork just hard enough that the sides touch. Immediately place the vibrating tuning fork gently but firmly on the top of the distal interphalangeal (DIP) joint of one great toe and begin counting the seconds. Instruct the subject to tell you when the "buzzing" stops. Repeat for the other great toe.

Vibration perception

a. Great toe DIP joint perception of vibration in seconds
b. Vibration perception score

0 = felt >10 seconds (normal)
1 = felt 6-10 seconds (mild loss)
2 = felt <5 seconds (moderate loss)
3 = not felt (severe loss)
8 = unable to or did not assess

RL
  

4. Evaluate Deep Tendon Reflexes

With the subject seated, the examiner uses one hand to press upward on the ball of the foot, dorsiflexing the subject's ankle to 90 degrees. Using a reflex hammer, the examiner then strikes the Achilles tendon. The tendon reflex is felt by the examiner's hand as a plantar flexion of the foot, appearing after a slight delay from the time the Achilles tendon is struck. Use reinforcement by having the subject clench his/her fist before classifying the reflex as absent.

Ankle Reflexes Score

0 = absent
1 = hypoactive
2 = normal deep tendon reflexes
3 = hyperactive
4 = clonus
8 = unable to or did not assess

RL
  

(Print tool)

References

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