AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

A distal painful sensorimotor polyneuropathy is the most common type of HIV-1 associated peripheral neuropathy. It usually develops during late HIV infection.

Pathophysiology

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 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 shown to be associated with distal painful sensorimotor polyneuropathy.
• Other factors may be involved, including nutritional and vitamin deficiencies.
• Since the advent of highly active antiretroviral therapy (HAART) (eg, didanosine, stavudine, zalcitabine, rarely lamivudine), antiretroviral toxic neuropathy (ATN), which occurs in up to 60% of patients and likely results from mitochondrial dysfunction, has been recognized.

Frequency

United States

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.

Sex

Distal painful sensorimotor polyneuropathy is more prevalent in males than in females.

Age

Distal painful sensorimotor polyneuropathy is more common in persons older than 50 years. It rarely occurs in children.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• 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
• Rare in otherwise healthy seropositive patients
• Can be asymptomatic

Physical

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Cerebrospinal fluid
  • Mildly elevated protein
  • Mild pleocytosis
• Consider the following 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.
• Electromyography/nerve conduction study
• • Symmetric features
  • Sensory findings predominate over motor abnormalities
  • Greater involvement of lower 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
• 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
• 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment options fall into 2 groups: causal and symptomatic.

• Causal treatment
• • Avoid neurotoxic medications, if possible.
  • Correct vitamin B-12 and folate deficiency.
  • Consider thiamine replacement if malnourished.
• Symptomatic treatment of painful dysesthesias is discussed in the Medication section.

Diet

A well-balanced diet is recommended to prevent vitamin deficiency.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Some antidepressants, anticonvulsants, and antiarrhythmics control neuropathic pain.

Drug Category: Tricyclic antidepressants

TCAs are effective in painful paresthesias. While dosages 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.

Drug Name	Nortriptyline (Aventyl HCl, Pamelor)
Description	Demonstrated effectiveness in neuropathic pain; increases synaptic concentration of serotonin and norepinephrine by reuptake inhibition at presynaptic neuronal membrane; additional pharmacodynamic effects such as desensitization of adenyl cyclase and downregulation of beta-adrenergic and serotonin receptors appear to be involved.
Adult Dose	Starting dose: 10-25 mg PO qhs; increase prn, as tolerated, in 3-7 d intervals and in 25-mg steps to about 125 mg qhs; >75 mg obtain ECG before each further dose increase to rule out AV block
Pediatric Dose	25-35 kg: 10-20 mg PO qhs 35-54 kg: 25-35 mg PO qhs
Contraindications	Documented hypersensitivity; in patients with AV block or who have taken MAOIs or fluoxetine in the past 14 d
Interactions	Cimetidine may increase levels when used concurrently; may increase PT in patients on warfarin
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with seizures, renal or hepatic impairment, cardiac disease, conduction disturbances, cognitive impairment, urinary retention, hyperthyroidism, or who receive thyroid hormones; particular caution in older patients; less sedative drugs may be tolerated better

Drug Name	Desipramine (Norpramin)
Description	Useful for neuropathic pain; may increase synaptic concentration of norepinephrine by reuptake inhibition at presynaptic neuronal membrane; may desensitize adenyl cyclase and downregulate beta-adrenergic and serotonin receptors.
Adult Dose	Starting dose: 10-25 mg PO qhs; increase prn, as tolerated, in 3-7 d intervals and in 25-mg steps to about 125 mg PO qhs; >75 mg obtain ECG before each further dose increase to rule out AV block
Pediatric Dose	<12 years: Not established >12 years: Initially 25 mg PO qhs; gradually increase to 100 mg PO qhs
Contraindications	Documented hypersensitivity; in patients that have taken MAOIs or fluoxetine in the past 14 d
Interactions	Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; phenytoin, carbamazepine, and barbiturates decrease effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with seizures, renal or hepatic impairment, cardiac disease, conduction disturbances, cognitive impairment, urinary retention, hyperthyroidism, or who receive thyroid hormones; particular caution in older patients

Drug Category: Anticonvulsants

Gabapentin alleviates painful dysesthesias and spasms. It is well tolerated with a wide dose range. Drug levels are not available, indicated, or meaningful. Lamotrigine has been shown to be effective in distal painful sensorimotor polyneuropathy but not ATN.

Drug Name	Carbamazepine (Tegretol, Carbatrol, Epitol)
Description	Has antineuralgic effects; may depress activity of the nucleus ventralis of the thalamus or decrease synaptic transmission or summation of temporal stimulation by limiting influx of sodium ions across cell membrane or by other unknown mechanisms.
Adult Dose	Initial dose: 200 mg PO bid; increase gradually prn over 2-wk interval to 200 mg PO tid; target blood serum concentrations are 4-12 mg/L Sustained release dosing: Therapeutic dose bid
Pediatric Dose	<6 years: Initially 10-20 mg/kg/d PO; titrate dose prn 6-12 years: Initially 100 mg PO bid; titrate dose prn >12 years: Initially 200 mg PO bid; titrate dose prn
Contraindications	Documented hypersensitivity; bone marrow suppression; MAOIs
Interactions	May interact with many drugs including cyclosporine, oral contraceptives, TCAs, warfarin, phenytoin, doxycycline, neuroleptics, fentanyl, calcium channel blockers, macrolide antibiotics, isoniazid, cimetidine, lamotrigine, and propoxyphene
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue MAOIs for a minimum of 14 d before carbamazepine is begun; caution in patients with history of cardiac damage or hepatic disease; blood cell abnormalities have been reported following treatment with this medication; check CBC once or twice a year; may worsen seizures in persons with primary generalized epilepsy and atypical absence seizures; 0.5-1% risk of spina bifida in children born to mothers who take carbamazepine during pregnancy

Drug Name	Lamotrigine (Lamictal)
Description	Triazine derivative useful in treatment of neuralgia. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane. Follow manufacturer's recommendation for dose adjustments.
Adult Dose	Monotherapy: 50-100 mg/d PO divided bid initial dose; 100-400 mg/d PO qd or divided bid maintenance; not to exceed 500 mg/d Adjunct therapy with valproic acid: 25 mg PO qod initial dose; 50-200 mg/d PO qd or divided bid maintenance; not to exceed 200 mg/d
Pediatric Dose	2-12 years: Monotherapy Weeks 1-2: 0.6 mg/kg/d PO divided bid, rounded down to nearest 5 mg Weeks 3-4: 1.2 mg/kg/d PO divided bid, rounded down to nearest 5 mg Maintenance: 5-15 mg/kg/d PO; not to exceed 400 mg/d divided bid; to achieve usual maintenance dose, increase subsequent doses q1-2wk as follows: calculate 1.2 mg/kg/d and round down to nearest 5 mg; add this amount to previously administered daily dose Concomitant therapy with valproic acid Weeks 1-2: 0.15 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg; if initial calculated daily dose is 2.5-5 mg, then take 5 mg on alternate days for first 2 wk Weeks 3-4: 0.3 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg Maintenance: 1-5 mg/kg/d PO; not to exceed 200 mg/d PO qd or divided bid; to achieve usual maintenance dose, increase subsequent doses q1-2wk as follows: calculate 0.3 mg/kg/d and round down to nearest 5 mg; add this amount to previously administered qd dose >12 years: Monotherapy Weeks 1-2: 50 mg/d PO Weeks 3-4: 100 mg/d PO divided bid Maintenance: 300-500 mg/d PO divided bid; to achieve maintenance, increase by 100 mg/d q1-2wk Concomitant therapy with valproic acid Weeks 1-2: 25 mg PO qod Weeks 3-4: 25 mg PO qd Maintenance: 100-400 mg/d PO qd or divided bid; to achieve maintenance, increase by 25-50 mg/d PO q1-2wk
Contraindications	Documented hypersensitivity
Interactions	Acetaminophen increases renal clearance of medication, decreasing effects; similarly, phenobarbital and phenytoin increase lamotrigine metabolism, causing a decrease in lamotrigine levels; administration of valproic acid with lamotrigine increases half-life; succinimide anticonvulsants (eg, methsuximide, phensuximide) decrease lamotrigine levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use appropriate dosing if used concurrently with valproic acid; caution in impaired renal or hepatic function; need to warn patients of potential rash (Stevens-Johnson syndrome)

Drug Category: Topical anesthetics

These agents are used to induce localized analgesia.

Drug Name	Capsaicin (Dolorac, Zostrix)
Description	Natural chemical derived from plants of Solanaceae family. Penetrates deep for temporary relief of minor aches and pains of muscles and joints associated in inflammatory reactions. May render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons. Has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic pain.
Adult Dose	Apply to affected area tid/qid for 3-4 consecutive wk and evaluate efficacy; not to exceed 4 applications/d; wash hands with soap and water after applying
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; broken or irritated skin
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	For external use only; avoid contact with eyes; do not use tight bandage; discontinue use if condition worsens or symptoms persist for 14-28 d

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• HIV-associated distal painful neuropathy is a progressive disease unless secondary causes, such as neurotoxic drugs or vitamin deficiencies, can be eliminated.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• This is a diagnosis of exclusion. All other secondary causes of distal sensorimotor polyneuropathy, as outlined in the workup section, must be excluded.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Cornblath DR, McArthur JC. Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology. May 1988;38(5):794-6. [Medline].
• Cornblath DR, Hoke A. Recent advances in HIV neuropathy. Curr Opin Neurol. 2006;5:446-50. [Medline].
• 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. Dec 15 2004;37(5):1584-6. [Medline].
• Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency virus-associated peripheral neuropathies. Mayo Clin Proc. Feb 2006;81(2):213-9. [Medline].
• Freeman R, Roberts MS, Friedman LS, Broadbridge C. Autonomic function and human immunodeficiency virus infection. Neurology. Apr 1990;40(4):575-80. [Medline].
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• Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. Jul 23 2004;18(11):1549-60. [Medline].
• Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology. Dec 1998;51(6):1682-8. [Medline].
• Luciano CA, Pardo CA, McArthur JC. Recent developments in the HIV neuropathies. Curr Opin Neurol. Jun 2003;16(3):403-9. [Medline].
• 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. Sep 2000;69(3):376-80. [Medline].
• 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. Apr 2004;61(4):546-51. [Medline].
• Said G, Saimont AG, Lacroix C. Neurological Complications of HIV and AIDS. Philadelphia, Pa: WB Saunders;1998.
• Schifitto G, McDermott MP, McArthur JC, et al. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology. Jun 25 2002;58(12):1764-8. [Medline].
• Simpson DM, Olney RK. Peripheral neuropathies associated with human immunodeficiency virus infection. Neurol Clin. Aug 1992;10(3):685-711. [Medline].
• Simpson DM, Kitch D, Evans SR, et al. HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology. Jun 13 2006;66(11):1679-87. [Medline].
• Watters MR, Poff PW, Shiramizu BT, et al. Symptomatic distal sensory polyneuropathy in HIV after age 50. Neurology. Apr 27 2004;62(8):1378-83. [Medline].
• 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. [Medline].

Article Last Updated: Feb 23, 2007