HIV-related Neuropathy

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Original Editor - Melissa Coetsee
Top Contributors - Melissa Coetsee, Kim Jackson and Pacifique Dusabeyezu

Introduction

Despite the introduction of combination antiretroviral therapy (ART), neuropathies (especially distal sensory neuropathy) are still a common complication of HIV. It is associated with significant morbidity.

Epidemiology

The prevalence of HIV-associated neuropathy varies from 1.73% tot 69.4% among people living with HIV (PLWH). This variability could be attributed to the introduction of ART, with its benefits and varying adverse effects with evolving drug-combinations. Diagnostic criteria and geographical region also influence the he prevalence of HIV-associated neuropathy. The estimated pooled frequency of DSN in Africa, prior to ART, was 27%. This increased to 52% in the post-ART era, and was mainly attributed to the widespread use of Nucleoside reverse transcriptase inhibitors (NRTIs) - like Stavudine.

It is however important to note that although the frequency appears to have increased since the introduction of ART, some studies indicate a significant reduction in pain associated with neuropathy - i.e. although patients test positive for neuropathy (based on signs), it is often asymptomatic.

Clinically Relevant Anatomy

add text here relating to clinically relevant anatomy of the condition

Pathophysiology

Although other mechanisms may be at play for the less common types of neuropathy (discussed below), HIV-related neuropathy is usually as a result of two distinct pathological processes that lead to distal axonal degeneration, neuronal loss in the dorsal root ganglia and reduced epidermal nerve fibre density:

1. Neurotoxic effect of HIV: Indirect neurotoxicity as a result of viral proteins and an inflammatory response to HIV
2. Neurotoxic effects of ART: Some ART drugs (NRTIs) associated with an increased incidence of peripheral neuropathy. These include Didanosine, Zalcitabine, Stavudine.ART related neuropathy typically develops 5-6 months after initiating ART.

Despite these two distinct pathological processes, the signs and symptoms of each process are not clinically distinguishable.

Clinical Presentation

Clinical presentation varies depending on the type of neuropathy (discussed below), but may include:

• Numbness
• Burning pain
• Altered sensation, including numbness and/or hypersensitivity
• Loss of balance as a result of impaired proprioception
• Diminished or absent lower limb reflexes
• Muscle weakness and muscle wasting (if motor nerves are affected)

Diagnostic Procedures

Diagnosis is based on medical history and clinical examination. Confirmed HIV infection and NRTI exposure history, along with signs and symptoms related to neuropathy.

Additional tests (mostly to rule out other conditions) may include:

• Laboratory tests - CD4 count and viral load; Vit B levels; Diabetic screening
• Nerve conduction studies - not routinely indicated
• Quantitative Sensory Testing - will reveal abnormalities in cases of peripheral and central nerve disorders

A clinical diagnostic tool (CHANT) has been validated for use in Africa, and include the following criteria:

Differential Diagnosis

Also see Neurological Complications of HIV and Neuropathies

• Myelopathy - including Vacuolar Myelopathy and Pott's Disease
• Opportunistic infections affecting the CNS - TB Meningitis, Neurosyphilis, Toxoplasmosis Encephalitis, Cryptococcal Meningitis
• Other CNS conditions - Stroke, Lymphoma, Aseptic Meningitis
• Vitamin B deficiency - Vit B12 deficient or excess of vit B6
• Alcoholic neuropathy
• Diabetic Neuropathy
• Neuropathy related to isolated nerve damage (eg. surgery, compression, traction injury)
• Claudication associated with Peripheral Vascular Disease
• Pain and weakness caused by Central Sensitisation
• Schwannoma
• Morton's Neuroma
• Thyroid dysfunction

B-Vitamins and HIV

B-vitamin deficiencies are prevalent in PLWH and are associated with poor health outcomes

Outcome Measures

• Neuropathic pain measures: DN4; LANSS; PainDETECT
• Pain intensity: VAS
• The Sensory Peripheral Neuropathy Screen (SPNS)
• HIV-PINS
• BPNS
• Quantitative Sensory Testing

Types

Neuropathy can occur at all stage of HIV, and various types of neuropathy have been documented. The neuropathies present in PLWH include:

1. Distal sensory neuropathy (DSN)
2. Inflammatory neuropathies
3. Radiculopathies
4. Mononeuropathies

1. Distal Sensory Neuropathy (DSN)

DSN is the most common type of neuropathy in PLWH.It affects the distal extremities (more commonly the feet, symmetric) and is caused by axonal damage secondary to dorsal root inflammation. It is more common in the advanced stages of HIV infection (WHO stages 3 and 4). Some patients with DSN (about 25%) do not experiences any sensory symptoms (asymptomatic DSN).

Signs and symptoms include:

• Burning, stabbing pain and numbness in the soles of the feet/palms of the hands - this ascends symmetrically (stocking-glove distribution)
• Sensitivity is most pronounced one the soles and palms
• Reduced or absent ankle reflexes
• Impaired pin prick and vibration sensation
• Impaired proprioception of the affected region
• Weakness and atrophy are rare as sensory nerves are involved

Risk factors for developing DSN:

• Advanced immunosuppression

• Lower CD4 count and high viral load
• A history of prior TB or alcohol abuse
• ART regime that includes Dideoxynucleoside revers transcriptase inhibitors (NRTIs), especially Stavudine
• Height and ethnicity may play a role
• Diabetes may exacerbate the risk of neuropathy in PLWH

2. Inflammatory Neuropathies

Two forms of inflammatory demyelinating polyneuropathy (IDP) can occur in PLWH:

1. Acute IDP (Guillan-Barré syndrome) - rapidly progressive symptoms
2. Chronic IDP - slower progression, often with a relapsing-remitting pattern

Both forms are characterised by ascending muscle weakness and areflexia with paraesthesia

3. Radiculopathy

Radiculopathy in less common and when present usually affects the lumbosacral nerve roots, mostly caused by TB, Cytomegalovirus (CMV) or lymphoma.

4. Mononeuropathy

PLWH are at increased risk of mononeuropathies. The most common mononeuropathies are:

• Facial nerve palsy (Bell's palsy): Usually occurs during the early, asymptomatic stages of HIV (at seroconversion). It may present as part of an acute inflammatory demyelinating neuropathy, but this is less common.
• Herpes zoster reactivation: One of the earliest signs of HIV, and affects the thoracic and trigeminal nerve. Complications include myelitis and post herpetic neuralgia.
• Median neuropathy: Leading to carpal tunnel syndrome

Medical Management

• HIV infection control - early diagnosis and treatment with ART
• Drug regime alteration if associated with ART - Avoiding NRTIs; discontinuing Stavudine if symptomatic DSP develops
• Pain control
  • With neuropathic medication (amitriptyline, gabapentin, pregabalin)- Although these medications have proven effectiveness in other neuropathic conditions, they seem to be less effective in HIV-related neuropathy. Gabapentin appears to be superior to other medications.
  • Topical capsaicin patches have shown promise in reducing neuropathic pain in PLWH
  • Complete resolution of pain is not common, but reduction is possible
  • See the page on Neuropathic Pain and Pain in PLWH
• Education - On possible other causes of neuropathy (alcohol, diabetes and Vit B6 deficiency secondary to isoniazid)
• Optimisation of contributing factors - medical management of diabetes, alcohol abuse and vitamin deficiencies
• Treatment of other infections - in the case of Herpes reactivation, treatment with acyclovir is indicated

Resources

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