HIV-related Neuropathy

This article or area is currently under construction and may only be partially complete. Please come back soon to see the finished work! (12/12/2023)

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 and negatively impacts quality of life.

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.

Pathophysiology

Peripheral nerve anatomy

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)

Patients may present with functional limitations and chronic painful symptoms. When poorly managed, this can contribute to anxiety, depression and loss of independence.

Diagnostic Procedures

Diagnosis is based on medical history and clinical examination. This may included a 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

For Distal Sensory Polyneuropathy (DSPN), a clinical diagnostic tool called HIV-associated Neuropathy Tool (CHANT) has been validated for use in Africa, and include the following assessment areas:

• Bilateral feet pain
• Bilateral feet numbness
• Bilateral ankle reflex - diminished
• Bilateral big toe vibration detection - diminished
  • The following minimum combinations are required to diagnose a patient with PNS: Bilateral feet pain/ reduced great toe vibrations AND Bilateral feet numbness/ reduced ankle reflex

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
• Myopathy or polymyositis

B-Vitamins and HIV

B-vitamin deficiencies are prevalent in PLWH and are associated with poor health outcomes. HIV itself causes vitamin-B deficiencies through various mechanisms mostly related to poor absorption.Since vitamin-B6 and B12 play have important immune support functions (eg. synthesis of CD4 cells), sufficient amounts of these vitamins could play a protective role HIV progression. Insufficient vitamin B levels could increase the risk of HIV-related neuropathy as Vitamin B12 is also involved in myelin production.

Outcome Measures

• Neuropathic pain measures: DN4; LANSS; PainDETECT
• Pain intensity: VAS
• Brief Neuropathy Screening Tool (BPNS): can be used as a screening tool and includes symptom reporting and physical assessment
• Quality of life: WHOQOL-BREF, EQ-5D
• Quantitative Sensory Testing
• Fall Risk Assessment Tool

Types of Neuropathy

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 polyneuropathy (DSPN)
2. Inflammatory neuropathies
3. Radiculopathies
4. Mononeuropathies

1. Distal Sensory Polyneuropathy (DSPN)

DSPN 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 DSPN (about 25%) do not experiences any sensory symptoms (asymptomatic DSPN).

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 only 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
• Psychosocial factors

2. Inflammatory Neuropathies

Although uncommon, two forms of autoimmune inflammatory demyelinating polyneuropathy (IDP) can occur in PLWH:

1. Acute IDP (Guillan-Barré syndrome) - rapidly progressive symptoms, with symmetrical limb weakness and areflexia. Can occur with intact immunity or at seroconversion.
2. Chronic IDP - slower progression, often with a relapsing-remitting pattern; symmetrical limb weakness with areflexia and sensory symptoms. Usually associated with moderately advanced HIV disease.

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 Tuberculosis, Cytomegalovirus (CMV) or lymphoma.This results in flaccid paraplegia with areflexia and urinary incontinence without upper limb involvement.

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 (especially vitamin B supplementation)
• Treatment of other infections/diroders - in the case of Herpes reactivation, treatment with acyclovir is indicated.Autoimmune inflammatory neuropathies require immunomodulation (acute type) or steroid treatment (chronic type).

Role of Physiotherapy

• Fall prevention: Even mild forms of neuropathy can result in altered gait and balance which increases the risk of falls.Gait and balance training may reduce fall risk and assistive devices can be prescribed to ensure improved, safer mobilisation. See Falls and Exercise
• Pain management: Neuropathies are often accompanied by neuropathic pain. A recent systematic review recommended exercise (resistance and aerobic) as an effective treatment to reduce neuropathic pain in PLWH. See Neuropathic Pain
• Resistance and Aerobic Exercises: A recent systematic review concluded that there is sufficient evidence that progressive resistance training improves balance, gait, and quality of life in PLWH on ART. See Exercise for PLWH.
  • Most of these studies focused on DSPN
  • Studies were conducted in a wide range of settings, including African settings (Rwanda and Zimbabwe).
  • Strengthening exercises should focus on lower limb muscle groups (quadriceps, tibialis anterior, hamstrings and gastrocnemius)
  • Aerobic exercise should be of moderate intensity and can include brisk walking and cycling.
  • The optimal duration of exercise programs appear to be 12 weeks, 2-3 times per week.
  • Although exercise has many proven benefits on symptoms and function, it does not however seem to alter neuropathy signs in the short term (absent reflexes and vibration sense) - this seems to suggest that exercise works by modifying pain modulation and compensatory strategies, rather than altering pathology. It is still however unsure whether long term results may indicate different findings.

• Neural mobility exercises: Sliding and tensioning techniques may enhance nerve gliding and improve neural mobility. This could translate into reduced pain and improved function by allowing more range of movement.
• Psychosocial factors: Assessing and exploring psychosocial factors that contribute to pain and/or non-adherence to medication/interventions
• Foot care: Education on proper footwear, hygiene and fall prevention; daily foot evaluation for skin damage

Resources

1 Yakasai Mkandla Zhang WiniasAmanitiTumusiime