Neurologic complications of HIV infection are common, and are a significant source of morbidity. The chronic nature of HIV today, the complexity of highly active antiretroviral therapy regimens, and the multiple and diffuse effects of HIV on the nervous system present an exciting diagnostic challenge, in which a systematic, comprehensive approach to diagnosis and treatment is necessary.
Advances in the treatment of HIV with highly active antiretroviral therapy have led to improved longevity and overall health in patients living with HIV. Prolonged lifespan results in increased cumulative exposure to the HIV virus, associated infectious agents, and potentially neurotoxic therapies, and provides increased opportunity for chronic neurologic conditions to develop. HIV affects both the central and peripheral nervous systems and different lesions may coexist in a single patient. HIV-positive patients may also develop neurologic disease unrelated to HIV. This article describes the complications of HIV in the peripheral nervous system (PNS) and muscle, summarized in Table 1 . Because of the potential for multiple lesions, the approach to an HIV-positive patient presenting with neurologic symptoms must be comprehensive. The evaluation begins with a detailed history and general physical and neurologic examination, which leads to neuroanatomic localization and differential diagnosis.
| Disease | Time of onset | Incidence | Clinical features | Prognosis | Treatment |
|---|---|---|---|---|---|
| Distal sensory polyneuropathy | May be more common in advanced HIV | Common: 30%–58% of patients | Sensory loss, pain, and parasthesias beginning in feet | Chronic; pain can significantly interfere with quality of life |
|
| Autonomic neuropathy | Any time in disease course | Common, but usually subclinical | Orthostatic hypotension, syncope, cardiac arrhythmias, diarrhea, erectile and urinary dysfunction | Chronic; symptoms may reduce quality of life | Symptomatic for orthostasis; cardiology consult for suspected arrhythmia |
| Inflammatory demyelinating polyneuropathy | Seroconversion or early or late HIV | Rare | Ascending weakness; parasthesias | Good; major recovery within 4 weeks typical, full recovery more protracted |
|
| HIV-associated neuromuscular weakness syndrome | Any time in disease course | Rare | Rapidly progressive weakness nausea, vomiting, weight loss, abdominal pain, hepatomegaly | Variable. Significant mortality, some patients with full recovery | Withdrawal of NRTI IVIg, plasmapheresis, corticosteroids; supportive care |
| Mononeuropathy multiplex | Early and late forms | Rare |
|
|
|
| Progressive poly-radiculopathy | Advanced infection | Rare | Rapid onset, flaccid paraparesis | Poor; high mortality if untreated; incomplete recovery common | Ganciclovir, foscarnet, cidofovir |
| Myopathy | Any stage | Moderate | Slowly, progressive proximal weakness | Fair; course slow, may improve with treatment | ZDV/NRTI withdrawal; corticosteroids, IVIg |
The PNS can be divided into somatic and autonomic systems, and further subdivided into motor and sensory systems. The somatic motor neurons arise in the anterior horn of the spinal cord, exit the spinal cord as the ventral nerve root, then join with sensory fibers, originating in the dorsal root ganglion to form nerve plexus and peripheral nerve. The motor axon terminates at the neuromuscular junction where it innervates muscle. Autonomic efferents arise in the brain stem and the intermediolateral cell column of the spinal cord, travel to sympathetic and parasympathetic ganglia, and ultimately to their target organs.
Disease processes may affect any of these neural elements. The pattern of deficits described by the patient and found on neurologic examination, provide clues to the localization, which in turn guides differential diagnosis. For example, in the absence of sensory symptoms, pure motor weakness, usually symmetric and more prominent proximally, suggests a lesion affecting the muscle or neuromuscular junction. Distal, symmetric sensory symptoms are seen in HIV-related polyneuropathies. Motor and sensory symptoms occur together focally in mononeuropathy multiplex, and more diffusely in acute inflammatory demyelinating polyneuropathy (AIDP) and progressive polyradiculopathy. The suspected localization of the lesion assists in guiding further evaluation, including laboratory, neuroimaging, and neurophysiologic studies, and ultimately leads to diagnosis, patient counseling, and a management strategy.
Neuropathies and radiculopathies
The primary components of peripheral nerves are motor and sensory axons and myelin. The motor axon is a projection of the anterior horn cell body, located in the spinal cord. The sensory axon takes its origin from the dorsal root ganglion, which also sends a projection to the spinal cord via the dorsal root. Myelin is produced by Schwann cells, and envelops many of the axons to provide the electrical insulation that permits rapid signal conduction. Neuropathies may result from damage either to the axon itself or to the myelin sheath. Radiculopathies occur when nerve roots are compromised, and may involve damage to both the myelin and axons.
Distal sensory polyneuropathy
Distal sensory polyneuropathy (DSP) is the most common neurologic complication of HIV, and may be present in 50% or more of patients with advanced disease. Although classically thought of as a feature of advanced HIV, DSP may also occur in patients with good immunologic status and virologic control . Recent cohort studies indicate that the primary risk factor for DSP is advancing age, and that CD4 count and HIV plasma viral load are no longer predictive .
Clinical features
Symptoms of DSP include pain, burning, and numbness. Patients may also experience allodynia, defined as pain caused by innocuous stimuli, such as light touch. Symptoms begin in a distal symmetric distribution, typically affecting the toes and soles of the feet first. As the neuropathy progresses, the distal legs, and ultimately fingers and hands, may become involved. Weakness is not a common early feature of DSP; however, in severe cases the muscles of the feet may be mildly weak.
Neurologic examination typically reveals diminished sense of temperature, pain, and vibration in a distal distribution. Proprioception is relatively spared. Ankle reflexes are diminished or absent. Reflexes at the knees are usually normal, or may even be hyperactive because of coexisting central nervous system disease. Weakness of the intrinsic muscles of the feet is assessed by asking the patient to curl the toes down, dorsiflex, or separate them. Loss of hair and tightness of the skin in the calves may be seen on general physical examination.
Pathogenesis
DSP is a length-dependent process resulting from damage to the most distal segments of the sensory axon. Small myelinated and unmyelinated fibers are typically the first affected; thus, DSP is often referred to as a “small fiber neuropathy.” DSP may occur as a result of HIV itself, or as a side effect of neurotoxic antiretroviral (ARV) therapy. There is no evidence for direct infection of axons or Schwann cells by the HIV virus, and the mechanism by which HIV causes axonal damage is likely caused by secondary factors, such as immune-mediated neurotoxicity. HIV-induced dysregulation of macrophages and overproduction of inflammatory cytokines is one possible mechanism . Schwann-cell mediated neurotoxicity caused by an HIV-associated glycoprotein, gp120, has also been proposed . ARV-associated DSP occurs most commonly in patients treated with the nucleoside analog reverse transcriptase inhibitors (NRTI) didanosine (ddI), zalcitarabine (ddC), and stavudine (d4T). These agents, commonly referred to as “d-drugs,” appear to cause mitochondrial toxicity . There is emerging evidence that several drugs of the protease inhibitor class—namely indinavir, saquinavir, and ritonavir—may also be associated with neuropathy .
Diagnostic testing
Although DSP in the HIV-positive patient is most often related to HIV infection or ARV toxicity, it is important to determine whether the patient has other risk factors for neuropathy, such as alcohol abuse, poor nutritional status, diabetes mellitus, autoimmune disease, malignancy, or dysfunction of the kidney, liver, or thyroid. Diagnostic studies should include blood tests, such as a complete metabolic panel, liver function tests, hemoglobin A1c, vitamin B 12 level, thyroid function tests, venereal disease research laboratory, hepatitis serology, erythrocyte sedimentation rate, antinuclear antibody, and serum protein electrophoresis.
DSP is primarily a clinical diagnosis and further diagnostic procedures may not be necessary. In atypical cases, nerve conduction studies (NCS) and electromyography (EMG) may be helpful; however, a normal result does not exclude DSP, as NCS and EMG have a low sensitivity for the detection of small fiber neuropathy. When abnormalities are seen, decreased or absent sensory nerve action potentials in the distal lower extremity are typically the earliest findings. In more advanced cases, motor conduction studies and late responses may be abnormal, and EMG may show denervation in distal muscles.
There has been increasing interest in the use of epidermal skin biopsy in the diagnosis of DSP . In this technique, a sample of skin is obtained by punch biopsy from a distal and proximal site in the lower extremity. The epidermal nerve fiber density is then determined and compared with standardized values. As small fiber neuropathies are difficult to detect by conventional studies, reduced epidermal nerve fiber density may be the only abnormal diagnostic result.
Therapy
Treatment of DSP is largely symptomatic, as there are currently no neuroregenerative agents available. Any reversible causes of neuropathy identified during the diagnostic evaluation should be addressed, especially discontinuation of any neurotoxic medications when possible. Of note, DSP secondary to ARV may persist and even worsen for several weeks after cessation of the offending medication, a phenomenon termed “coasting syndrome” .
Symptomatic treatment of DSP focuses on management of the positive symptoms of neuropathy, such as pain and paresthesias. There are no specific treatments for the negative symptoms, such as numbness, ataxia, and weakness, other than rehabilitation therapy. Before beginning treatment, and at each visit throughout the course of treatment, the patient’s pain level should be systematically documented. Pain scales are helpful for quantifying the patient’s pain. A numeric pain intensity scale is commonly used in adults and rates pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst possible pain. The pain intensity scale can be used as part of a pain management flow sheet to document changes over time ( Table 2 ). The degree of pain that the patient experiences and the frequency of pain throughout the day will guide the course of treatment.
| Patient name: |
| Date: |
| What is your current pain level a ? |
| What is the worst pain you have experienced in the last 24 hours a ? |
| What percentage of the time do you experience your worst pain? |
| What is your average pain level a ? |
| What percentage of the time are you pain free? |
There are limited clinical trials, and no Food and Drug Administration (FDA)-approved therapies for the treatment of HIV-associated DSP. However, there is extensive experience with medications used in an off-label fashion. For mild or intermittent discomfort it is reasonable to begin with an over-the-counter analgesic, such as acetaminophen, used as needed. For more chronic or severe pain, a standing pain management regimen with an additional agent used as needed for breakthrough pain, is more appropriate. For intractable pain, multiple agents used in combination may be needed. Medications used for the management of DSP fall into four main categories: antiepileptics, antidepressants, topical agents, and nonspecific analgesics ( Table 3 ).
| Drug | Dosage | Common side effects |
|---|---|---|
| Amitriptyline, other TCA | 10 mg po qhs to start, titrate to efficacy | Sedation, confusion, orthostatic hypotension, urinary retention, dry mouth, and blurred vision |
| Duloxetine | 30 mg po qd to start, increase to 60 mg po qd | Nausea, dizziness, somnolence, fatigue |
| Gabapentin | 100 mg po tid to start, titrate to 800 mg–1,200 mg tid | Somnolence, dizziness, fatigue |
| Lamotrigine | 25 mg po daily to start, slow titration to 200 mg bid to avoid rash | Rash, dizziness, ataxia, somnolence, headache |
| Lidocaine patch | Apply patch to affected area for 12–24 hours | Local irritation |
| Pregabalin | 75 mg po bid to start, titrate to 150 mg–300 mg bid | Somnolence, dizziness |
Nearly all of the newer antiepileptic drugs (AEDs) have been used in the treatment of neuropathic pain. Pregabalin provides analgesia by inhibiting the α-2-Δ presynaptic voltage gated calcium channels, and reducing calcium influx and the release of excitatory neurotransmitters associated with neuropathic pain . Pregabalin is FDA-approved for the treatment of painful diabetic neuropathy . Pregabalin is currently being studied in clinical trials for the treatment of HIV-associated DSP, but is already commonly used off-label.
Pregabalin is commonly initiated at 75 mg, twice a day, and may be increased to a maximum dose of 300 mg, twice a day. It is typically well tolerated, and the most common side effects, dizziness and somnolence, are frequently transient and minimized by beginning with a low dose. Pregabalin is metabolized and excreted by the kidney, which is advantageous in HIV-positive patients who are often taking hepatically metabolized ARV.
Gabapentin is an older compound with a similar mechanism of action, side effect profile, and metabolism to pregabalin. Gabapentin has been used extensively in clinical practice and was shown to be effective in reducing pain in HIV-associated DSP in one small placebo-controlled trial . As with pregabalin, gabapentin is usually started at low doses, such as 100 mg three times a day, although doses as large as 3,600 mg daily are often tolerated. Gabapentin is now available in a generic form. While there are no head-to-head comparison studies of gabapentin and pregabalin, pregabalin has linear pharmacokinetics, better bioavailability, and a more convenient titration schedule.
Among the other AEDs, lamotrigine has been found to be effective in HIV-DSP, but is used less frequently in clinical practice in part because of the potential side effect of rash, and a long titration schedule . Zonisamide, topiramate, and oxcarbazepine have demonstrated some efficacy for painful diabetic neuropathy in clinical trials, but the role for these agents in the treatment of HIV-associated DSP is unclear .
Antidepressants, specifically the tricyclic antidepressants (TCAs) and the selective serotonin-norepinephrine reuptake inhibitors (SNRIs), are another major class of medications used in the treatment of DSP. TCAs inhibit the reuptake of numerous neurotransmitters, including monoamines and acetylcholine, while SNRIs are selective for serotonin and norepinepherine. These agents are thought to exert their analgesic effect via enhancement of central descending pain inhibition pathways.
Duloxetine, an SNRI, is FDA-approved for the treatment of diabetic neuropathic pain . Although it has not been studied in the treatment of HIV-associated DSP, it is often used off-label. The most common side effect of duloxetine is nausea, which is usually transient. This symptom may be minimized by beginning duloxetine at a low dose, such as 20 mg to 30 mg daily, and titrating to the recommended and proven effective dose of 60 mg daily by the second week of treatment. The dose may be further increased to 90 mg to 120 mg daily if there is insufficient response. Duloxetine undergoes hepatic metabolism, and levels may be increased by medications that inhibit the 2D6 isozyme of cytochrome P450, such as tipranavir, ritonavir, and delavirdine . Similarly,duloxetine inhibits 2D6 metabolism, and thus may increase serum levels of drugs that are 2D6 substrates, such as tricyclic antidepressants. Caution must also be exercised in combining duloxetine with other serotonergic drugs because of the risk of serotonin syndrome. Venlafaxine is another SNRI that has been studied for the treatment of neuropathic pain, particularly diabetic, although it is not FDA-approved for this indication.
TCAs have been available for over 50 years, and agents of this class, such as amitriptyline and nortriptyline, are still commonly used for neuropathic pain and other chronic pain syndromes. Although quite effective as neuropathic analgesics, the use of TCAs is commonly limited by side effects that include sedation, confusion, orthostatic hypotension, urinary retention, dry mouth, blurred vision, and cardiac arrythmia . Starting with a single low evening dose, such as amitriptyline 10 mg to 25 mg, may improve tolerability. Nortriptyline typically has fewer side effects than amitriptyline. Like duloxetine, TCAs also undergo extensive hepatic metabolism via the cytochome P450, and therefore have potential for interaction with ARV.
Topical therapies are attractive for the treatment of DSP because the symptoms are often localized to a circumscribed area, and there is minimal potential for systemic side effects or interaction with oral medications. Topical lidocaine, in gel and patch form, has been used with limited success . A high dose capsaicin patch was found to be safe and effective in controlled clinical trials of painful HIV DSP, but is not yet commercially available .
Antiepileptics, antidepressants, and topical treatments are all therapies which must be used regularly to provide around the clock analgesia, but are not useful in the treatment of acute pain. It is increasingly recognized that even patients whose pain is generally well controlled may experience acute exacerbations, termed “breakthrough pain” . A model for treatment of chronic pain with a standing regimen, supplemented with additional fast-acting medications for breakthrough pain, was initially described by the World Health Organization for the treatment of cancer-related pain . This model is now being explored in the treatment of neuropathic pain. A recent meta-analysis of opioids in the treatment of neuropathic pain showed efficacy of standing opioid therapy for chronic pain, and mixed results for the treatment of acute pain . Recent studies support the safety and efficacy of a rapid-acting opioid, fentanyl buccal tablet in the treatment of neuropathic pain . Further study of the clinical features and optimal treatment for neuropathic breakthrough pain is needed.
Distal sensory polyneuropathy
Distal sensory polyneuropathy (DSP) is the most common neurologic complication of HIV, and may be present in 50% or more of patients with advanced disease. Although classically thought of as a feature of advanced HIV, DSP may also occur in patients with good immunologic status and virologic control . Recent cohort studies indicate that the primary risk factor for DSP is advancing age, and that CD4 count and HIV plasma viral load are no longer predictive .
Clinical features
Symptoms of DSP include pain, burning, and numbness. Patients may also experience allodynia, defined as pain caused by innocuous stimuli, such as light touch. Symptoms begin in a distal symmetric distribution, typically affecting the toes and soles of the feet first. As the neuropathy progresses, the distal legs, and ultimately fingers and hands, may become involved. Weakness is not a common early feature of DSP; however, in severe cases the muscles of the feet may be mildly weak.
Neurologic examination typically reveals diminished sense of temperature, pain, and vibration in a distal distribution. Proprioception is relatively spared. Ankle reflexes are diminished or absent. Reflexes at the knees are usually normal, or may even be hyperactive because of coexisting central nervous system disease. Weakness of the intrinsic muscles of the feet is assessed by asking the patient to curl the toes down, dorsiflex, or separate them. Loss of hair and tightness of the skin in the calves may be seen on general physical examination.
Pathogenesis
DSP is a length-dependent process resulting from damage to the most distal segments of the sensory axon. Small myelinated and unmyelinated fibers are typically the first affected; thus, DSP is often referred to as a “small fiber neuropathy.” DSP may occur as a result of HIV itself, or as a side effect of neurotoxic antiretroviral (ARV) therapy. There is no evidence for direct infection of axons or Schwann cells by the HIV virus, and the mechanism by which HIV causes axonal damage is likely caused by secondary factors, such as immune-mediated neurotoxicity. HIV-induced dysregulation of macrophages and overproduction of inflammatory cytokines is one possible mechanism . Schwann-cell mediated neurotoxicity caused by an HIV-associated glycoprotein, gp120, has also been proposed . ARV-associated DSP occurs most commonly in patients treated with the nucleoside analog reverse transcriptase inhibitors (NRTI) didanosine (ddI), zalcitarabine (ddC), and stavudine (d4T). These agents, commonly referred to as “d-drugs,” appear to cause mitochondrial toxicity . There is emerging evidence that several drugs of the protease inhibitor class—namely indinavir, saquinavir, and ritonavir—may also be associated with neuropathy .
Diagnostic testing
Although DSP in the HIV-positive patient is most often related to HIV infection or ARV toxicity, it is important to determine whether the patient has other risk factors for neuropathy, such as alcohol abuse, poor nutritional status, diabetes mellitus, autoimmune disease, malignancy, or dysfunction of the kidney, liver, or thyroid. Diagnostic studies should include blood tests, such as a complete metabolic panel, liver function tests, hemoglobin A1c, vitamin B 12 level, thyroid function tests, venereal disease research laboratory, hepatitis serology, erythrocyte sedimentation rate, antinuclear antibody, and serum protein electrophoresis.
DSP is primarily a clinical diagnosis and further diagnostic procedures may not be necessary. In atypical cases, nerve conduction studies (NCS) and electromyography (EMG) may be helpful; however, a normal result does not exclude DSP, as NCS and EMG have a low sensitivity for the detection of small fiber neuropathy. When abnormalities are seen, decreased or absent sensory nerve action potentials in the distal lower extremity are typically the earliest findings. In more advanced cases, motor conduction studies and late responses may be abnormal, and EMG may show denervation in distal muscles.
There has been increasing interest in the use of epidermal skin biopsy in the diagnosis of DSP . In this technique, a sample of skin is obtained by punch biopsy from a distal and proximal site in the lower extremity. The epidermal nerve fiber density is then determined and compared with standardized values. As small fiber neuropathies are difficult to detect by conventional studies, reduced epidermal nerve fiber density may be the only abnormal diagnostic result.
Therapy
Treatment of DSP is largely symptomatic, as there are currently no neuroregenerative agents available. Any reversible causes of neuropathy identified during the diagnostic evaluation should be addressed, especially discontinuation of any neurotoxic medications when possible. Of note, DSP secondary to ARV may persist and even worsen for several weeks after cessation of the offending medication, a phenomenon termed “coasting syndrome” .
Symptomatic treatment of DSP focuses on management of the positive symptoms of neuropathy, such as pain and paresthesias. There are no specific treatments for the negative symptoms, such as numbness, ataxia, and weakness, other than rehabilitation therapy. Before beginning treatment, and at each visit throughout the course of treatment, the patient’s pain level should be systematically documented. Pain scales are helpful for quantifying the patient’s pain. A numeric pain intensity scale is commonly used in adults and rates pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst possible pain. The pain intensity scale can be used as part of a pain management flow sheet to document changes over time ( Table 2 ). The degree of pain that the patient experiences and the frequency of pain throughout the day will guide the course of treatment.
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