Abstract
The most frequent neurologic complication of HIV is neuropathy. Within the wide range of HIV-related neuropathies, distal sensory polyneuropathy (DSP) is the most common. The presentation of HIV DSP is similar in history and physical findings to other peripheral neuropathies, including distal sensory findings. The degree of HIV immunosuppression does not predict the development or severity of DSP. The course can be progressive, and any potential causative agents, including medications, should be adjusted accordingly. The diagnosis is largely based on history and physical examination findings. Diagnostic tests include blood analysis and nerve conduction tests with electromyography to rule out other causes of neuropathy and confirm DSP. Treatments include removing any offending agents or contributing factors, rehabilitation therapies, medications, interventional pain management procedures and continued HIV treatments. Rehabilitation therapies may incorporate physical therapy, occupational therapy, psychiatric pain management techniques, and acupuncture. Medication management typically involves anticonvulsants, antidepressants, topical treatments, and analgesics. Optimal pain control often requires a combination of these treatments with removal of causative agents, appropriate HIV medications, and reduction of any factors that may contribute to neuropathy in the non-HIV population.
Keywords
Antiretroviral, HIV, Human immunodeficiency virus, Neuropathic pain, Neuropathy
HIV-related neuropathies are the most common neurologic complication of HIV. These neuropathies have increased in frequency as the mortality rate of people with HIV decreases as a result of improved pharmacologic treatments. Neuropathies related to HIV include distal sensory polyneuropathy (DSP), antiretroviral toxic neuropathy, acute inflammatory demyelinating polyneuropathy, and multiple others ( Box 11.1 ). People with HIV may also develop neuropathy related to hepatitis C, diabetes, chemotherapy, vitamin deficiencies, alcohol abuse, and other causes in the non-HIV population. Furthermore, diabetes mellitus and other causes of neuropathy may increase the risk for HIV DSP. The most frequent HIV-related neuropathy is DSP. HIV-related peripheral sensory neuropathy is the focus of this chapter.
HIV-related peripheral sensory neuropathy
Distal sensory polyneuropathy
Antiretroviral toxic neuropathy
Acute inflammatory demyelinating polyneuropathy
Chronic inflammatory demyelinating polyneuropathy
Mononeuritis multiplex
Diffuse infiltrative lymphocytosis syndrome
Progressive polyradiculopathy
Presentation: Historical and Physical Features
The primary complaints are similar to those of other distal neuropathies, including symmetric, distal sensory loss with tingling and/or numbness. Patients may describe sensory loss in the lower limbs or in a glove and stocking distribution. Other complaints are sensitivity to light touch in the feet and distal weakness. Typically, patients describe a progressive onset of symmetric, abnormal sensation in the feet with feelings of walking on rocks, sand, or a sunburned area. The degree of pain may fluctuate and be worse at night as is commonly found in neuropathic pain. It is important to take a full history and note the course, onset, intensity, duration, exacerbating or remitting factors, and associated symptoms. A thorough family history and social history should be reviewed to rule out other causes of these symptoms.
Physical features on examination are distal sensory loss beginning with decreased vibratory sense, hyporeflexia and/or absent reflexes, and possible distal weakness.
Demographics
In 2001, DSP was reported in 35% of people with HIV. More recently, the prevalence of DSP has been reported as greater than 50% and both the development and severity of neuropathy are not necessarily correlated to the amount of immunosupression. At the time of autopsy, it has been reported that nearly 100% of patients with AIDS have evidence of neuropathy on biopsy.
Diagnostic Criteria
Course
The course can be progressive and include symptoms ascending proximally and incorporating the upper limbs. If there is a known cause, including medication or an additional neuropathic condition that can be modified or treated, it is important to do so quickly to minimize progression. The differential diagnosis includes other causes of neuropathy as seen in the general population ( Box 11.2 ).
Diabetic neuropathy
Nutritional neuropathy
Toxic neuropathy
Uremic neuropathy
Vitamin B 12 -associated neuropathy
Alcoholic neuropathy
Metabolic neuropathy
Paraneoplastic neuropathies
Monoclonal gammopathy
Acute inflammatory demyelinating polyradiculoneuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy
Mononeuritis multiplex
Diffuse infiltrative lymphocytosis syndrome
Progressive polyradiculopathy
Diagnostic Testing
An assessment tool such as the Brief Peripheral Neuropathy Screen may be used as a quick method to make an initial diagnosis of neuropathy. It is not specific to HIV-related neuropathy. Diagnostic testing should be used to rule out other causes of neuropathy and confirm the diagnosis ( Box 11.3 ).
Laboratory studies
HIV RNA viral load
Complete blood cell count
Complete metabolic panel
Hemoglobin A1C
Thyroid function tests
Hepatitis workup
Vitamin B 12 , folate levels
Serum, urine protein electrophoresis
Skin biopsy, optional
Electromyography/nerve conduction features include symmetric:
Lower > upper limbs
Sensory > motor abnormalities
Severely decreased sensory and motor amplitudes
Normal to slightly decreased sensory and motor conduction velocities
Normal to slightly prolonged sensory and motor distal latencies
Treatment
Treatment of neuropathic pain in patients who are HIV positive is challenging for a variety of reasons. It requires an approach to each individual patient that includes:
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Treating the HIV illness itself
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Adjusting drug therapy if possible when antiretroviral therapy (ART) drugs are causing/contributing to neuropathy and when concerns about pain medicine interactions with ART drugs exists
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Mitigating/managing other factors that predispose to neuropathy or chronic pain (for example, HIV-infected patients with a history of substance abuse)
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Employing multimodal palliative treatment of neuropathic symptoms (nonpharmacologic and pharmacologic treatments)
HIV infection, itself a chronic condition, is a causative factor for neuropathy, and to complicate things further, treatments required to manage the viral infection (antiviral medications) may be causative agents as well. Immunosuppression caused by HIV infection predisposes the patient to other medical comorbidities that can contribute to neuropathy and other painful disorders. Furthermore, in HIV-positive patients with a history of substance abuse there is a higher incidence of chronic pain, and substance abuse itself can increase the risk of neuropathy in certain HIV-positive cohorts.
Mitigating the disease process and controlling the viral load while maintaining optimal CD 4+ counts may be helpful in minimizing neuropathy and associated symptoms. However, in the age of highly active ART, more recent studies have not shown an association with viral load/CD 4+ counts and distal symmetric polyneuropathy. Careful monitoring for neuropathy caused by drug therapy (specifically reverse-transcriptase inhibitors) is also necessary as part of disease management. If possible the offending agent should be removed or adjusted.
Addressing other factors unique to each patient, specifically a history of substance abuse, is also a paramount concern if treatment of neuropathy symptoms via pharmacologic treatments is provided.
HIV-infected patients have a high incidence of distal symmetric polyneuropathy. However, careful diagnostic evaluation should be undertaken to look for myriad other causes of neurologic compromise specific to the HIV-positive patient, including but not limited to herpes zoster or cytomegalovirus infection, tuberculosis, inflammatory demyelinating polyneuropathy (acute or chronic), and central nervous system complications of HIV. Currently available treatment modalities do not reverse painful neuropathy; the focus is on pain relief and palliation with available treatments.
Rehabilitation and Physical Medicine Options
Physical therapy
Physical therapy interventions may be more beneficial for general HIV symptoms such as fatigue and decreased mobility as opposed to neuropathic pain. Interventions directed at the individual’s functional capacity should be undertaken. Neuropathic pain, in general, has been shown to have a significant illness burden on the patient; high pain levels associated with poor function, compromised health status and sleep, and increased anxiety and depression have been documented. An outcomes-measure study of HIV-infected patients found that 27% had a mood disorder and 8.4% reported substance abuse. In this study, pain was considered an independent risk factor for the impairment in mobility, self-care, and usual activities and physiotherapy to address these impairments may be helpful.
Decreased mobility and lack of movement can be due to kinesophobia (fear of movement), and active therapy aimed at not only moving past these fears, but also improving balance, endurance, and posture may be beneficial. Aquatherapy can be considered for the population with neuropathic pain with limited tolerance for land-based therapies.
Occupational therapy
In the patient with HIV-associated neuropathic pain, occupational therapy can address functional limitations through several pathways. Goals should include energy conservation techniques for patients with endurance and mobility limitations, as well as body mechanics and environmental modifications. Patients whose pain includes a component of allodynia or hypersensitivity may benefit from a structured graded desensitization program. With regards to a patient’s work capacity, there may be a role for a work hardening/conditioning program that employs work-specific activities.
Psychiatric/behavioral/hypnosis
HIV-infected individuals with chronic pain often initiate some self-management strategies, including physical activity, social support, and cognitive and spiritual strategies. Brief hypnosis interventions may be beneficial in patients and allow for self-care/participation on behalf of the patient. Cognitive-behavioral therapy (CBT) has been employed for patients with neuropathic pain and can be a helpful self-management strategy that allows patients to cope with limiting thoughts of pain and disability. A 2003 randomized controlled trial demonstrated CBT as a useful intervention in the HIV-infected population.
Acupuncture has been explored as a treatment modality for HIV-distal sensory neuropathic pain. Studies investigating the use of acupuncture with and without the medication amitriptyline did not demonstrate either intervention as being better than placebo.
Orthotics
Orthotics may be helpful in patients with HIV-associated distal symmetric neuropathy who have muscle weakness. They may be beneficial with regards to improved mobility and perhaps function, but there is little evidence suggesting that they reduce neuropathic pain, particularly in HIV-associated neuropathy.
Transcutaneous electrical nerve stimulation
There is little evidence supporting the use of a transcutaneous electrical nerve stimulation unit with regards to HIV-associated neuropathy. It has been tried for acute herpes zoster neuropathy, also without consistent supporting findings, but it does appear to be safe. Passive modalities may facilitate patient participation in therapy but may not provide long-lasting benefit.
Medication Options
As a general rule, pharmacotherapy has been considered the mainstay of treatment for pain attributable to a neuropathy ( Box 11.4 ). It is noteworthy that HIV-infected patients continue to report moderate to severe chronic pain (not solely because of polyneuropathy) and elevated depression symptoms despite pharmacologic treatment. Specifically, with regards to pain from distal symmetric neuropathies in HIV-positive patients, the more recent literature suggests that commonly used medications are not as effective as they may be for other types of neuropathic pain. These findings suggest that an emphasis on nonpharmacologic therapies may be beneficial for HIV-related neuropathic pain.
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