Dr Faktorovich and Dr Simpson are with the Department of Neurology, Icahn School of Medicine, Mt Sinai, New York, NY.
Human immunodeficiency virus (HIV) is responsible for a wide spectrum of neurologic manifestations, with etiologies ranging from inflammatory, infectious, neoplastic. and more. The development of antiretroviral therapy (ART) has dramatically increased life expectancy, however neurologic complications remain a significant cause of long-term disability. Understanding and recognizing these conditions is crucial in effectively managing HIV.
Peripheral neuropathy is the most common neurological complication in HIV/AIDS, it affects between 30% to 60% of individuals. It can be related to the virus itself, ART neurotoxicity, and other comorbidities. Distal symmetric polyneuropathy (HIV-DSP) is the most common type of peripheral neuropathy, typically presenting with ascending numbness, paresthesia, and burning-type pain that occurs in a “stocking-glove” distribution.
Neurological evaluation reveals depressed ankle reflexes, increased vibratory threshold, and decreased sensation to pain and temperature. Proprioceptive loss, muscle weakness, and atrophy can be seen late in the disease course. Electrodiagnostic testing demonstrates a symmetrical, sensorimotor axonal neuropathy. Skin biopsy may also be useful, given the loss of epidermal nerve fibers which has been shown to correlate with clinical severity of DSP.1
In the pre-ART era, HIV-DSP was associated with high viral load and low CD4 count. However, since the development of ART, this association has not been clearly demonstrated. Furthermore, some anti-retroviral agents, specifically dideoxy-nucleoside reverse transcriptase inhibitors have neurotoxic effects on peripheral nerve. Although the presentation can be similar, drug-related peripheral neuropathy is typically rapidly progressive, often within weeks of initiating an offending agent. Recognition is important, as the neuropathy typically improves with discontinuing the agent.
Inflammatory demyelinating polyneuropathy
HIV-related, inflammatory demyelinating polyneuropathy can occur at any point in the disease course, presenting in the acute or chronic form, similar to non-HIV related inflammatory demyelinating polyneuropathy. Acute inflammatory demyelinating polyneuropathy typically occurs as a monophasic illness, with symptoms peaking around 2 weeks followed by variable recovery time. It is more commonly seen with CD4 count of greater than 200 cells/mm3 (eg, during seroconversion).2 Chronic inflammatory demyelinating polyneuropathy progresses over 8 weeks or more.
Clinical presentation usually involves progressive, ascending weakness that starts in the legs. Pain accompanies the condition in more than 80% of cases, described as dysesthesias and/or deep, aching pain in the legs or lower back.3 Symptoms are notable for areflexia, ascending weakness, and relative sparing of sensation although some sensory impairment can occur. As in HIV negative individuals, these conditions are thought to be immune-mediated. In advanced AIDS, additional studies (ie, viral testing and nerve biopsy) may be necessary to rule out primary cytomegalovirus (CMV) infection of the peripheral nerve.
Electrodiagnostic testing typically reveals a primarily demyelinating, sensorimotor neuropathy, although secondary axonal loss may occur, especially in chronic inflammatory demyelinating polyneuropathy. Unlike seronegative patients where high protein without pleocytosis in the cerebral spinal fluid is a classic finding; cerebrospinal fluid testing is less reliable in the HIV population. HIV patients can have mild lymphocytic pleocytosis. MRI studies are usually normal, however may reveal evidence of nerve root enhancement.
Treatment of these conditions relies on immunomodulatory therapies such as intravenous immunoglobulin, plasmapheresis, and with caution, steroids, as well as neuropathic pain medications as needed.
Progressive polyradiculopathy is a rare, rapidly progressive condition that may resemble cauda equina syndrome. It can be seen in advanced HIV/AIDS, often associated with CMV infection. MRI is crucial to rule out a lesion compressing the cauda equina as well as to evaluate for the presence of lumbosacral nerve root enhancement. cerebrospinal fluid testing most commonly reveals lymphocytic pleocytosis and positive CMV polymerase chain reaction. Early diagnosis and anti-viral treatment is crucial in preventing root necrosis and irreversible damage.
Mononeuritis multiplex presents as asymmetric, multifocal peripheral neuropathies affecting both motor and sensory modalities. Deep, aching pain or allodynia in affected regions is commonly described. Early on in the course of HIV, mononeuritis multiplex is typically an immune-mediated, self-limiting process. Opportunistic infections including CMV can be the cause in advanced HIV/AIDS and have a worse prognosis. Vasculitis is another possibility, which can be associated with HIV or coinfection with hepatitis C.
HIV infection is associated with a number of myopathies, although the mechanism by which HIV leads to muscle inflammation is not well understood. HIV-associated myopathy is the most common myopathy in these patients, typically presenting with a slowly progressive, symmetrical muscle pain and weakness affecting primarily proximal muscles. Laboratory results include elevated CK level, electrodiagnostic evidence of irritative myopathy and muscle biopsy revealing myofiber degeneration, often associated with inflammatory infiltrates. Although treatment guidelines have not been well established, immunomodulatory therapies including corticosteroids and IVIG have been successfully used.4 A similar condition, has been described in the setting of immune reconstitution inflammatory syndrome.
Additional inflammatory myopathies including dermatomyositis and inclusion body myositis has also been described.4 Furthermore, myopathy can be a rare adverse effect of zidovudine therapy. Infectious myopathies due to opportunistic infections such as Staphylococcus aureus can also occur.
Treatment of neuropathic pain
Pain, estimated to affect between 20% to 90% of HIV-infected individuals, is one of the most significant causes of disability in the HIV/AIDS population.5-7 Categorizing pain into two categories, nociceptive and neuropathic, is helpful in determining the appropriate treatment plan (Figure). Neuropathic pain, which is the focus of this section, results from abnormal neural transmission following an initial injury to the peripheral or CNS, which persists even in the absence of additional damaging stimuli. Aberrant reorganization of neural tissues after the initial injury can result in ongoing, abnormal signaling and chronic, neuropathic pain.
Pharmacologic therapy is the mainstay of treating neuropathic pain. Because of the lack of HIV-specific guidelines, current recommendations are based on those for other forms of peripheral neuropathy including diabetic neuropathy and post-herpetic neuralgia.
Multiple categories of drugs have long been used in the treatment of neuropathic pain. Among anti-depressants, tricyclic antidepressants including amitriptyline and nortriptyline have demonstrated efficacy in diabetic neuropathy, post-herpetic neuralgia as well as primary headaches, low back pain, and fibromyalgia. However, these agents failed to show benefit is HIV-related neuropathy.8,9 Of note, protease inhibitors may increase TCA serum levels, increasing the risk of toxic adverse effects.10
Several SNRIs including duloxetine and venlafaxine have shown benefit in the treatment of diabetic polyneuropathy and migraines, with fewer adverse effects than amitriptyline.11-13 These agents have unfortunately not been studied in HIV-related polyneuropathy. SSRIs have not shown any analgesic benefit.
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