Important note: Information in this article was accurate in July 2002. The state of the art may have changed since the publication date.
Peripheral nerve damage is one of the most common neurological complications of HIV infection and its treatment. Of these, the distal sensory neuropathies, which occur in the advanced stages of HIV disease, are the most common, affecting approximately 30% of AIDS patients. It is important, however, to recognize that other forms of peripheral nerve disease occur in HIV infection. Many are caused by other infectious agents and are therefore potentially treatable. This article will briefly review less common forms of peripheral nerve injury in HIV and will then focus on the HIV associated sensory neuropathies.
Peripheral Neuropathies other than HIV Associated Sensory Neuropathies
In the early phase of HIV disease, patients may develop acute or chronic inflammatory demyelinating neuropathy (AIDP, CIDP). AIDP, also known as Guillain Barré syndrome (GBS), can be the initial manifestation of HIV infection and is indistinguishable clinically and electrophysiologically from that seen in uninfected patients. One feature of HIV-associated AIDP is a mononuclear CSF pleocytosis accompanying elevated CSP. This contrasts with non-HIV GBS in which there are typically no cells in spinal fluid. The precise epidemiologic figures of AIDP in HIV disease are unknown, though there is some evidence that the pleocytosis from HIV infection is directly related to the neuropathy. The mainstay of treatment is plasmapheresis and IV immune globulin, and the prognosis does not appear to be different from non-HIV associated AIDP.
CIDP (Chronic inflammatory demyelinating polyneuropathy) may also be the presenting illness for HIV disease and generally occurs with CD4 counts between 200-500 cells/mm3. This condition can be thought of as a chronic form of GBS. Patients typically have absent or reduced reflexes as well as patchy numbness and weakness. CSF examination often shows a mild mononuclear pleocytosis in addition to an elevated protein. Treatment centers on immunomodulation and is potentially problematic in the setting of HIV disease given the pre-existing immuno-suppression. Corticosteroids, plasmapheresis, IVIG and cyclosporin have all been used successfully. No clear guidelines for anti-retroviral therapy exist, though it seems prudent to avoid potentially neurotoxic agents.
Mononeuropathies such as Bell’s palsy have been suggested to occur at higher rates in HIV-infected people, though precise figures are unknown. Mononeuropathy multiplex (MM) can occur early in HIV disease as a result of immune dysfunction or vasculitis. Clinically, these patients have asymmetric, patchy sensory or motor deficits. In vasculitis, pain generally precedes motor or sensory deficits. Nerve biopsy is necessary to confirm the diagnosis. Electrodiagnostic testing is helpful in confirming asymmetric abnormalities, excluding multiple entrapment neuropathies as well as in identifying an appropriate site for biopsy. Therapy is determined by etiology, with vasculitis requiring immunosuppression.
An often painful, distal sensorimotor neuropathy associated with CD8 hyper-lymphocytosis and a Sjögren’s-like syndrome can occur during symptomatic HIV infection and potentially could be confused with
HIV-associated sensory neuropathy. This disorder has been termed diffuse infiltrative lymphocytosis syndrome (DILS). Only patients with CD8 hyperlymphocytosis and MHC class HLA DR5 or DR6 alleles appear to be at risk, and the mean CD4 cell count in DILS patients is 260 cells/mm3, with one third having AIDS. Clinically, DILS develops as a subacute, often painful neuropathy commonly accompanied by parotid enlargement and sicca syndrome. Many patients have systemic involvement, such as lymphadenopathy, splenomegaly or intersitial pneumonia. Electrodiagnostic testing generally reveals a length-dependent axonal process, though evidence of demyelination is present in 15% of cases. CSF analysis is notable for a
nonspecific mononuclear pleocytosis and striking xanthochromia. Pathology reveals a non-destructive angiocentric T cell infiltrate in the epi- and endoneurium. Treatment is centered on HIV suppression, with HAART resulting in complete recovery in two-thirds of patients.
A progressive polyradiculopathy (PP) can develop in patients with advanced HIV disease and CD4 cell counts of 50 cells/mm3 or less. Patients usually present with subacute low back and radicular pain over a period of days. Weakness progresses to flaccid paralysis with sensory loss and frequently urinary difficulties. The upper extremities are rarely involved. The most common cause is CMV, with approximately 10% of cases occurring while on CMV maintenance therapy and 38% having evidence of CMV infection elsewhere, usually retinitis. Other causes include lymphomatous meningitis, syphilitic radiculopathy, herpes simplex or herpes zoster myeloradiculopathy, toxoplasmosis, and mycobacterial infection. CSF analysis is essential in distinguishing among these possibilities. A predominant polymorpho-nuclear pleocytosis, commonly above 200 cells/mm3, with a low CSF glucose is typical of CMV infection. CSF cytology, VDRL and viral PCR studies are also useful, while imaging studies are important in ruling out mass lesions. Early recognition and treatment of CMV polyradiculopathy can prevent an otherwise devastating outcome.
A mononeuropathy multiplex occurring in the setting of advanced HIV disease is almost always due to CMV infection. As with CMV polyradiculopathy, evidence of CMV infection elsewhere is common, particularly in the retina. CSF analysis in CMV mono-neuropathy multiplex differs from CMV PP in that a polymorphonuclear pleocytosis is often not present, though CMV PCR is usually positive. Most patients improve after treatment with foscarnet or ganciclovir.
The HIV Associated Sensory Neuropathies
The most common peripheral nerve complication in HIV infection is a length-dependent, axonal sensory neuropathy that is dominated by neuropathic pain. The HIV associated sensory neuropathies (HIV-SN) include both distal sensory polyneuropathy (DSP) due to IV infection, and antiretroviral drug toxic neuropathy (ATN) caused by the dideoxynucleosides (ddC, d4T, and ddI). These two forms of HIV-SN are pheno-typically identical and affect approximately 30% of AIDS patients. They are characterized by painful dysesthesias in the feet and legs, described as “painful numbness,” “aching,” or “burning.” HIV-SN is a major source of morbidity among AIDS patients. Symptoms are generally worse at night and can be aggravated by innocuous stimuli, such as bed sheets or wearing shoes. Abnormalities on examination are generally limited to sensory nerve fibers and include reduced or absent ankle reflexes and increased vibratory and pin thresholds. Affected patients can often test normally on routine nerve conduction testing. This reflects the prominent small caliber sensory nerve involvement in HIV-SN and the fact that these nerves are “invisible” to nerve conduction/EMG testing. Skin biopsy and visualization of epidermal nerve fibers is a useful diagnostic tool in such instances.
DSP is associated with advanced HIV disease, with lower CD4 count and higher viral load being risk factors. An association between viral set point and the subsequent development of HIV-SN has been suggested. Autopsy studies have demonstrated pathological abnormalities in the peripheral nerves of virtually all patients dying from AIDS, and sub-clinical abnormalities in peripheral nerve function are common on detailed testing. This suggests a gradual progression of nerve damage in HIV disease with much of it being silent, before development of DSP. HIV itself appears to play an indirect role in the development of DSP in that macrophage activation and aberrant proinflammatory cytokines are thought to mediate the neurotoxicity.
While the incidence of most neurological complications of HIV has fallen dramatically over the past decade, HIV-SN has become more prevalent, coinciding with the use of dideoxynucleoside drugs. ATN has sub-sequently emerged as a common cause of HIV-SN.
The only distinguishing characteristic of ATN is the temporal association with use of dideoxynucleoside NRTIs; otherwise the two conditions are virtually indistinguishable. The onset of ATN ranges from one week to 6 months, depending on the NRTI and the dose administered. Symptoms may continue to worsen after discontinuation of the offending agent, followed by improvement in most but not all patients over a period of weeks to months. Pathophysiologically, ATN differs from DSP and has been linked to mitochondrial dysfunction. Importantly, patients with pre-existing DSP appear to be at increased risk of developing ATN. Dideoxynucleoside NRTIs may trigger neuropathic symptoms in patients with pre-exiting, silent neuronal damage due to HIV infection.
Treatment of HIV-SN is largely symptomatic. In the case of ATN, the suspected offending agent should be discontinued or the dose reduced, if possible. Several agents that have been effective in other painful neuropathies have not shown efficacy in HIV-SN, including amitriptyline, mexiletine, topical capsaicin and acupuncture. Both 5% lidocaine and gabapentin have been used successfully in open-label trials, but controlled data is lacking. Anecdotal evidence suggests that topiramate may also be beneficial. Currently, the only therapies shown to be effective in randomized, placebo-controlled clinical trials are lamotrigine and recombinant human nerve growth factor, of which the latter is not commercially available. The beneficial effect of lamotrigine appears to be most pronounced in ATN patients, and the risk of rash is minimal if the dose is slowly titrated upwards. Both lamotrigine and topiramate have the added advantage of not affecting the cytochrome P450 pathway and therefore not interacting with antiretroviral agents.
Peripheral nerve disease is common in HIV infection. Other infectious causes are infrequent but important to recognize, as they are potentially treatable. HIV-SN is the most prevalent neuropathy associated with HIV infection and is now the most common neurological complication of HIV disease. Two forms of HIV-SN exist, distal sensory polyneuropathy (DSP) related to macro-phage and cytokine dysregulation resulting from HIV infection and antiretroviral toxic neuropathy (ATN), produced by mitochondrial dysfunction. ATN can require alteration of antiviral regimens at the risk of reducing virologic control and may act to trigger or unmask clinically silent HIV-mediated neuropathy.
Dr. Polydefkis is an Assistant Professor of Medicine in the Department of Neurology, Johns Hopkins University, School of Medicine.
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