HIV-associated peripheral neuropathy

Prevalence and Risk Factors of HIV-Associated Peripheral Neuropathy... 

Paice JA, Ferrans CE et al (2000) Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symptom Manage 19(l) 45-52 Palella FJ Jr, Delaney KM et al (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338(13) 853-860... 

The reported risk factors for HIV-associated sensory neuropathy are varied and may have changed since the availability of HAART. In the pre-HAART era, age, nutritional deficiencies, alcohol exposure, higher HIV viral load, and low CD4 counts (Moyle and Sadler 1998 Childs et al. 1999), as well as mood, other neurologic disorders and functional abnormalities (Schifitto et al. 2002) were neuropathy risk factors. In the HAART era, the use of NRTI (Cherry et al. 2006 Pettersen et al. 2006) and exposure to protease inhibitor (PI) medication (Pettersen et al. 2006 Smyth et al. 2007) are considered additional risk factors. Although hepatitis C mono-infection has been associated with peripheral nerve disease, and there is... 

Abrams DI, Jay CA et al (2007) Cannabis in painful HIV-associated sensory neuropathy a randomized placebo-controUed trial. Neurology 68(7) 515-521 Anderson TD, Davidovich A et al (1992) Peripheral neuropathy induced by 2 , 3 -dideoxycytidine. 

Kennedy JM, Hoke A et al (2004) Peripheral neuropathy in lentivirus infection evidence of inflammation and axonal injury. AIDS 18(9) 1241-1250 Keswani SC, Pardo CA et al (2002) HIV-associated sensory neuropathies. AIDS 16(16) 2105-2117... 

Distal sensory peripheral nenropathy (DSPN) has been associated with the nse of ddC, ddl, and stavndine, alone or in combination. The symptoms of this condition inclnde a bnming sensation in feet and hands, nnmbness and tingling in the feet, cramps in the legs, and absent ankle reflexes. The patient may also exhibit decreased sensation to temperatnre, pinprick, vibration, and proprioception (Dieterich, 2003). The symptoms are similar to HIV associated axonal neuropathy. This condition may become irreversible, so it is important to diagnose it earlier. The treatment of choice is symptomatic therapy and discontinuation of the toxic agent when possible. 

Peripheral neuropathy may be the most frequent neurologic disorder associated with HIV infection (Cherry et al., 2005). Its symptoms cause substantial morbidity and discomfort to patients with AIDS. A 30%-35% prevalence of peripheral neuropathy has been documented in patients with HIV infection, but autopsy-based studies have found it in nearly 100% of patients who died of AIDS. The most common peripheral neuropathy associated with HIV occurs in the later stages of HIV disease, usually after the patient has had other AIDS defining illnesses. Symptoms of HIV-associated sensory neuropathies are almost identical to those of other sensory neuropathies. Both distal sensory neuropathy due to HIV infection (seen mainly in late disease) and antiretroxdral toxic neuropathy occur, or sensory neuropathy is caused by a combination of both (Cherry et al., 2005). 

There is a similar high prevalence of peripheral neuropathy (34%) in the pediatric population infected with HIV (Araujo et al. 2000). The frequency of IDP in the HIV-infected population is unknown but is thought to be rare (Wulff et al. 2000). In an outpatient population of HIV positive patients, mononeuritis multiplex and lumbosacral polyradiculopathy were found in less than 1% of patients with AIDS (Fuller et al. 1993). HIV-associated autonomic nervous system dysfunction is also not uncommon as up to 66% of patients have papillary involvement and 15% have sympathetic and parasympathetic involvement causing orthostatic hypotension and respiratory sinus arrhythmia (Gluck et al. 2000). 

The phenotype and clinical presentation of antiretroviral toxic neuropathy (ATN) are similar to those of HIV-associated DSP. However, ATN is more likely to be painful, and has an abrupt onset and rapid progression. The main diagnostic clue is the temporal relationship of peripheral neuropathy to the start of NRTI therapy and stabilization, or at least the partial resolution when therapy is interrupted (Moyle and Sadler 1998). ATN most often develops after a mean of 16 to 20 weeks of treatment, unless there are other conditions that lower the threshold. Symptomatic improvement over weeks to months has been reported in two thirds of patients after discontinuation of the offending drug, but may be preceded by an initial period of worsening symptoms, also known as coasting (Berger et al. 1993). Despite the improvement, most patients do not return to a completely asymptomatic state (Hoke and Comblath 2004). 

Overall, it appears that immune reconstitution is only rarely associated with peripheral neuropathies in HIV-infected individuals. 

The neuropathological analysis of HIV-associated neuropathies should include the different central and peripheral nervous system structures associated with sensory pathways, including spinal cord, dorsal root ganglia (DRG), peripheral nerve, and cutaneous nerve fibers (Pardo et al. 2001) (Fig. 4.1). The majority of studies have focused on the evaluation of the peripheral nerve, often from sural nerve biopsies and the DRG. Few studies have examined the pathology of sensory pathways in the... 

Cornblath DR, Hoke A (2006) Recent advances in HIV neuropathy. Curr Opin Neurol 19(5) 446-450 Cornblath DR, McArthur JC (1988) Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology 38(5) 794-796 Cornblath DR, McArthur JC et al (1987) Inflammatory demyeUnating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol 21(l) 32-40 Corral I, Quereda C et al (1997) Acute poly radiculopathies in HIV-infected patients. J Neurol 244(8) 499-504... 

Cui L, Locatelli L et al (1997) Effect of nucleoside analogs on neurite regeneration and mitochondrial DNA synthesis in PC-12 cells. J Pharmacol Exp Ther 280(3) 1228-1234 Dal Pan GJ, Glass JD et al (1994) Clinicopathologic correlations of HIV-l-associated vacuolar myelopathy an autopsy-based case-control study. Neurology 44(11) 2159-2164 Dalakas MC (2001) Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 6(l) 14-20 Dalakas MC, Semino-Mora C et al (2001) Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2 3 -dideoxycytidine (ddC). Lab Invest 81(11) 1537-1544... 

Le Lostec Z, Fegueux S et al (1994) Peripheral neuropathy associated with cryoglobuUnaemia but not related to hepatitis C virus in an HIV-infected patient. AIDS 8(9) 1351-1352 Leger JM, Henin D et al (1992) Lymphoma-induced polyradiculopathy in AIDS two cases. J Neurol 239(3) 132-134... 

Riedel DJ, Pardo CA et al (2006) Therapy Insight CNS manifestations of HIV-associated immune reconstitution inflammatory syndrome. Nat Clin Pract Neurol 2(10) 557-565 Rizzuto N, Cavallaro Tet al (1995) Role of HIV in the pathogenesis of distal symmetrical peripheral neuropathy. Acta Neuropathol 90(3) 244-250... 

Skopehtis EE, Kokotis PI et al (2006) Distal sensory polyneuropathy in HIV-positive patients in the HAART era an entity underestimated by clinical examination. Int J STD AIDS 17(7) 467-472 Smyth K, Affandi JS et al (2007) Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006. HIV Med 8(6) 367-373 Snider WD, Simpson DM et al (1983) Neurological complications of acquired immune deficiency syndrome analysis of 50 patients. Ann Neurol 14(4) 403-418 So YT, Olney RK (1994) Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome experience in 23 patients. Ann Neurol 35(l) 53-58 So YT, Holtzman DM et al (1988) Peripheral neuropathy associated with acquired immunodeficiency syndrome. Prevalence and clinical features from a population-based survey. Arch Neurol 45(9) 945-948... 

Neurologic symptoms Motor weakness has been reported rarely. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy. Stavudine therapy has been associated with peripheral neuropathy, which can be severe and is dose-related. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see Adverse Reactions). 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

Grunke M, Kraetsch HG, Low P, Rascu A, Kalden JR, Harrer T. Nelfinavir associated with peripheral neuropathy in an HIV-infected patient. Infection 1998 26(4) 252. 

Certain adverse reactions can also be associated with individuals who are carriers of rare disease genes, patients with compromised immune systems, and patients with certain chronic diseases. Peripheral neuropathy from anticancer drugs such as vincristine can be accelerated in specific patients with Charcot-Marie tooth syndrome [38], Park et al. [39] has discussed potential mechanisms that make HIV-positive patients more susceptible to enhanced drug toxicity, and Graham et al. [40] showed that the risk of developing rhab-domyolysis from statin-fibrin combinations increased significantly in older patients with diabetes mellitus. 

Zalcitabine toxicides are similar to those of the other dideoxynucleoside analogs didanosine and stavudine. Severe peripheral neuropathy has been reported in up to 15% of patients. Peripheral neuropathy is dose related and more common with preexisting HIV-associated neuropathy and advanced HIV disease. This is a symmetrical dislal sensory neuropathy that begins in the feet but may progress to a stock-ing/glove distribution. Other specific risk factors for neuropathy include alcohol consumption, diabetes, and low vitamin Bi2 concentrations. If the dmg is stopped as soon as symptoms appear, the neuropathy usually stabilizes and should improve or resolve. Pancreatitis occurs rarely with zalcitabine therapy and appears to be less frequent than with didanosine. 

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