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by Thorsten Rosenkranz and Christian Eggers

Polyneuropathy and polyradiculopathy

Peripheral neuropathies may complicate all stages of HIV infection. During the early asymptomatic stages peripheral neuropathies are uncommon, but electrodiagnostic testing reveals subclinical evidence of peripheral nerve involvement in about 10 % of cases. In later stages, symptomatic neuropathies occur in some 30-50 % of patients. Neuropathological studies have shown pathological changes with a prevalence approaching 100 % in patients with AIDS.

The neuropathies can be classified as primary HIV-associated or as secondary diseases caused by neurotoxic substances or opportunistic infections. Although neuropathies related to HIV infection have been on the decline since the introduction of HAART, there has been an increase in the prevalence of toxic neuropathies (Authier 2003). Different types of peripheral neuropathies can be distinguished on the basis of when they occur with respect to the stage of HIV disease, and by the clinical course, major symptoms and electrophysiological and neuropathological features.

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Clinical features Acute inflammatory demyelinating polyneuropathy (AIDP), Guillain-Barré syndrome (GBS) AIDP usually occurs at seroconversion or at asymptomatic stages of HIV infection. In addition, it seems to be rarely associated with immune reconstitution (Piliero et al. 2003). The typical clinical presentation is that of areflexia, symmetrical ascending weakness and relative sparing of sensory nerve fibers. Involvement of cranial nerves and cervical and thoracic spinal nerves leads to respiratory insufficiency, dysarthria and dysphagia. Parasympathetic and sympathetic nerve involvement may cause life threatening cardiac arrhythmias and severe arterial hypo- or hypertension. Cerebrospinal fluid (CSF) typically shows a raised concentration of protein caused by the dysfunction of the blood-CSF-barrier. In contrast to HIV-negative patients with AIDP, a moderate pleocytosis of up to 50 leucocytes/µl CSF is found in most HIV-positive patients. The progressive stage is followed by a few days or weeks of stable disease until recovery begins. If secondary axonal damage has occurred, recovery can last up to two years. A persistent disability of varying degrees develops in about 30 %. Table 1: Polyneuropathies and polyradiculopathies in HIV infection Type HIV infection Clinical features Findings Primary HIV-associated polyneuropathies Acute, inflammatory, demyelinating polyneuropathy (Guillain-Barré syndrome, GBS) Seroconversion, asymptomatic, no or beginning immunosuppression Symmetrical weakness > sensory loss, areflexia ENG with demyelinating features, elevated CSF protein and moderate CSF-pleocytosis (< 50 c/µl) Chronic demyelinating inflammatory polyneuropathy (CIDP) Asymptomatic beginning immunosuppression, rarely AIDS Distal and proximal weakness > sensory loss, areflexia ENG with demyelinating features, elevated CSF protein and moderate CSF-pleocytosis (< 50 c/µl) Vasculitic neuropathy Asymptomatic no or beginning immuno-suppression, rarely AIDS Mostly asymmetric, acute loss of function of single nerves, rarely distal symmetrical sensory and motor disturbances Elevation of ANA, cryoglobulinemia, hepatitis C virus coinfection; vasculitis in nerve biopsy but also in muscle, kidney and other organs Neuropathy in diffuse, infiltrative leukocytosis syndrome (DILS) Moderate immuno-suppression Mostly asymmetrical weakness and sensory loss, rarely distal symmetrical disturbances Disease resembling Sjögren's syndrome; CD8+ cells > 1200/µl Distal symmetrical sensory polyneuropathy (DSSP) AIDS or advanced immuno-suppression Distal symmetrical sensory loss, paresthesia and pain of the legs ENG with axonal features predominantly involving sensory nerves of the legs Secondary polyneuropathies Medication-related toxic neuropathy Beginning or advanced immuno-suppression Distal symmetrical sensory loss, paresthesia and pain of the lower legs Treatment with ddI, ddC, d4T, vincristine, dapsone Acute neuromuscular weakness syndrome Beginning or advanced immuno-suppression Acute progressive tetraparesis Lactic acidosis during NRTI treatment, axonal nerve damage, additional myopathy Mononeuritis multiplex in CMV-infection or non-Hodgkin lymphoma AIDS Asymmetric, acute loss of function of single nerves CMV infection of other organs, CMV DNA detection in plasma; non-Hodgkin lymphoma Polyradiculitis in CMV or M. tuberculosis infection or due to meningeal lymphoma AIDS Flaccid paraparesis, sensory loss, bladder dysfunction CMV or mycobacterial infection at other sites, detection of mycobacteria in CSF, malignant cells in CSF Chronic, inflammatory, demyelinating polyneuropathy (CIDP) Whereas AIDP is a monophasic, self-limiting disease, the course of CIDP is chronic progressive or relapsing-remitting. Weakness and sensory disturbances commonly develop over several months. In some cases, relapses, incomplete remissions and periods of stable disease alternate with each other. In CIDP, as in AIDP, the CSF is abnormal with an elevated protein level. A moderate pleocytosis is often found instead of the classical acellularity. The underlying pathological mechanisms of both AIDP and CIDP seem to be macrophage and complement-mediated demyelination. The reason why a chronic persistence of the autoimmune process occurs in CIDP is unknown. CIDP is a rare complication of seroconversion or the early stages of infection before AIDS. Vasculitic neuropathy Necrotizing vasculitis with involvement of peripheral nerves is a rare cause of neuropathy in HIV infection. Most patients develop a mononeuritis multiplex characterized by acute, relapsing dysfunction of individual peripheral nerves. The prognosis of the disease is determined by the involvement of other organs such as heart, kidneys or muscles in the vasculitic process. An immune complex attack associated with Hepatitis C virus infection or cryoglobulins appears to play an essential role in the pathological mechanism. Diffuse infiltrative lymphocytosis syndrome (DILS) DILS is a rare cause of distal symmetrical and often painful neuropathy. It resembles Sjögren's syndrome, but has multivisceral infiltration characterized by CD8 hyperlymphocytosis (CD8+ T-cell count >1000/µl). Sicca syndrome with parotidomegaly, lymphadenopathy, splenomegaly, pneumonitis and renal dysfunction may occur in association with axonal neuropathy (Gherardi 1998). Distal symmetrical sensory polyneuropathy (DSSP) DSSP is the most common neuropathy in HIV-positive patients and becomes symptomatic in the later stages of infection when the CD4+ T-cell count is at or below 200/µl. The clinical course is predominated by slowly progressive sensory symptoms such as numbness, dys- and paresthesia of feet and lower legs (Table 2). Approximately 30-50 % of patients complain of burning, lacerating or stabbing pain. It mainly involves toes and soles and sometimes makes walking difficult. Leading clinical findings are depressed or absent ankle reflexes, an elevated vibration threshold at toes and ankles and decreased sensitivity to pain and temperature in a stocking distribution, whereas proprioception is usually normal. Weakness and atrophy of intrinsic foot muscles are mild and are not features of the disease. The fingers and hands are rarely involved. Involvement of the upper legs and trunk, significant weakness of leg muscles or decreasing proprioception are not typical for DSSP and should raise suspicion of other disorders, for instance a conjoined myelopathy. Loss and dysfunction of small sympathetic and parasympathetic nerve fibers may cause postural hypotension, erectile dysfunction, gastroparesis and alterations of skin or nails in many DSSP patients. Table 2: Clinical features of distal symmetrical sensory polyneuropathy Numbness, pain, dys- and paresthesia of the feet and lower legs Decreased or absent deep ankle tendon reflexes Decreased or absent vibratory sense of the toes and ankles No or only minimal motor dysfunction No or only minimal involvement of the hands and arms Slowly progressive course Electrodiagnostic studies with features of axonal nerve damage Autonomic dysfunction: orthostatic hypotension, erectile dysfunction Medication-related toxic neuropathy A distal symmetrical sensory peripheral neuropathy occurs in about 10-30 % of patients treated with ddI, d4T or ddC. It is indistinguishable from HIV-induced DSSP on clinical examination or in electrodiagnostic studies. The only difference is in the exposure to neurotoxic nucleoside antiretroviral medication. Brew et al. (Brew 2003) found an elevation of serum lactate in over 90 % of patients with d4T-related neuropathies. Nucleoside neuropathy develops after a mean of 12-24 weeks of treatment. After withdrawal, there can be a temporary worsening for 2-4 weeks and improvement usually begins after 6-12 weeks. In several cases the restitution remains incomplete. In these cases there may have been an additional pre-existent damage to the peripheral nerves due to the HIV infection. Subclinical disturbance of peripheral nerve function confirmed by pathological findings in electrodiagnostic studies elevates the risk of developing NRTI-related neuropathy. In the American TORO-1 study, 11 % of patients treated with T-20 (enfurvitide) developed neuropathy versus 5 % in the control group (Lalezari 2003), but the European TORO-2 study did not confirm these results (Lazzarin 2003). Whether protease inhibitors (indinavir, saquinavir, ritonavir, and atazanavir) increase the risk of neuropathy, is still a matter of debate (Crabb 2004, Pettersen 2006) Table 3: Neurotoxic drugs frequently used in HIV medicine NRTI ddI, ddC, d4T Antibiotic dapsone, metronidazole, isoniazid Cytotoxic vincristine Acute neuromuscular weakness syndrome In the course of a NRTI-induced lactic acidosis a life threatening tetraparesis resembling AIDP may occur. In most cases axonal peripheral nerve damage was found, but in a few patients demyelination was also detected. In addition, muscle biopsy revealed myositis or mitochondrial myopathy in some cases (Simpson 2004). Table 4: Diagnostic work-up Procedure Findings Condition Basic examinations (recommended for all cases) Medical history Drugs Opportunistic diseases Alcohol abuse Medication-related toxic PNP Neuropathy associated with CMV infection or lymphoma Alcoholic PNP Neurological examination Clinical type of PNP (distal symmetrical, mononeuritis multiplex, etc.) Symptoms not due to myelopathy or myopathy Electromyography Electroneurography Confirmation of neuropathy Demyelinating features Axonal features Symptoms not due to myelopathy or myopathy AIDP, CIDP DSSP, Multiplex Neuropathy, DILS Blood tests HbA1c, glucose Vit B12, B1, B6, Fe, ferritin ANA, cryoglobulins, HCV-serology, circulating immune complexes, ANCA TPHA CD8+ T-cells > 1200/µl lactate CMV DNA (if CD4+ T- cells < 100/µl) Diabetic polyneuropathy PNP due to malnutrition or malassimilation Vasculitic neuropathy Neurosyphilis Neuropathy associated with DILS NRTI-induced toxic neuropathy Mononeuritis multiplex due to CMV-infection Additional tests (necessary only in particular cases) CSF Elevated total protein Pleocytosis (granulocytes), CMV DNA Lymphoma cells, EBV DNA Elevated IgA, acid fast bacilli, mycobacterial DNA AIDP, CIDP Polyradiculitis due to CMV infection Lymphomatous meningitis Tuberculous polyradiculitis Autonomic tests (sympathetic skin reaction, heart rate variability) Involvement of sympathetic or parasympathetic nerves Additional autonomic neuropathy MRI (lumbar spine) Compression of the cauda equina Spinal lymphoma Spinal toxoplasmosis Nerve and muscle biopsy Necrotizing vasculitis Perivascular CD8 infiltration without necrosis Vasculitic neuropathy DILS-associated neuropathy Polyneuropathy and polyradiculopathy due to other diseases In patients with advanced HIV disease, mononeuritis multiplex may be caused by CMV infection or non-Hodgkin lymphoma. Acute or subacute polyradiculopathies of the cauda equina with rapidly progressive flaccid paraparesis of the legs, bowel dysfunction and sensory disturbances occur in the course of opportunistic infections (CMV, M. tuberculosis) or meningeal non-Hodgkin lymphoma. Other important causes of a polyneuropathy are alcohol abuse, diabetes mellitus, malnutrition in patients with long lasting gastrointestinal diseases, neoplastic diseases or cachexia. Diagnosis A diagnosis of neuropathy can usually be made based on medical history and clinical examination. Electrodiagnostic studies may be performed for confirmation and for differentiation from other diseases such as myelopathy. Cerebrospinal fluid analysis may be necessary if there is a suspicion of infection with, for example, CMV or syphilis. Sural nerve and muscle biopsy may only be necessary in atypical cases - for instance painful DSSP with a high CD4+ T-cell count and low viral load and without neurotoxic medication or other risk factors. Table 4 gives some recommendations for practical purposes in clinical practice. Treatment Causative treatment options only exist for some of the rare neuropathies or polyradiculopathies. Intravenous immunoglobulins and plasmapheresis have been proved effective in the therapy of AIDP. Corticosteroids are also effective in CIPD. In clinical trials on the treatment of CIDP, no difference in the efficacy of immunoglobulins, plasmapheresis or corticosteroids has been shown. However, an individual patient may just respond to one out of the three procedures. In patients who only respond to higher dosages of corticosteroids, other immunosuppressive agents such as azathioprine, low dose weekly methotrexate or cyclosporin may replace long term steroid therapy. We have seen CIDP patients who were in partial remission after temporary steroid therapy and who have remained stable for years with ART alone. In medication-related neuropathy the offending agent should be withdrawn. However, replacement of ddI or d4T might be difficult in some cases of multiple drug-resistant HIV infection. In this situation, the reduction in the quality of life by neuropathic symptoms must be balanced against the risk of deterioration of immunological and viral parameters. A small open-label study with 2 x 3,500 mg L-acetyl-carnitine resulted in peripheral nerve regeneration, demonstrated in skin biopsies, and in improvement of neuropathic symptoms induced by neurotoxic NRTI (Hart 2004). Two small open studies confirmed the effectiveness of L-acetyl-carnitine in reducing pain in patients with neurotoxic neuropathy (Herzmann 2005, Osio 2006), but a randomized controlled trial is still lacking. A causative treatment for DSSP does not exist. ART might improve the function of sensory nerves in a few cases, and therefore starting ART or optimizing a current ART should be considered in newly diagnosed DSSP. In most cases the neuropathic symptoms still persist. Symptomatic treatment is directed at irritative symptoms such as pain and paresthesia. It is not effective against deficits of nerve function including sensory loss or weakness. Table 5: Causative treatment of polyneuropathies and polyradiculopathies Condition Treatment AIDP Intravenous immunoglobulins 0.4 g/kg daily for 5 days or: plasmapheresis (5 x in 7-10 days) CIDP Intravenous immunoglobulins 0.4 g/kg daily for 5 days or: plasmapheresis (5 x in 7-10 days) or: prednisone 1-1.5 mg/kg daily for 3-4 weeks with subsequent tapering for 12-16 weeks Vasculitic neuropathy Prednisone 1-1.5 mg/kg daily for 3-4 weeks with subsequent tapering for 12-16 weeks Neuropathy due to DILS Start or improvement of ART plus prednisone 1-1.5 mg/kg daily for 3-4 weeks with subsequent tapering for 12-16 weeks Distal symmetrical sensory polyneuropathy A causative treatment is not known, ART may improve nerve function, for symptomatic treatment. See table 6 Medication-related toxic neuropathy Withdrawal of the neurotoxic substances, if possible. Mononeuritis multiplex or polyradiculitis due to CMV-infection Intravenous foscarnet 2 x 90 mg/kg daily plus intravenous ganciclovir 2 x 5 mg/kg daily. Lymphomatous meningitis Start or improvement of ART plus intrathecal methotrexate (intraventricular shunt or lumbar puncture) 12-15 mg 2 x/weekly until CSF is free of malignant cells, subsequently 1 x/week for 4 weeks and subsequently 1 x/month plus 15 mg oral folinate after each injection plus systemic treatment of lymphoma (see chapter "Malignant Lymphoma") Polyradiculitis due to infection with M. tuberculosis Treat tuberculosis (see chapter "OIs") The agents listed in table 6 are recommended because they have proved useful in daily practice and because they interfere only slightly and in a predictable way with ART. A controlled study showed that lamotrigine was effective in reducing the symptoms of neurotoxic neuropathy (Simpson 2003). The drug is well tolerated if one adheres to the slow dose escalation regimen and stops treatment or reduces the dose when a skin reaction occurs. In a small study, gabapentin was shown to be effective in reducing DSSP-induced pain (Hahn 2004). The advantages of this substance are good tolerability and lack of interference with ART. Pregabalin, an anticonvulsant drug similar to gabapentin, has recently been approved for the treatment of painful neuropathy. It effectively relieves pain in studies of patients with painful diabetic peripheral neuropathy. Like gabapentin, it does not interfere with ART and is well tolerated. We are successfully treating an increasing number of patients with DSSP and neurotoxic neuropathy with this new substance. A randomized controlled trial could not detect a therapeutic benefit of lidocaine 5 % gel for the treatment of pain in HIV-associated neuropathy (Estanislao 2004). Table 6: Symptomatic treatment of painful neuropathy Treatment Adverse effects Step 1: Physical therapy, supporting measures (wide shoes, etc.), L-acetyl-carnitine 2 x 2-4 g Rarely allergy, mild diarrhea Step 2: Temporarly 3-4 x 1000 mg paraceta-mol or 2-3 x 50 mg diclofenac or 4 x 40 drops novaminsulfone for 10-14 days Nausea, vomiting, allergy (rarely) Step 3: Gabapentin 300 mg at night, dose escalation of 300 mg a day every third day up to a maximum of 3 x 1200 mg or Pregabalin 2 x 75 mg for 1 week, dose escalation to 2 x 150 in 2nd week, possible escalation up to 2 x 300 mg or Lamotrigine 25 mg at night, dose escalation of 25 mg every 5 days up to 300 mg or Amitriptyline 25 mg at night, dose escalation of 10-25 mg every 2-3 days up to 3 x 50 mg o r Nortriptyline 25 mg in the morning, dose escalation of 25 mg every 2-3 days up to 2-3 x 50 mg or Duloxetine 1 x 60 mg in the morning Sedation, nausea, dizziness, rarely pancreatitis Nausea, vomiting, diarrhea, allergic drug rash Allergy, sedation, cephalgia, nausea Sedation, orthostatic hypotension, constipation, dizziness, dry mouth, dysrhythmia, retention of urine, caveat: glaucoma Orthostatic hypotension, constipation, dizziness, dry mouth, dysrhythmia, retention of urine, caveat: glaucoma Nausea, diarrhoe, agitation Step 4: Flupirtine 3 x 100, dose escalation up to 3 x 600 mg or Retarded morphine 2 x 10 mg gradual escalation up to 2 x 200 mg Sedation, constipation, nausea Sedation, constipation, nausea General practice Proceed one step if symptoms persist. Substances within step 3 may be combined (for instance an anticonvulsant and an antidepressant), substances of step 3 and step 4 may also be combined (for instance flupirtine and an anticonvulsant). If a rapid relief of symptoms is necessary, treatment should be started with step 4 substances and a low dose step 3 drug should simultaneously be started with slow escalation. The slower the escalation the greater the possibility of reaching an effective dosage. The tricyclic antidepressants amitriptyline and nortriptyline both have significant anticholinergic side effects. The dose necessary for reducing neuropathic pain is in the same range as for treating depression and many patients do not tolerate these dosages. However, lower dosages have proved ineffective in DSSP. Nortriptyline has no sedative side effects. We use this substance with good success rates, although clinical trials for its use in HIV-associated neuropathy are lacking. Duloxetine is the first of the new antidepressants that has proved effective in painful diabetic neuropathy. In our first experience, it seems to be also effective in HIV-related DSSP and toxic neuropathy. The anticonvulsant carbamazepine is widely used for the treatment of neuropathic pain. However, it induces some enzymes of the CYP450 system and interferes significantly with ART. Thus its use in HIV medicine is very limited. Potent opioids may be used to manage moderate or severe pain if a slow dose esca-lation of an antidepressant or anticonvulsant is not possible and an immediate anal-gesic effect is desired (Sindrup 1999). Even in cases of substituted or non-substituted drug abuse, opioids should be used (Breitbart 1997). Sometimes, the dosage of methadone must only be moderately increased for a sufficient analgesic effect. Myopathy Myopathies occur in 1-2 % of all HIV patients. They may appear at any stage of the disease. Table 7 gives a synopsis of the most important types of myopathy in HIV infection. Polymyositis mediated by cytotoxic T-cells is the most common HIV-associated myopathy. AZT-induced myopathy occurs very infrequently with the AZT dosages used today. Some substances commonly used in HIV medicine (ddI, co-trimoxazole, pentamidine, sulfadiazine, lipid lowering drugs) may rarely cause acute rhabdomyolysis with tetraparesis and marked elevation of serum CK levels. Notably, PIs raise the serum concentration of statins increasing the risk of statin-induced myopathy and rhabdomyolysis (Hare 2002). An elevated serum CK activity is frequently observed during treatment with TDF, especially in patients with HBV- or HCV-coinfection. This is due to a type 2 macroenzyme creatine kinase (Macro CK) and must not lead to suspicion of ischemic or muscular disease. The accumulation of this liver-derived isoenzyme seems to be the result of an insufficient Macro CK2 clearance capacity mediated by TDF (Schmid 2005). Clinical features Myopathy in HIV infection usually presents with exercise-induced myalgia of proximal muscles followed by slowly progressive, symmetrical weakness and atrophy of proximal muscles. Limb girdle muscles are most commonly involved, but distal muscles and muscles of trunk, neck, face or throat may also be affected. Diagnosis Myalgia, fatigue and elevated serum CK levels are frequently found in HIV infection. But these unspecific symptoms and signs on their own do not warrant the diagnosis of myopathy. The diagnosis of probable myopathy requires weakness, muscle atrophy or myopathic features demonstrated by electromyography. A muscle biopsy confirms the diagnosis and may give some additional clues to the classification and pathogenesis of the muscle disease. Table 7: Myopathies in HIV infection Primary HIV-associated Secondary Polymyositis AZT myopathy Nemaline (rod body) myopathy Vasculitic myopathy Vacuolar myopathy Lymphomatous muscle infiltration Inclusion body myositis Infectious myositis Medication-related toxic rhabdomyolysis Treatment Moderate myalgia may respond to non-steroidal anti-inflammatory drugs. Prednisone (100 mg daily for 3-4 weeks, subsequent tapering) or intravenous immunoglobulin (0.4 g/kg for 5 days) have been shown to be effective in treatment of polymyositis (Espinoza 1991, Viard 1992). The treatment of AZT myopathy is cessation of the drug. Myalgia usually resolves within 1-2 weeks. If symptoms persist for 4-6 weeks, prednisone as described above may be effective. References 1. Breitbart W, Rosenfeld B, Passik S, et al. A comparison of pain report and adequacy of analgesic therapy in ambulatory AIDS patients with and without a history of substance abuse. Pain 1997; 72: 235-243. http://amedeo.com/lit.php?id=9272808 2. Brew BJ, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV neuropathy. AIDS 2003; 17: 1094-6. http://amedeo.com/lit.php?id=12700465 3. Deutsche Neuro-AIDS-Arbeitsgemeinschaft DNAA. Erkrankungen des peripheren Nervensystems und der Muskulatur bei der HIV-Infektion. Nervenarzt 2000; 71: 442-50. http://amedeo.com/lit.php?id=10919138 4. Espinoza LR, Aguilar JL, Espinoza C, et al. Characteristics and pathogenesis of myositis in HIV infection. Distinction from Azidithymidine-induced myopathy. Rheum Dis Clin North Am 1991; 17: 117-19. 5. Gherardi RK, Chrétien F, Delfau-Larue MH, et al. Neuropathy in diffuse infiltrative lymphocytosis syndrome. Neurology 1998; 50:1041-4. http://amedeo.com/lit.php?id=9566392 6. Hahn K, Arendt G, Braun JS et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol 2004; 251:1260-1266. http://amedeo.com/lit.php?id=15503108 7. Hare CB, Vu MP, Grunfeld C, Lampiris HW. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis 2002; 35: e111-2. http://amedeo.com/lit.php?id=12410494 8. Osio M, Muscia F, Zampini L et al. Acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in human immunodeficiency virus patients : an open label study. J Peripher Nerv Syst 2006 ; 11:72-76. http://amedeo.com/lit.php?id=16519785 9. Pettersen JA, Jones G, Worthington C et al. Sensory neuropathy in human immunodeficiency virus acquired immunodeficiency syndrome patients : protease inhibitor-mediated neurotoxicity. Ann Neurol 2006 ; 59: 816-824. http://amedeo.com/lit.php?id=16634006 10. Rosenstock J, Tuchman M, LaMoreaux et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004; 110: 628-638 http://amedeo.com/lit.php?id=15288403 11. Schmidt H, Mühlbayer D, Bogner JR et al. Macroenzyme Creatine Kinase Type 2 accumulation in sera of HIV-infected patients: Significant association with Tenofovir DF (TDF) treatment. 12th Conference on Retroviruses and opportunistic Infections 2005, Boston. http://www.retroconference.org/2005/cd/PDFs/827.pdf 12. Simpson DM, McArthur JC, Olney MD et al. Lamotrigine for HIV-associated painful sensory neuropathies. Neurology 2003; 60: 1508-14. http://amedeo.com/lit.php?id=12743240 13. Simpson DM, Estanislao L, Evans et al. HIV-associated neuromuscular weakness syndrome. AIDS 2004; 18: 1403-12. http://amedeo.com/lit.php?id=15199316 14. Viard JP, Vittecoq D, Lacroix C, et al. Response of HIV-1 associated polymyositis to intravenous immunoglobulin. Am J Med 1992; 92: 580-1. http://amedeo.com/lit.php?id=1580311