Journal of the Peripheral Nervous System 7:243–247 (2002)

© 2002 Peripheral Nerve Society, Inc.

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Neuropathy Abstracts

Abstracts of selected articles recently published in the medical literature

CAN ELECTROPHYSIOLOGY DIFFERENTIATE POLYNEUROPATHY WITH ANTI-MAG/SGPG ANTIBODIES FROM CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY?

Capasso M, Torrieri F, Di Muzio A, De Angelis MV,Lugaresi A, Uncini A.

Clinical Neurophysiology 113: 346–353, 2002. Reprinted with permission from Elsevier ScienceIreland, Ltd.

Objectives: Patients with polyneuropathy and antibod-ies to myelin-associated glycoprotein (MAG) and sulphatedglucuronyl paragloboside (SGPG) differ from chronic inflam-matory demyelinating polyneuropathy (CIDP) because of aslower, progressive course, symmetrical and predominantlysensory involvement of legs, predominantly distal slowing ofmotor conductions, and poorer response to therapy. Westudied whether a wide set of electrophysiologic parametersmay differentiate these two neuropathies. Methods: We re-viewed the electrophysiological studies of 10 patients withanti-MAG/SGPG antibodies and 22 with CIDP examining: (1)motor conduction velocity and distal compound muscle ac-tion potential amplitude; (2) conduction block (CB) and tem-poral dispersion; (3) distal motor latency and terminal latencyindex (TLI); (4) F wave and proximal conduction time; and (5)sensory conduction and occurrence of abnormal medianwith normal sural sensory potential. Results: Anti-MAG/SGPG neuropathies showed: (1) more severe involvement ofperoneal nerves; (2) more frequent disproportionate distalslowing of motor conductions (TLI less than or equal to 0.25)and absent sural potential; and (3) no CB. However 3/22CIDP patients also had at least two nerves with TLI 0.25 andno CB. Conclusions: Electrophysiologic findings suggest inanti-MAG/SGPG neuropathy a length-dependent processwith a likely centripetal evolution. A disproportionate slowingof conduction in distal segments of motor nerves suggeststhe diagnosis of anti-MAG/SGPG neuropathy, although it isnot pathognomonic.

COLD PRESSOR TEST DEMONSTRATES RESIDUAL SYMPATHETIC CARDIOVASCULAR ACTIVATION IN FAMILIAL DYSAUTONOMIA

Hilz MJ, Axelrod FB, Braeske B, Stemper B.

Journal of theNeurological Sciences 196: 81–89, 2002. Reprinted with per-mission from Elsevier Science BV.

In familial dysautonomia (1713), i.e. Riley-Day-syndrome,sympathetic cardiovascular function, as well as afferent tem-

perature and pain mediating neurons, are significantly re-duced. Thus, it was questioned if cold pressor test (CPT),which normally enhances sympathetic outflow and inducesperipheral vasoconstriction by the activation of thermo- andnociceptive system activation, could be used to assess sym-pathetic function in FD. To evaluate whether CPT can beused to assess sympathetic activation in FD, we performedCPT in 15 FD patients and IS controls. After a 35-min restingperiod, participants immersed their right hand and arm up tothe elbow into 0-1

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C cold water while we monitored heartrate (HR), respiration, beat-to-beat radial artery blood pres-sure (BP), and laser Doppler skin blood flow (SBF) at theright index finger pulp. From these measurements, heartrate variability parameters were calculated: root mean squareof successive differences (RMSSD), coefficient of variation(CV), low and high frequency (LF, HF) power spectra of theelectrocardiogram (ECG). All participants perceived coldstimulation and indicated discomfort. In controls, SBF de-creased and HR and BP increased rapidly upon CPT. After 60s, SBF indicated secondary vasodilatation in six controls, BPrise attenuated and HR returned to baseline in all controls. Inthe patients, SBF remained unchanged, HR and BP in-creased significantly, but after 50-60 s of CPT and changeswere lower than in controls (p*LT0.05). RMSSD and CV de-creased and LF increased significantly only in the controls.We conclude that CPT activates sympathetic HR and BPmodulation despite impaired pain and temperature percep-tion in FD patients. BP increase in the presence of almostunchanged SBF might be due to HR increase and to noci-ceptive arousal and emotionally induced catecholamine re-lease as seen in emotional crises of FD patients. CPT as-sesses sympathetic cardiovascular responses independentlyfrom baroreflex function, which is compromised in FD.

IS CARDIOVASCULAR DISEASE A RISK FACTOR IN THE DEVELOPMENT OF AXONAL POLYNEUROPATHY?

Teunissen LL, Franssen H, Wokke JHJ, van der Graaf Y,Linssen WHJP, Banga JD, Laman DM, Notermans NC.

Journal of Neurology Neurosurgery and Psychiatry 72: 590–595, 2002. Reprinted with permission from the British Medi-cal Journal Publishing Group.

Objectives: To determine if cardiovascular disease maybe a risk factor in the development of chronic idiopathic ax-onal polyneuropathy (CIAP). Methods: In this incidencecase-control study, the prevalence of cardiovascular disease

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and risk factors in 97 patients with CIAP (mean age 67.5 (SD7.9) years) and the prevalence of neuropathic features in 97patients with peripheral arterial disease (PAD) (mean age67.1 (SD 7.3) years) were investigated. The results were com-pared with those for 96 age and sex matched controls with-out diagnosed PAD or polyneuropathy (mean age 67.5 (SD9.1) years). In a randomly chosen subgroup of 23. patientswith CIAP, 42 patients with PAD, and 48 controls, an elec-trodiagnostic investigation was performed. Results: Patientswith CIAP more often had manifest cardiovascular diseaseand cardiovascular risk factors than controls (stroke 18% v6% of patients, odds ratio (OR) 3.2 (95% confidence interval(0) 1.8 to 5.9); heart disease 29% v 15%, OR 2.4 (95% Cl 1.2to 4.9); family history of cardiovascular disease 42% v 21%,OR 2.8 (95% Cl (1.5 to 5.2); hypertension 56% v 39%, OR2.0 (95% Cl 1.1 to I I 3.6); hypercholesterolaemia 46% v21%, OR 3.3 (95% Cl 1.5 to 7.3); current smoking 38% v23%, OR 2.1 (95% Cl I. I to 3.9)). The prevalence of cardio-vascular disease and cardiovascular risk factors was lowerthan in patients with PAD. Patients with PAD more often hadpolyneuropathy than controls (15% v 5%, OR 3.3 (95% Cl1.1 to 10.0)). There was a trend towards lower nerve conduc-tion velocities and lower amplitudes on electrodiagnostic in-vestigation compared with controls. Conclusion: This studyshows that cardiovascular disease and CIAP often coexist,and therefore cardiovascular disease may be a cofactor inthe development of CIAP.

DISEASE SEVERITY IN MULTIFOCAL MOTOR NEUROPATHY AND ITS ASSOCIATION WITH THE RESPONSE TO IMMUNOGLOBULIN TREATMENT

Van den Berg-Vos RM, Franssen H, Visser J, de Visser M,de Haan RJ, Wokke JHJ, Van den Berg LH.

Journal ofNeurology 249: 330–336, 2002. Reprinted with permissionfrom Dr. Dietrich Steinkopff Verlag.

Disease progression in multifocal motor neuropathy(MMN) was studied by comparing severity and duration ofdisease. We assessed disease severity by determining mus-cle weakness, disability, conduction block (CB), and distaland proximal compound muscle action potential (CMAP) am-plitude in 38 patients with MMN in whom disease durationranged from 6 months to 34 years. As indicator for an ongo-ing immune-mediated process, the response to one courseof IVIg treatment was measured in 34 patients and associ-ated with disease severity. With increasing disease duration,weakness and disability became significantly more severe,and the distal and proximal CMAP-amplitude decreased sig-nificantly. The number of CBs was significantly higher in pa-tients with a disease duration longer than 10 years than inthose affected less than 10 years. Thirty of the 34 patientsresponded to IVIg treatment. Non-responsiveness to IVIgwas not associated with any of the disease variables. Severeand widespread weakness was significantly associated witha response greater than or equal to 2 on the MRC-sum-score. Our results provide evidence for a slowly progressivedisease course of MMN. The good response to IVIg treat-ment in patients with severe and prolonged disease indi-cates that progression may be the result of an ongoing im-

mune-mediated process. These findings imply that earlytreatment may prevent future progression of weakness anddisability in patients with MMN.

BEDSIDE SCORING PROCEDURE FOR THE DIAGNOSIS OF DIABETIC PERIPHERAL NEUROPATHY IN YOUNG PATIENTS WITH TYPE 1 DIABETES MELLITUS

Shalitin S, Josefsberg Z, Lilos P, de-Vries L, Phillip M,Weintrob N.

Journal of Pediatric Endocrinology & Metabo-lism 15: 613–620, 2002. Reprinted with permission fromFreund Publishing House, Ltd.

Objective: To test the applicability of a bedside scoringmethod for screening for diabetic peripheral neuropathy(DPN) in patients with type 1 diabetes mellitus (DM) in anambulatory clinic. The prevalence of DPN was estimated andits risk factors identified. Methods: A total of 217 patients(102 males) with type 1 DM, median age 23.4 years (7.5–49years) and median duration of DM 13.2 years (1–34 years)were evaluated for DPN using the bedside Neuropathy Dis-ability Score (NDS). A score of 3–5 indicated mild DPN, 6-8moderate DPN and 9–10 severe DPN. The presence of DPNwas correlated with possible predictive factors. Results: TheNDS was reliable and highly reproducible. The overall preva-lence of DPN was 17.1%: mild in 14.3%, moderate in 2.3%,and severe in 0.5% of patients. The prevalence and severityof DPN were significantly related to long-term glycemic con-trol (p

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0.001), DM duration (p

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0.005), age (p

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0.005), andduration of pubertal DM duration (p

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0.03). The prevalenceof DPN was significantly associated with the presence of re-tinopathy (p

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0.002) and overt proteinuria (p

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0.005). Conclu-sions: The NDS is a simple, reliable and reproducible screen-ing method for use in the ambulatory clinic to identify theearly signs of DPN, leading to early institution of intensive di-abetes control measures and preventive foot care.

CONTACT-DEPENDENT DEMYELINATION BY MYCOBACTERIUM LEPRAE IN THE ABSENCE OF IMMUNE CELLS

Rambukkana A, Zanazzi G, Tapinos N, Salzer JL.

Science296: 927–931, 2002. Reprinted with permission from theAmerican Association for the Advancement of Science.

Demyelination results in severe disability in many neu-rodegenerative diseases and nervous system infections, andit is typically mediated by inflammatory responses. Myco-bacterium leprae, the causative organism of leprosy, inducedrapid demyelination by a contact-dependent mechanism inthe absence of immune cells in an

in vitro

nerve tissue cul-ture model and in Rag1-knockout (Rag1(

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)) mice, whichtack mature B and T lymphocytes. Myelinated Schwann cellswere resistant to M. leprae invasion but undergo demyelina-tion upon bacterial attachment, whereas nonmyelinatedSchwann cells harbor intracellular M. leprae in large num-bers. During M. leprae-induced demyelination, Schwanncells proliferate significantly both

in vitro

and

in vivo

and gen-erate a more nonmyelinated phenotype, thereby securingthe intracellular niche for M. leprae.

Abstracts Journal of the Peripheral Nervous System 7:243–247 (2002)

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A MOUSE MODEL FOR PERIPHERAL NEUROPATHY PRODUCED BY A PARTIAL INJURY OF THE NERVE SUPPLYING THE TAIL

Back SK, Sung B, Hong SK, Na HS.

Neuroscience Letters322: 153–156, 2002. Reprinted with permission from ElsevierScience Ireland, Ltd.

We attempted to develop a mouse model for peripheralneuropathy by a partial injury of the nerve supplying the tail.Under enflurane anesthesia, the unilateral superior caudaltrunk was resected between the S3 and S4 spinal nerves.Tests for thermal allodynia were conducted by immersing thetail into 4 or 38

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C water. The mechanical allodynia was as-sessed by stimulating the tail with a von Frey hair (1.96 mN,0.2 g). After the nerve injury, the experimental animals hadshorter tail withdrawal latencies to cold and warm water im-mersion than the presurgical latency, and exhibited an in-crease in tail response to von Frey stimulation. We interpretthese abnormal sensitivities as the signs of mechanical, coldand warm allodynia following the superior caudal trunk injuryin the mouse.

MYELIN PROTEIN P-0-SPECIFIC IGM PRODUCING MONOCLONAL B CELL LINES WERE ESTABLISHED FROM POLYNEUROPATHY PATIENTS WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)

Kvarnstrom M, Sidorova E, Nilsson J, Ekerfelt C, Vre-them M, Soderberg O, Johansson M, Rosen A, ErnerudhJ.

Clinical and Experimental Immunology 127: 255–262, 2002.Reprinted with permission from Blackwell Publishing, Ltd.

Monoclonal expansion of B cells and plasma cells, pro-ducing antibodies against ‘self’ molecules, can be found notonly in different autoimmune diseases, such as peripheralneuropathy (PN), but also in malignancies, such as Walden-stroms'macroglobulinaemia and B-type of chronic lympho-cytic leukaemia (B-CLL), as well as in precancerous condi-tions including monoclonal gammopathy of undeterminedsignificance (MGUS). About 50% of patients with PN-MGUShave serum antibodies against peripheral nerve myelin, butthe specific role of these antibodies remains uncertain. Theaims of the study were to establish, and characterize, my-elin-specific B cell clones from peripheral blood of patientswith PN-MGUS, by selection of cells bearing specific mem-brane Ig-receptors for myelin protein P-0, using beadscoated with P-0. P-0-coated magnetic beads were used forselection of cells, which subsequently were transformed byEpstein-Barr virus. The specificity of secreted antibodies wastested by ELISA. Two of the clones producing anti-P-0 anti-bodies were selected and expanded. The magnetic selectionprocedure was repeated and new clones established. Thecells were CD5(

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) positive, although the expression de-clined in vitro over time. The anti-P-0 antibodies were of IgM-lambda type. The antibodies belonged to the V(H)3 genefamily with presence of somatic mutations. The IgM reactedwith P-0 and myelin-associated glycoprotein (MAG), andshowed no evidence for polyreactivity, in contrast to otherIgM CD5(

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) clones included in the study as controls. The ex-panded clones expressed CD80 and HLA-DR, which is com-patible with properties of antigen-presenting cells. The im-

munomagnetic selection technique was successfully usedfor isolation of antimyelin protein P-0-specific clones. The celllines may provide useful tools in studies of monoclonal gam-mopathies, leukaemia, and autoimmune diseases, includingaspects of antigen-presentation by these cells followed by Tcell activation.

THROMBOMODULIN DEFICIENCY IN HUMAN DIABETIC NERVE MICROVASCULATURE

Hafer-Macko CE, Ivey FM, Gyure KA, Sorkin JD, Macko RF.

Diabetes 51: 1957–1963, 2002. Reprinted with permissionfrom the American Diabetes Association.

Human diabetic neuropathy is multifactorial in etiology,with ischemia as a final common pathology. Although im-paired vascular endothelial cell function in diabetic micro-vascular injury is established, the role of thrombomodulin(TM)-dependent protein C antithrombotic mechanism in thepathogenesis of neuropathy is unclear. This neuropathologiccase-control study investigated whether vascular endothelialTM expression is deficient in peripheral nerve microvesselsin diabetic neuropathy. Sural nerve biopsies from 7 patientswith diabetic neuropathy and 10 with axonal neuropathywithout vasculopathy were immunostained with anti-TMand anti-von Willebrand factor (vWF; an endothelial cellmarker) antibodies. The proportion of TM-positive microves-sels was expressed relative to total vWF-staining vessels,according to vessel caliber and regional distribution withinthe nerve. In diabetic nerves compared with reference con-trols, the proportion of TM-positive endoneurial microvesselswas 15-fold lower (0.02 vs. 0.30 in diabetic nerves vs. con-trols, P

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0.004), and the proportion of small-caliber epineur-ial microvessels was 10-fold lower (0.04 vs. 0.43, P

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0.001).No TM expression was detected at the perineurium in dia-betic or control nerves. We demonstrate a substantial reduc-tion of vascular endothelial TM expression throughout hu-man diabetic neuropathy. These findings suggest that animpaired native TM-dependent protein C antithromboticmechanism may contribute to microvascular ischemia in thepathogenesis of diabetic neuropathy.

INFLUENCE OF EXPERIMENTAL DIABETES ON THE MICROCIRCULATION OF INJURED PERIPHERAL NERVE - FUNCTIONAL AND MORPHOLOGICAL ASPECTS

Kennedy JM, Zochodne DW.

Diabetes 51: 2233–2240,2002. Reprinted with permission from the American Diabe-tes Association.

Regeneration of diabetic axons has delays in onset, rateand maturation. It is possible that microangiopathy of vasanervorum, the vascular supply of the peripheral nerve, mayrender an unfavorable local environment for nerve regenera-tion. We examined local nerve blood flow proximal and distalto sciatic nerve transection in rats with long-term (8 month)experimental streptozotocin diabetes using laser Dopplerflowmetry and microelectrode hydrogen clearance polarog-raphy. We then correlated these findings, using in vivo perfu-sion of an India ink preparation, by outlining the lumens ofmicrovessels from unfixed nerve sections. There were nodifferences in baseline nerve blood flow between diabetic

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and nondiabetic uninjured nerves, and vessel number, den-sity, and area were unaltered. After transection, there weregreater rises in blood flow in proximal stumps of nondiabeticnerves than in diabetic animals associated with a highernumber, density, and caliber of epineurial vessels. Hypere-mia also developed in distal stumps of nondiabetic nervesbut did not develop in diabetic nerves. In these stumps, dia-betic rats had reduced vessel numbers and smaller meanendoneurial vessel areas. Failed or delayed upregulation ofnerve blood flow after peripheral nerve injury in diabetesmay create a relatively ischemic regenerative microenviron-ment.

HERPES SIMPLEX-MEDIATED GENE TRANSFER OF NERVE GROWTH FACTOR PROTECTS AGAINST PERIPHERAL NEUROPATHY IN STREPTOZOTOCIN-INDUCED DIABETES IN THE MOUSE

Goss JR, Goins WF, Lacomis D, Mata M, Glorioso JC,Fink DJ.

Diabetes 51: 2227–2232, 2002. Reprinted with per-mission from the American Diabetes Association.

Peripheral neuropathy is a common and debilitating com-plication of diabetes. In animal models, neurotrophic factorscan prevent progression of the neuropathy, but adverse ef-fects prevent systemic administration in adequate doses totreat human disease. We examined whether gene transferwith replication-defective genomic herpes simplex virus(HSV) vectors modified to express nerve growth factor(NGF) could be used to prevent progression of neuropathy inmice. Diabetes induced by streptozotocin (STZ) resulted in asensory neuropathy manifest by a decrease in the foot sen-sory nerve amplitude (FSA; control

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0.1 muV,treated

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0.1 muV). Transduction of dorsal root gan-glia in vivo with an HSV-based vector expressing NGF underthe control of the human cytomegalovirus immediate earlypromoter (vector SHN) or the HSV latency active promoter 2(vector SLN) by footpad inoculation 2 weeks after STZ ad-ministration protected against the decrease in FSA (22

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1.4 muV and 21

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1.7 muV, respectively) measured 4weeks later. Injection of SHN into inguinal adipose tissue 2weeks after onset of diabetes also prevented the decreasein FSA (20

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3.3 muV). These results suggest that genetransfer with an NGF-producing herpes-based vector mayprove useful in the treatment of diabetic neuropathy.

IDENTIFICATION OF THE REGULATORY REGION OF THE PERIPHERAL MYELIN PROTEIN 22 (PMP22) GENE THAT DIRECTS TEMPORAL AND SPATIAL EXPRESSION IN DEVELOPMENT AND REGENERATION OFPERIPHERAL NERVES

Maier M, Berger P, Nave KA, Suter U.

Molecular and Cel-lular Neuroscience 20: 93–109, 2002. Reprinted with per-mission from Academic Press, Inc.

Minor changes in PMP22 gene dosage have profoundeffects on the development and maintenance of peripheralnerves. This is evident from the genetic disease mecha-nisms in Charcot-Marie-Tooth disease type 1A (CMT1A) andhereditary neuropathy with liability to pressure palsies(HNPP) as well as transgenic animals with altered PMP22gene dosage. Thus, regulation of PMP22 is a crucial aspect

in understanding the function of this protein in health anddisease. In this study, we have generated transgenic micecontaining 10 kb of the 5

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-flanking region of the PMP22gene, including the two previously identified alternative pro-moters, fused to a lacZ reporter gene. We show that thispart of the PMP22 gene contains the necessary informationto mirror the endogenous expression pattern in peripheralnerves during development and regeneration and in mousemodels of demyelination due to genetic lesions. Transgeneexpression is strongly regulated during myelination, demy-elination, and remyelination in Schwann cells, demonstratingthe crucial influence of neuron-Schwann cell interactions inthe regulation of PMP22. In addition, the region of thePMP22 gene present on this transgene confers also neu-ronal expression in sensory and motor neurons. These re-sults provide the crucial basis for further dissection of the el-ements that direct the temporal and spatial regulation of thePMP22 gene and to elucidate the molecular basis of themaster program regulating peripheral nerve myelination.

AGGRESOME FORMATION IN NEUROPATHY MODELS BASED ON PERIPHERAL MYELIN PROTEIN22 MUTATIONS

Ryan MC, Shooter EM, Notterpek L.

Neurobiology of Dis-ease 10: 109–118, 2002. Reprinted with permission fromAcademic Press, Inc.

Alterations in peripheral myelin protein 22 (PMP22)gene expression are associated with demyelinating periph-eral neuropathies. Overexpression of wild type (wt) PMP22or inhibition of proteasomal degradation lead to the forma-tion of aggresomes, intracellular ubiquitinated PMP22 aggre-gates. Aggresome formation has now been observed withtwo mutant PMP22s, the Tr- and TrJ-PMP22 when the pro-teasome is inhibited. The formation of these aggresomes re-quired intact microtubules and involved the recruitment ofchaperones, including Hsp40, Hsp70, and alphaB-crystallin.Spontaneously formed ubiquitinated PMP22 aggregates werealso observed in Schwann cells of homozygous TrJ mice. Sig-nificant upregulation of both the ubiquitin-proteasomal andlysosomal pathways occurred in affected nerves suggestingthat two pathways of PMP22 degradation are present. Thus,the presence of aggresomes appears to be a common find-ing in neuropathy models of PMP22 overexpression and ofsome point mutations known to cause neuropathy in miceand humans.

OXIDATIVE STRESS AND DIABETIC NEUROPATHY: PATHOPHYSIOLOGICAL MECHANISMS ANDTREATMENT PERSPECTIVES

van Dam PS.

Diabetes-Metabolism Research and Reviews18: 176–184, 2002. Reprinted with permission from JohnWiley & Sons, Ltd.

Increased oxidative stress is a mechanism that probablyplays a major role in the development of diabetic complica-tions, including peripheral neuropathy. This review sum-marises recent data from in vitro and in vivo studies thathave been performed both to understand this aspect of thepathophysiology of diabetic neuropathy and to develop ther-

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apeutic modalities for its prevention or treatment. Extensiveanimal studies have demonstrated that oxidative stress maybe a final common pathway in the development of diabeticneuropathy, and that antioxidants can prevent or reverse hy-perglycaemia-induced nerve dysfunction. Most probably, theeffects of antioxidants are mediated by correction of nutritive

blood flow, although direct effects on endoneurial oxidativestate are not excluded. In a limited number of clinical studies,antioxidant drugs including alpha-lipoic acid and vitamin E werefound to reduce neuropathic symptoms or to correct nerve con-duction velocity. These data are promising, and additional largerstudies with alpha-lipoic acid are currently being performed.

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