Peripheral Neuropathy with Hypomyelinating Features in Adult-onset Krabbe's Disease

NeuropathyAbstracts

Abstracts of selected articles recently published in themedical literature

SODIUM VALPROATE IN THE MANAGEMENT OF PAINFUL

NEUROPATHY IN TYPE 2 DIABETES – A RANDOMIZED

PLACEBO CONTROLLED STUDY

Kochar DK, Jain N, Agarwal RP, SrivastavaT, Agarwal P, Gupta S.Acta Neurologica Scandinavica 106: 248–252, 2002.

Reprinted with permission from Blackwell Munksgaard.

OBJECTIVE: To study the effectiveness and safety

aspects of sodium valproate in the management of painful

neuropathy in patients of type 2 diabetes mellitus. MATERIAL

AND METHODS: A randomized double-blind placebo

controlled trial of sodium valproate was done in type 2 diabetic

patients to assess its efficacy and safety in themanagement of

painful neuropathy. We screened 60 patients but eight patients

could not complete the study; hence, the present study was

done on 52 patients. Each patient was assessed by clinical

examination, pain score by short form of the McGill pain

questionnaire (SF-MPQ) and electrophysiological examination,

which included motor and sensory nerve conduction velocity,

amplitude and H-reflex initially and at the end of 1 month of

treatment. RESULTS: Significant improvement was noticed in

the pain score of patients receiving sodium valproate in com-

parison to patients receiving placebo at the end of 1 month

(P< 0.05). The changes in electrophysiological data were not

significant. The drug was well tolerated by all patients except

one who developed a raised aspartate transaminase (AST)/

alanine transaminase (ALT) level after 15 days of treatment.

CONCLUSION: Sodium valproate is a well-tolerated drug and

provides significant subjective improvement in painful diabetic

neuropathy. These data provide a basis for future trials of

longer duration in a larger group of patients.

LOSS OF PHOSPHATASE ACTIVITY IN MYOTUBULARIN-

RELATED PROTEIN 2 IS ASSOCIATED WITH CHARCOT-

MARIE-TOOTH DISEASE TYPE 4B1

Berger P, Bonneick S, Willi S, Wymann M, Suter U. Human

Molecular Genetics 11: 1569–1579, 2002. Reprinted with

permission from Oxford University Press.

Mutations in the gene encoding myotubularin-related

protein 2 (MTMR2) are responsible for autosomal recessive

Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe

hereditary motor and sensory neuropathy characterized by

focally folded myelin sheaths and demyelination. MTMR2

belongs to the myotubularin family, which is characterized

by the presence of a phosphatase domain. Myotubularin

(MTM), the archetype member of this family, is mutated in

X-linked myotubular myopathy. Although MTMR2 and MTM

are closely related, they are likely to have different functions.

Recent studies revealed that MTM dephosphorylates specif-

ically phosphatidylinositol 3-phosphate. Here we analyze the

biochemical properties of the mouse MTMR2 protein, which

shares 97% amino acid identity with human MTMR2. We

show that phosphatidylinositol-3-phosphate is also a sub-

strate for MTMR2, but, unlike myotubularin, MTMR2 dephos-

phorylates phosphatidylinositol 3,5-bisphosphate with high

efficiency and peak activity at neutral pH. We demonstrate

that the known disease-associated MTMR2 mutations lead

to dramatically reduced phosphatase activity, suggesting that

the MTMR2 phosphatase activity is crucial for the proper

function of peripheral nerves in CMT4B1. Expression analysis

of MTMR2 suggests particularly high levels in neurons. Thus,

the demyelinating neuropathy CMT4B1 might be triggered

by the malfunction of neural membrane recycling, membrane

trafficking, and/or endocytic or exocytotic processes, com-

bined with altered axon-Schwann cell interactions. Further-

more, the different biochemical properties of MTM and

MTMR2 offer a potential explanation for the different human

diseases caused by mutations in their respective genes.

PERIPHERAL NEUROPATHY WITH HYPOMYELINATING

FEATURES IN ADULT-ONSET KRABBE’S DISEASE

SabatelliM,QuarantaL,MadiaF,LippiG,ConteA,LoMonacoM,Di Trapani G, Rafi MA, Wenger DA, Vaccaro AM, Tonali P.Neuromuscular Disorders 12: 386–391, 2002. Reprinted

with permission from Pergamon–Elsevier Science, Ltd.

We describe three brothers suffering from Krabbe’s dis-

ease with onset in the fifth decade. The proband showed a

complete deficiency of leukocyte enzyme galactocerebrosi-

dase and was found to be heterozygous for two previously

described mutations: G>A809 and 502T/del consisting of a

30 kb deletion. In all three brothers the neurological examin-

ation showed features of asymmetrical peripheral neuropathy

associated with pyramidal signs and the electrophysiological

examination showed a generalized slowing of nerve conduc-

tion velocities. Two patients died at 59 and 61 years of age

due to respiratory failure. Both the proband and his brother

underwent a sural nerve biopsy. In the former the most

striking finding was the presence of uniformly thin myelin

sheaths without evidence of demyelination; a complete

absence of fibers was found in the latter. Our findings con-

firm that peripheral neuropathy may be the presenting fea-

ture of late-onset Krabbe’s disease. Hypomyelination rather

than demyelination may represent the distinguishing patho-

logical finding of this condition.

Journal of the Peripheral Nervous System 8:128–133 (2003)

� 2003 Peripheral Nerve Society, Inc. 128 Blackwell Publishing

ACRYLAMIDE NEUROPATHY – I. SPATIOTEMPORAL

CHARACTERISTICS OF NERVE CELL DAMAGE IN RAT

CEREBELLUM

Lehning EJ, Balaban CD, Ross JF, Reid MA, LoPachin RM.Neurotoxicology 23: 397–414, 2002. Reprintedwith permission

from Elsevier Science BV.

Based on evidence from morphometric studies of PNS,

we suggested that acrylamide (ACR)-induced distal axon

degeneration was a secondary effect related to duration of

exposure (Toxicol Appl Pharmacol 151 [1998] 211). To test

this hypothesis in CNS, the cupric-silver stain method of de

Olmos was used to define spatiotemporal characteristics of

nerve somal, dendritic, axonal and terminal degeneration in rat

cerebellum. Rats were exposed to ACR at either 50mg/kg

per day (i.p.) or 21mg/kg per day (p.o.) and at selected times

(i.p.¼ 5, 8 and 11 days; p.o.¼ 7, 14, 21, 28 and 38 days)

brains were removed and processed for silver staining.

Results demonstrate that intoxication at the higher ACR

dose-rate produced early (day 5) and progressive degener-

ation of Purkinje cell dendrites in cerebellar cortex. Nerve

terminal degeneration occurred concurrently with somato-

dendritic argyrophilia in cerebellar and brainstent nuclei that

receive afferent input from Purkinje neurons. Relatively

delayed (day 8), abundant axon degeneration was present

in cerebellar white matter but not in cortical layers or in tracts

carrying afferent fibers (cerebellar peduncles) from other

brain nuclei. Axon argyrophilia coincided with the appearance

of perikaryal degeneration, which was selective for Purkinje

cells since silver impregnation of other cerebellar neurons

was not evident in the different cortical layers or cerebellar

nuclei. Intoxication at the lower ACR dose-rate produced

simultaneous (day 14) dendrite, axon and nerve terminal

argyrophilia and no somatic Purkinje cell degeneration. The

spatiotemporal pattern of dendrite, axon and nerve terminal

loss induced by both ACR dose-rates is consistent with Pur-

kinje cell injury. Injured neurons are likely to be incapable of

maintaining, distal processes and, therefore, axon degener-

ation in the cerebellum is a component of a ‘‘dying-back’’

process of neuronal injury. Because cerebellar coordination

of somatomotor activity is mediated solely through efferent

projections of the Purkinje cell, injury to this neuron might

contribute significantly to gait abnormalities that characterize

ACR neurotoxicity.

ACRYLAMIDE NEUROPATHY – II. SPATIOTEMPORAL

CHARACTERISTICS OF NERVE CELL DAMAGE IN

BRAINSTEM AND SPINAL CORD

LehningEJ,BalabanCD,RossJF, LoPachinRM.Neurotoxicology23: 415–429, 2002. Reprinted with permission from Elsevier

Science BV.

Previous studies of acrylamide (ACR) neuropathy in rat

PNS (Toxicol Appl Pharmacol 151 [1998] 211) and cerebellum

(Neurotoxicology, 2002a) have suggested that axon degen-

eration was not a primary effect and was, therefore, of

unclear neurotoxicological significance. To continue morpho-

logical examination of ACR neurotoxicity in CNS, a cupric

silver stain method was used to define spatiotemporal char-

acteristics of nerve cell body, dendrite, axon and terminal

degeneration in brainstem and spinal cord. Rats were

exposed to ACR at a dose-rate of either 50mg/kg per day

(i.p.) or 21mg/kg per day (p.o.), and at selected times brains

and spinal cord were removed and processed for silver stain-

ing. Results show that intoxication at the higher ACR dose-

rate produced a nearly pure terminalopathy in brainstem and

spinal cord regions, i.e. widespread nerve terminal degener-

ation and swelling were present in the absence of significant

argyrophilic changes in neuronal cell bodies, dendrites or

axons. Exposure to the lower ACR dose-rate caused initial

nerve terminal argyrophilia in selected brainstem and spinal

cord regions. As intoxication continued, axon degeneration

developed in white matter of these CNS areas. At both dose-

rates, argyrophilic changes in brainstem nerve terminals

developed prior to the onset of significant gait abnormalities.

In contrast, during exposure to the lower ACR dose-rate the

appearance of axon degeneration in either brainstem or

spinal cord was relatively delayed with respect to changes

in gait. Thus, regardless of dose-rate, ACR intoxication pro-

duced early, progressive nerve terminal degeneration. Axon

degeneration occurred primarily during exposure to the lower

ACR dose-rate and developed after the appearance of ter-

minal degeneration and neurotoxicity. Spatiotemporal analysis

suggested that degeneration began at the nerve terminal and

then moved as a function of time in a somal direction along

the corresponding axon. These data suggest that nerve ter-

minals are a primary site of ACR action and that expression of

axonopathy is restricted to subchronic dosing-rates.

CHRONIC NEUROPATHIC PAIN IS ACCOMPANIED BY

GLOBAL CHANGES IN GENE EXPRESSION AND SHARES

PATHOBIOLOGY WITH NEURODEGENERATIVE DISEASES

Wang H, Sun H, Della Penna K, Benz RJ, Xu J, Gerhold DL,Holder DJ, Koblan KS. Neuroscience 114: 529–546, 2002.

Reprinted with permission from Elsevier Science BV.

Neuropathic pain is induced by injury or disease of the

nervous system. Studies aimed at understanding tile molecu-

lar pathophysiology of neuropathic pain have so far

focused on a few known molecules and signaling pathways

in neurons. However, the pathophysiology of neuropathic

pain appears to be very complex and remains poorly under-

stood. A global understanding of the molecular mechanisms

involved in neuropathic pain is needed for a better under-

standing of the pathophysiology and treatment of neuro-

pathic pain. Towards this end, we examined global gene

expression changes as well as the pathobiology at the cellu-

lar level in a spinal nerve ligation neuropathic pain model

usingDNAmicroarray, quantitative real-timePCRand immuno-

histochemistry. We found that the behavioral hypersensi-

tivity that is manifested in the persistent pain state is

accompanied by previously undescribed changes in gene

expression. In the DRG, we found regulation of: (1) immedi-

ate early genes; (2) genes such as ion channels and signaling

molecules that contribute to the excitability of neurons; and

(3) genes that are indicative of secondary events such as

neuroinflammation. In addition, we studied gene regulation

in both injured and uninjured DRG by quantitative PCR, and

observed differential gene regulation in these two populations

Neuropathy Abstracts Journal of the Peripheral Nervous System 8:128–133 (2003)

129

of DRGs. Furthermore, we demonstrated unexpected

co-regulation of many genes, especially the activation of neu-

roinflammation markers in both the PINS and CNS. The

results of our study provide a new picture of the molecular

mechanisms that underlie the complexity of neuropathic pain

and suggest that chronic pain shares common pathobiology

with progressive neurodegenerative disease.

DEJERINE-SOTTAS NEUROPATHY WITH MULTIPLE

NERVE ROOTS ENLARGEMENT AND HYPOMYELINATION

ASSOCIATED WITH A MISSENSE MUTATION OF THE

TRANSMEMBRANE DOMAIN OF MPZ/P0

Simonati A, Fabrizi GM,Taioli F, Polo A, Cerini R, Rizzuto N.Journal of Neurology 249: 1298–1302, 2002. Reprinted with

permission from Dr. Dietrich Steinkopff Verlag.

In a patient affected with a slowly progressive, severe

form of Dejerine-Sottas syndrome, symmetric enlargement

of cranial nerves and focal hypertrophy of cervical and caudal

roots were detected following MRI. Neuropathological fea-

tures of the sural nerve disclosed a dramatic loss of myelin-

ated fibres, with skewed-to-the-left, unimodal distribution

of the few residual fibres, consistent with the diagnosis of

congenital hypomyelination neuropathy. Genetic analysis

revealed this condition to be associated with a heterozygous

G to A transition at codon 167 in the exon 4 of the MPZ/P0

gene causing a Gly138Arg substitution in the transmembrane

domain of the mature MPZ/P0 protein. Focal enlargement of

the nerve trunks in demyelinating, hereditary motor and sens-

ory neuropathies (HMSN) was previously reported in both

asymptomatic and symptomatic cases with root compres-

sion, but peculiar to this case is the diffuse involvement of

both cranial and spinal nerves. We believe that the relevance

of nerve trunk hypertrophy in HMSN is probably under-

evaluated: therefore MRI investigation of the head and spine

should be included in the diagnostic study of selected

HMSN patients. Molecular analysis of peripheral myelin

genes will help to rule out misdiagnosed cases.

FAVORABLE IMPACT OF A VEGAN DIET WITH EXERCISE

ON HEMORHEOLOGY: IMPLICATIONS FOR CONTROL OF

DIABETIC NEUROPATHY

McCarty MF. Medical Hypotheses 58: 476–486, 2002.

Reprinted with permission from Churchill Livingstone.

A little-noticed clinical report indicates that a low-fat,

whole-food vegan diet, coupled with daily walking exercise,

leads to rapid remission of neuropathic pain in the majority of

type 2 diabetics expressing this complication. Concurrent

marked improvements in glycemic control presumably con-

tribute to this benefit, but are unlikely to be solely respon-

sible. Consideration should be given to the possibility that

improved blood rheology – decreased blood viscosity and

increased blood filterability – plays a prominent role in medi-

ating this effect. There is considerable evidence that neural

hypoxia, secondary to impaired endoneurial microcirculatory

perfusion, is a crucial etiologic factor in diabetic neuropathy;

the unfavorable impact of diabetes on hemorheology would

be expected to exacerbate endoneurial ischemia. Conversely,

measures which improve blood fluidity would likely have

a beneficial impact on diabetic neuropathy. There is indeed

evidence that vegan diets, as well as exercise training,

tend to decrease the viscosity of bothwhole blood and plasma;

reductions in hematocrit and in fibrinogen may contribute

to this effect. The fact that vegan diets decrease the white

cell count is suggestive of an improvement in blood filter-

ability as well; filterability improves with exercise training

owing to an increase in erythrocyte deformability. Whether

these measures influence the activation of leukocytes in

diabetics – an important determinant of blood filterability –

remains to be determined. There are various reasons for

suspecting that a vegan diet can reduce risk for other major

complications of diabetes – retinopathy, nephropathy, and

macrovascular disease – independent of its tendency to

improve glycemic control in type 2 patients. The vegan diet/

exercise strategy represents a safe, ‘low-tech’ approach to

managing diabetes that deserves far greater attention from

medical researchers and practitioners.

PHRENIC NERVE PARALYSIS, VEGETATIVE SYMPTOMS

AND RESTRICTIVE CARDIOMYOPATHY IN A CASE OF

POEMS SYNDROME

Delalande S, Stojkovic T, Rose C, Millaire A, Hurtevent JF,Vermersch P. Revue Neurologique 158: 737–740, 2002.

Reprinted with permission from Masson Editeur.

We report a case of POEMS syndrome (Polyneuropathy,

Organomegaly, Endocrinopathy, M protein and Skin changes)

with unusual clinical features. A 62-year-old woman

presented a severe polyneuropathy with dysphonia and

vegetative symptoms, including bradycardia and sphincterial

disorders. The clinical examination showed facial hyper-

pigmentation, cachexia, anasarca and splenomegaly. She

also presented restrictive cardiomyopathy and endocrine dis-

turbances. Nerve conduction studies revealed a severe

demyelinating sensorimotor neuropathy. Cerebrospinal fluid

analysis showed an elevated protein level. We detected a

biclonal gammapathy (Ig G and Ig A with lambda light chain)

and lytic pelvic bone lesions. Later, she developed a severe

ventilatory failure due to a bilateral phrenic nerve paralysis

leading to a mechanical ventilation. Steroids followed by

localized radiotherapy partially improved the respiratory

status and stabilized the neuropathy. Phrenic nerve paralysis,

restrictive cardiomyopathy, vegetative symptoms and cranial

nerve palsy are exceptional in POEMS syndrome. Moreover,

this case emphasizes the importance of radiological investi-

gations since the discover of plasmocytoma may improve

the prognosis of POEMS syndrome.

CHRONIC INFLAMMATORY DEMYELINATING

NEUROPATHY AND AXONAL CYTOSKELETON:

MORPHOMETRIC AND IMMUNOCYTOCHEMICAL DATA

Fressinaud C, Jean I. Revue Neurologique 158: 713–718,

2002. Reprinted with permission from Masson Editeur.

We report morphometric and immunocytochemical data

obtained from nervous biopsy in 7 patients with chronic

inflammatory demyelinating neuropathy (CIDP), compared


130

to 5 controls (without neurological involvement). Fiber loss

was present in all cases and reached 50 p. 100 or more in 4

cases. The g myelination ratio was elevated in 3 cases only,

indicating demyelination. The number of fibers labelled for

the L subunit of neurofilaments was normal in cases with

moderate fiber loss and dropped down for densities <3900/

mm2 (4 cases). Labelling with anti-GAP43 antibody was con-

siderably increased in 3 cases, but did not correlate with fiber

density or disease duration. These data confirm the import-

ance of axonal lesions in CIDP and offer the opportunity to

discuss their pathophysiological mechanisms.

ALTERED ARACHIDONIC ACID BIOSYNTHESIS AND

ANTIOXIDANT PROTECTION MECHANISMS IN SCHWANN

CELLS GROWN IN ELEVATED GLUCOSE

Miinea C, Kuruvilla R, Merrikh H, Eichberg J. Journal of Neuro-chemistry 81: 1253–1262, 2002. Reprinted with permission

from Blackwell Publishing, Ltd.

In cultured Schwann cells, elevated glucose induces

alterations in arachidonic acid metabolism that cause a

decrease in the content of glycerophospholipid arachido-

noyl-containing molecular species (ACMS). This could result

from decreased de novo arachidonic acid biosynthesis, or

increased arachidonic acid release from phospholipids. Incorp-

oration of radioactive 8,11,14-eicosatrienoic acid into ACMS

was lower for cells grown in 30mm versus 5mm glucose,

consistent with a decrease in Delta5 desaturase activity.

However, neither basal arachidonic acid release from prela-

beled cells nor stimulated generation of arachidonic acid in

the presence of the reacylation inhibitor, thimerosal, the

phosphotyrosine phosphatase inhibitor, bipyridyl peroxovan-

adium, or both together, were altered by varying the glucose

concentrations, indicating that arachidonic acid turnover did

not contribute to ACMS depletion. Free cytosolic NAD(þ)/

NADH decreased, whereas NADP(þ)/NADPH remained

unchanged for cells grown in elevated glucose, implying

that decreased desaturase activity is a result of metabolic

changes other than cofactor availability. Schwann cells in

elevated glucose were susceptible to oxidative stress, as

shown by increased malondialdehyde, depleted glutathione

levels, and reduced cytosolic superoxide dismutase activity.

Glutathione-altering compounds had no effect on ACMS

levels, in contrast to N-acetylcysteine and alpha-lipoic acid,

which partly corrected ACMS depletion in phosphatidylcho-

line. These findings suggest that in the Schwann cell cul-

tures, a high glucose level elicits oxidative stress and

weakens antioxidant protection mechanisms which could

decrease arachidonic acid biosynthesis and that this deficit

can be partly corrected by treatment with exogenous anti-

oxidants.

INTERACTIONS OF COPPER WITH GLYCATED PROTEINS:

POSSIBLE INVOLVEMENT IN THE ETIOLOGY OF DIABETIC

NEUROPATHY

EatonJW,QianMW.Molecular and Cellular Biochemistry 234:

135–142, 2002. Reprinted with permission from Kluwer Aca-

demic Publishers.

Humans and animals with diabetes frequently develop

peripheral vascular dysfunction and peripheral neuropathies.

There is accumulating evidence that impaired peripheral

nerve function may derive from diminished endoneural

blood flow. The decrements in nerve blood flow may, in

turn, be due to diminished endothelium-dependent vasodila-

tion. Although a number of possible causes of this defective

vasodilation have been suggested, none has been definitely

proven. Regardless of the precise cause, the impaired vaso-

dilatory activity may reflect diminished availability of endo-

thelium-derived relaxing factor (EDRF), variously thought to be

nitric oxide or thiol adducts of nitric oxide. Other investigators

have reported that administration of transition metal chela-

tors to diabetic rats corrects EDRF-mediated arterial relax-

ation and restores both neural blood flow and nerve

conduction velocity, suggesting the involvement of transition

metals. Our investigations center about the hypothesis that

glycated proteins bind transition metals such as copper and

iron, and that such ‘glycochelates’ accumulate within the

vasculature in diabetes and catalytically inactivate EDRF. In

partial support of this hypothesis: (1) Glycated albumin binds

3-fold greater amounts of both copper and iron. (2) Copper

bound to glycated albumin remains redox active (e.g. capable

of supporting the oxidation of ascorbic acid). (3) Copper and

copper-containing glycochelates cause the rapid decompos-

ition of one putative form of EDRF, nitrosocysteine. (4) The

amount of exchangeable (i.e. chelatable) copper in the

plasma of diabetic rats is approximately twice that in normal

rat plasma. (5) Similarly, tail tendons of diabetic animals have

about twice as much bound copper as do tendons of normal

rats. (6) Implants bearing adsorbed glycated albumin placed

in the peritonea of normal mice for 48 h accumulate 5 times

as much bound copper as do implants coated with control

albumin. Overall, these observations support—but do not

conclusively prove—the hypothesis that transition metals

such as copper, bound to glycated proteins, may blunt nor-

mal EDRF-dependent relaxation of diabetic arteries and pro-

vide a rationale for the use of transition metal chelators in the

therapy of diabetic vasculopathy and neuropathy.

EFFECT OF TREATMENT OF DIABETIC RATS WITH

DEHYDROEPIANDROSTERONE ON VASCULAR AND

NEURAL FUNCTION

YorekMA,CoppeyLJ,GellettJS,DavidsonEP,BingXY,LundDD,Dillon JS. American Journal of Physiology. Endocrinology

and Metabolism 283: E1067–E1075, 2002. Reprinted with

permission from the American Physiological Society.

Nutritional supplementation with dehydroepiandroster-

one (DHEA) may be a candidate for treating diabetes-induced

vascular and neural dysfunction. DHEA is a naturally occur-

ring adrenal androgen that has antioxidant properties and is

reportedly reduced in diabetes. Using a prevention protocol,

we found that dietary supplementation of streptozotocin-

induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused

a concentration-dependent prevention in the development of

motor nerve conduction velocity and endoneurial blood flow

impairment, which are decreased in diabetes. At 0.25%,

DHEA significantly prevented the diabetes-induced increase


131

in serum thiobarbituric acid-reactive substances and sciatic

nerve conjugated diene levels. This treatment also reduced

the production of superoxide by epineurial arterioles of the

sciatic nerve. DHEA treatment (0.25%) significantly

improved vascular relaxation mediated by acetylcholine in

epineurial vessels of diabetic rats. Sciatic nerve Naþ�Kþ

�ATPase activity and myoinositol content was also improved

by DHEA treatment, whereas sorbitol and fructose content

remained elevated. These studies suggest that DHEA, by

preventing oxidative stress and perhaps improving sciatic

nerve Naþ�Kþ�ATPase activity, may improve vascular and

neural dysfunction in diabetes.

EFFECTS OF THE PROTEIN KINASE C BETA INHIBITOR

LY333531 ON NEURAL AND VASCULAR FUNCTION IN

RATS WITH STREPTOZOTOCIN-INDUCED DIABETES

Cotter MA, Jack AM, Cameron NE. Clinical Science 103:

311–321, 2002.Reprintedwithpermission fromPortlandPress.

Elevated protein kinase C activity has been linked to the

vascular and neural complications of diabetes. The aim of the

present study was to examine the involvement of the beta-

isoform of protein kinase C in abnormalities of neuronal

function, neural tissue perfusion and endothelium-dependent

vasodilation in diabetes, by treatment with the selective

inhibitor LY333531 (10mg � kg�1 � day�1). Diabetes was

induced in rats by streptozotocin; the duration of diabetes

was 8 weeks. Nerve conduction velocity was monitored, and

responses to noxious mechanical and thermal stimuli were

estimated by the Randall-Sellito and Hargreaves tests

respectively. Sciatic nerve and superior cervical ganglion

blood flow were measured by microelectrode polarography

and hydrogen clearance. Vascular responses were examined

using the in vitro mesenteric bed preparation. An 8-week

period of diabetes caused deficits in sciatic motor (20%)

and saphenous nerve sensory (16%) conduction velocity,

which were reversed by LY333531. Diabetic rats had

mechanical and thermal hyperalgesia. LY333531 treatment

did not affect mechanical thresholds, but corrected thermal

hyperalgesia. Sciatic nerve and superior cervical ganglion

blood flow were both reduced by 50% by diabetes; this

was almost completely corrected by 2 weeks of LY333531

treatment. Diabetes caused a 32% reduction in vasodilation

of the mesenteric vascular bed in response to acetylcholine,

mediated by nitric oxide and endothelium-derived hyperpolar-

izing factor. When the former was abolished during nitric

oxide synthase inhibition, an 80% diabetic deficit in the

remaining relaxation was noted. LY333531 treatment attenu-

ated the development of these defects by 64% and 53%

respectively. Thus protein kinase Cbeta contributes to the

neural and vascular complications of experimental diabetes;

LY333531 is a candidate for further study in clinical trials of

diabetic neuropathy and vasculopathy.

EARLY, SELECTIVE, AND MARKED LOSS OF

SYMPATHETIC NERVES FROM THE ISLETS OF

BIOBREEDER DIABETIC RATS

Mei Q, Mundinger TO, Lernmark A, Taborsky GJ. Diabetes

51: 2997–3002, 2002. Reprinted with permission from the

American Diabetes Association.

To discover whether islet sympathetic nerves are

damaged during the autoimmune destruction of islet

B-cells, we immunostained sections of pancreas from Bio-

Breeder (BB) diabetic rats, using antibodies against vesicular

monoamine transporter 2 (VMAT2), a marker of sympathetic

nerve terminals. We found a marked decrease in the VMAT2-

positive fiber area in the islets of BB rats that had been

diabetic for only 1–2 weeks compared with their nondiabetic

controls. In contrast, there was no significant decrease in the

VMAT2-positive fiber area in the exocrine pancreas in these

early diabetic BB rats. Furthermore, streptozotocin-diabetic

rats showed no decrease in VMAT2-positive fiber area in their

islets comparedwith controls. The classical diabetic autonomic

neuropathy (DAN) that eventually occurs in the heart was not

present in BB diabetic rats at this early stage as evidenced by

normal cardiac VMAT2 immunostaining and normal cardiac

norepinephrine content. Also, in contrast to DAN, this islet

neuropathy did not worsen with duration of diabetes. These

data provide evidence of a heretofore unrecognized early sym-

pathetic islet neuropathy (eSIN). Because eSIN occurs select-

ively in the islet, is rapid in onset, and is associated with

autoimmune but not chemically induced diabetes, it is distinct

from DAN in location, time course, and mechanism.

PERIPHERAL NEUROPATHY IN ACRODERMATITIS

CHRONICA ATROPHICANS – EFFECT OF TREATMENT

Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E.ActaNeurologica Scandinavica 106: 253–257, 2002. Reprinted

with permission from Blackwell Munksgaard.

Forty-seven patients with the late borrelial manifestation

acrodermatitis chronica atrophicans (ACA) and with objective

neurological and/or neurophysiological findings were fol-

lowed up after antibiotic treatment with dermatological, sero-

logical, neurological and neurophysiological controls.

Despite a good therapeutic effect on ACA lesions, specific

antibody values and symptoms of irritative nerve lesions, the

objective neurological and neurophysiological findings of

nerve deficit remained unchanged. There was no progress

of neuropathy findings during the follow-up time. Our interpre-

tation of the results is that the remaining neuropathy

signs after treatment of ACA are neurological sequelae and

not manifestations of persisting Borrelia infection.

PERIPHERAL NERVE REGENERATION IN

GALACTOSAEMIC RATS

King RHM, Muddle JR, Nourallah M,Wong J,Workman JM,Thomas PK. Neuropathology and Applied Neurobiology 28:

381–389, 2002. Reprinted with permission from Blackwell

Publishing, Ltd.

The use of galactosaemia as a model for some aspects

of diabetic polyneuropathy allows the influence of glycation

to be studied independently of other effects. There are well-

studied abnormalities of the peripheral nerves in galacto-

saemic rats, one of which is that the efficiency of regeneration


132

is initially reduced. One possible cause could be that glycated

myelin debris in macrophages is less degradable and inter-

feres with macrophage function. Macrophage recognition

and ingestion of myelin glycosylated in vitro increases with

the duration of incubation in a sugar-rich medium. This study

was performed to investigate a possible correlation between

galactosaemia and regeneration, together with the role of

macrophages. Galactosaemia was induced by adding galact-

ose to the rats’ diet for 2 months before injury. Following a

crush lesion to the sciatic nerve, regeneration was found to

be delayed, demonstrated by a reduction in mean myelinated

fibre size and density 1 month after crush, although, 2 and 3

months later, the differences did not reach statistical signifi-

cance. There were also more macrophages in the galacto-

saemic rats than in the control animals at all time points. The

initial delay in regeneration in galactosaemic rats was there-

fore only temporary and there was little evidence of long-

term deleterious effects. In addition to the morphometric

results, immunohistochemistry showed that there were

more macrophages in the galactosaemic rats than in the

control animals at all time points. Correlating macrophage

and myelinated fibre counts suggests that the persistence

of debris-containing macrophages does not appear to have a

significant inhibitory effect on nerve regeneration. No evi-

dence was found for persistent basal laminal tubes around

the regenerating clusters.

TRENDS IN OPIOID USE FOR CHRONIC NEUROPATHIC

PAIN: A SURVEY OF PATIENTS PURSUING ENROLLMENT

IN CLINICAL TRIALS

Gilron I, BaileyJM. Canadian Journal of Anaesthesia – Journal

canadien d’anesthesie 50: 42–47, 2003. Reprinted with per-

mission from the Canadian Anesthesiologists Society.

PURPOSE: Clinical trials suggest that opioids relieve

neuropathic pain and decrease pain-related disability. We

conducted a pilot study of current prescribing trends and

patients’ attitudes towards opioids for neuropathic pain.

METHODS: A patient questionnaire was completed by indi-

viduals pursuing enrollment in neuropathic pain clinical trials

at our facility. RESULTS: Of 154 patients with diabetic neuro-

pathy (55.2%), postherpetic neuralgia (29.9%), idiopathic per-

ipheral neuropathy (9.7%) and other neuropathies (5.2%),

73.4% complained of inadequate pain control, the mean

pain duration was 4.7 (SD¼ 4.4) yr and the mean pain inten-

sity (0–10) was 7.7 (SD¼ 2.3). In this group, 40.9% had never

tried opioids and 24.7% had never tried any opioids, tricyclic

antidepressants or anticonvulsants. Only 9.7% were receiv-

ing long-acting opioids or ‘‘around the clock’’ dosing whereas

25.3% were receiving opioids on an ‘‘as needed’’ basis.

Opioids combined with tricyclic antidepressants and/or anti-

convulsants were used in 11.0%. Fear of addiction and

adverse effects were expressed by 31.8% and 46.8%

respectively. CONCLUSION: These data suggest that bar-

riers to opioid therapy for neuropathic pain include patients’,

and possibly physicians’, fears of addiction and adverse

effects, which are exaggerated in light of current evidence.

The merits of continuous treatment with sustained-release

opioids, ‘‘as needed’’ dosing with short-acting preparations,

or combining opioids with other agents are discussed, Con-

tinued research and communication between health profes-

sionals, law enforcement officials and legislators is vital in

order to facilitate appropriate opioid use which has a minimal

negative impact on the public yet optimally benefits individ-

uals who suffer from disabling neuropathic pain.


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