NON-DIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY (LSRPN)
Dyck P.J.B., Norell J., Dyck P.J. Mayo Clinic, Rochester, MN
Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) is a crippling, painful disorder associated with weight loss and mild diabetes mellitus (DM). Previously, we found evidence of ischemic injury from microscopic vasculitis in distal nerves. Here, we identified 42 LSRPN patients without DM who had a distal cutaneous nerve biopsy. Twenty-one were men, 21 were women. Means (±SD) values were: age (yr) 67.6±10.5; glucose (mg/dl) 96.9±12.0; glycosylated hemoglobin (%) 5.6±0.8; ESR (mm/hr) 17.4±14.5; CSF protein (mm/dl) 84.5±53.3; and weight loss (lb) 19.9± 21.0. All cases had pain and weakness and most had paresthesia (39/42). The neuropathy started acutely or subacutely in all patients. It began focally and unilaterally (37/42) in proximal or distal segments but progressed to widespread and bilateral involvement (39/42). The mean time to bilateral involvement was 7.3±12.6 mo. In most cases (37/42), pain was the initial symptom, but on evaluation, weakness (34/42) had become the major problem. Distal and proximal levels were about equally affected. In biopsied distal LSRPN nerves, we found similar abnormalities to those seen in DLSRPN nerves - alterations typical of ischemic injury (multifocal fiber loss, perineurial degeneration and thickening, neovascularization, and injury neuroma) and of microscopic vasculitis (perivascular inflammation and inflammation within vessel walls). In conclusion: 1) LSRPN and DLSRPN appear to be alike in that they are both subacute, paralytic, painful, asymmetric, predominantly lower limb neuropathies associated with weight loss. 2) Because of their similarities, the mechanistic role of DM in DLSRPN needs to be rethought. 3) Ischemic injury from microscopic vasculitis best explains the pathologic findings in LSRPN. 4) LSRPN is potentially a treatable condition.
EXPRESSION OF PROINFLAMMATORY CYTOKINES AND MMP9 IN HUMAN SURAL NERVE BIOPSIES
Mathey E.K., Pollard J.D., Armati P.J. University of Sydney, Sydney, NSW, Australia 2006
Breakdown of the BNB is a critical factor in the pathogenesis of CIDP. Degeneration of the BNB allows antibodies and other potentially damaging molecules unaccustomed access to the endoneurial compartment of the nerve. Proinflammatory cytokines and metalloproteinases contribute to both the regulation of the disease process in inflammatory neuropathies and to the breakdown of the BNB. Cellular localisation of cytokine expression in CIDP nerve biopsies should provide further insight into the pathogenic mechanisms of the disease and the individual cells involved. In this study in situ hybridisation was used to determine the exact localisation and identity of cells that express TNF-a, IFN-g and IL-2 mRNA within CIDP nerve. Paraffin embedded and frozen sural nerve biopsies from three acute phase CIDP patients and control specimens were used for the study. Sections of these samples were probed with DIG-labelled oligoprobes for TNF-a, IFN-g and IL-2. The results demonstrate localisation of cytokine expression to the inner rim of the perineurium, epineurial and endoneurial blood vessels and infiltrating inflammatory cells. Moreover, strong staining for TNFa mRNA was widespread in the endoneurium in areas consistent with/ suggestive of Schwann cells. CIDP sural nerve biopsies were also examined for the presence of the protein matrix metalloproteinase 9. Immunofluorescence was used to study expression of MMP9 molecules in CIDP and control nerve. This study presents the preliminary data that MMP9 is present in vascular and endoneurial regions. This implicates a role for MMP9 in BNB breakdown in CIDP.
IgG RECEPTOR IIa ALLELES DETERMINE SUSCEPTIBILITY AND SEVERITY OF THE GUILLAIN BARRÉ SYNDROME
van den Berg L.H., van der Pol W.L., van Doorn P.A., Wokke J.H.J. University Hospital Utrecht and Rotterdam, the Netherlands.
BACKGROUND: Guillain-Barré syndrome (GBS) is a subacute symmetrical polyneuropathy with an immune mediated pathogenesis. Infiltrating leukocytes and auto-antibodies of the IgG isotype directed against nerve constituents proposedly initiate peripheral nerve damage. Receptors for IgG (FcgR) on leukocytes constitute an important link between humoral and cellular parts of the immune system and confer potent cellular effector functions to myelin-directed antibodies. Three FcgR subclasses exhibit genetically determined bi-allelic functional polymophisms (FcgRIIa:R131 vs. H131; FcgRIIIa: 158F vs; FcgRIIIb: NA1 vs. NA2) which determine efficacy of the cellular immune response. To study the relevance of these polymorphisms for susceptibility and severity of GBS we compared FcgR genotype distributions in GBS patients with those in controls. METHODS: We performed a cross-sectional case-control study. Genomic DNA was isolated from whole blood of 31 randomly selected GBS patients and 187 healthy blood donors. Genotypes of the three polymorphic RFcg genes were determined by means of polymerase chain reaction. RESULTS: FcgRIIa-HI31 homozygosity was significantly increased in GBS patients as compared to healthy controls (Odds ratio 2.45; 95% confidence interval 1.12-5.36; p=0.037). Furthermore, FcgRIIa-H131 homozygos GBS patients had a higher risk for severe disease than patients with other genotypes (Odds ratio 18.57; 95% confidence interval 1.95-176.49; p=0.007). CONCLUSION: FcgRIIa allotypes capable of initiating efficient cellular effector functions are associated with both increased risk for GBS and a more severe disease course. This finding is consistent with the concept of combined action of auto-antibodies and cellular immune functions in the pathogenesis of GBS. FcgR alleles may constitute novel genetic risk markers for GBS.
THE SUBCLASSIFICATION CHRONIC DYSIMMUNE NEUROPATHY.
Busby M.I., Donaghy M.J. University department of clinical neurology, Oxford. England.
BACKGROUND/OBJECTIVES: The chronic dys-immune neuropathies
(CDN) are a heterogeneous group united by an apparent immune mediated
aetiology. The present subdivision into Chronic Inflammatory Demyelinating
Polyneuropathy, Multifocal Motor Neuropathy and the paraproteinaemic
neuropathies is of limited use largely because of overlap between,
and heterogeneity within, such groups. The aim of this study was
to investigate whether subdivision was tenable and if so to suggest
a subclassification useful both in patient management and the
study of pathogenic mechanisms. METHODS: A retrospective
review of 102 patients with CDN. RESULTS: Based solely
on clinical presentation 6 distinct subgoups were defined: Sensory
Ataxic Neuropathy (SAN; 5 patients), Chronic Motor Sensory Demyelinating
Neuropathy (CMSDN; 45), Subacute Motor Sensory Demyelinating Neuropathy
(SMSDN 26), Multifocal Motor Sensory Motor Neuropathy (MMSN; 6),
Pure Motor Demyelinating Neuropathy (PMDN; 7), and Multifocal
Motor Neuropathy (MMN, 13). Important differences were found between
groups with regard to neurophysiological features and responses
to immunosuppressive treatment. Compared to the CMSDN group, patients
with SMSDN not only had a more acute onset, they were more likely
to be female, to have relapsing/ remitting disease, more widespread
weakness, cranial nerve involvement and a good response to steroid
treatment. The pure motor neuropathies (MMN and PMDN) were characterised
by a high incidence of conduction block, a poor response to steroids
and excellent response to IVIg. Most subgroups included patients
with an associated serum paraproteinaemia but such patients did
not differ from others in the subgroup in terms of clinical presentation
or response to treatment. Although the comparison of patients
with demyelinating motor and sensory neuropathies with and without
an IgM paraproteinaemia, and with and without anti-MAG activity,
produced significant differences there were no differences when
comparing such patients with other patients in the CMSDN group.
CONCLUSIONS: The subclassification of patients with CDN
on clinical grounds is useful in choosing first line treatment
and predicting responsiveness. It should also serve as a basis
for the investigation of the pathogenic mechanisms that interact
to cause the symptoms of CDN
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