MANNOSE-BINDING LECTIN GENE-2 POLYMORPHISMS ASSOCIATED WITH SUSCEPTIBILITY AND SEVERITY OF GUILLAIN-BARRÉ SYNDROME: NEW EVIDENCE AND META-ANALYSIS

Journal of the Peripheral Nervous System 19:250–289 (2014)

PROCEEDINGS

2014 Inflammatory Neuropathy Consortium of the Peripheral

Nerve Society

July 13–16, 2014

Düsseldorf, Germany

SPONTANEOUS AUTOIMMUNE PERIPHERALNEUROPATHY DUE TO AIRE DEFICIENCY IS B CELLINDEPENDENT BUT REQUIRES PHAGOCYTIC CELLS

Allard DE, Howard H, Su M. University of North Carolina,Chapel Hill, NC, USA.

The cellular mechanism of chronic inflammatorydemyelinating polyneuropathy (CIDP) pathogenesis remainsunclear. Mice with a dominant Autoimmune Regulator gene(Aire) G228W mutation on an autoimmune-prone non-obesediabetic (NOD) background (NOD.AireGW/+ mice) developspontaneous autoimmune peripheral polyneuropathy (SAPP)resembling CIDP. CD4+ T cells contribute significantly toSAPP; however, the role of B cells and macrophages isless well understood. Thus, we sought to determine therole of B cells and macrophages in the pathogenesis ofautoimmune peripheral neuropathy. NOD.AireGW/+ micehave high titers of autoantibodies against peripheral nerveantigens and increased frequency and number of marginalzone B cells, a subset enriched for autoreactive B cellspecificities. These findings suggest a potential role forB cells in SAPP pathogenesis. To test this, we generatedNOD.AireGW/+ μMT−/− mice, which lack functional μ heavychain and thus fail to develop mature B cells. Our data showthat NOD.AireGW/+ μMT−/− mice lack B cells, but neverthelessdevelop peripheral neuropathy characterized by immune cellinfiltration of peripheral nerve, demyelination and impairednerve function. Furthermore, treatment with anti-CD20 ornon-depleting anti-CD19 antibodies also failed to protectNOD.AireGW/+ mice from neuropathy development. Thus,B cells are dispensable for SAPP development. F4/80+macrophages are highly represented in the peripheralnerves of neuropathic NOD.AireGW/+ mice and represent14% of viable cells in neuropathic nerve tissue. To deter-mine the role of phagocytic cells in SAPP pathogenesis,we treated mice adoptively transferred with NOD.AireGW/+

splenocytes with clodronate liposomes, which specificallydelete phagocytic cells including F4/80+ macrophages. 88%of adoptively transferred mice treated with control liposomesdeveloped SAPP by 9 weeks post transfer whereas only27% of clodronate liposome treated mice developed SAPP

in the same timeframe. Our findings indicate that phagocyticcells, but not B cells, are required for the development ofdemyelinating peripheral neuropathy in NOD.AireGW/+ miceand provide evidence that treatment targeting phagocyticcells may be efficacious for CIDP patients.

NONMYELOABLATIVE AUTOLOGOUS HEMATOPOIETICSTEM CELL TRANSPLANT FOR THE TREATMENT OFCIDP: 2014 INTERIM REPORT

Allen JA1,2, Ajroud-Driss S1, Sufit R1, Burt R1.1Northwestern University, Chicago, IL, USA; 2Universityof Minnesota, Minneapolis, MN, USA.

Most patients with CIDP improve after initiation of cor-ticosteroids, IVIg or plasmapheresis. Rare patients do notrespond to one of the first-line options, or become refrac-tory or intolerant to conventional treatments. We report theoutcome of refractory CIDP treated with nonmyeloablativeautologous hematopoietic stem cell transplantation (HSCT).Patients eligible for this open label, non-randomized trial arerequired to have definite or probable CIDP as defined byEFNS/PNS criteria and fail at least 2 first-line agents. Periph-eral blood stem cells are harvested with cyclophosphamideand G-CSF. The conditioning protocol is a nonmyeloablativeregimen of cyophosphamide, rabbit antithymocyte globulin,methylprednisolone, and rituximab. Hemopoietic stem cellsare reinfused after cyclophosphamide completion. Patientsare followed for up to 5 years. Accumulated data hasbeen updated through April 1, 2014. Forty-two patientshave been enrolled. Mobilization and transplantation proce-dures were well tolerated. There were no non-hematologicaltoxicities≥ grade III severity or neutropenic-related oppor-tunistic infections. Two patients died of pre-existing con-ditions (gastric cancer, cardiovascular disease) during thefollow-up period. Drug free remission was observed in 68%(6 month, n= 38), 75% (1 year, n=32), 75% (2 year, n=20),78% (3 year, n= 14), 55% (4 year, n=9), and 40% (5 year,n= 5). Modified Rankin scale (p=0.001) and SF-36 question-naire (p<0.001) significantly improved at last follow-up. MRCsum score, averaged compound muscle action potential

© 2015 Peripheral Nerve Society 250

Abstracts Journal of the Peripheral Nervous System 19:250–289 (2014)

amplitude, and averaged motor conduction velocity improvedat each interval, although differences were generally not sta-tistically significant. Not all patients improved. Fifteen (40%)received immunotherapy at some point after HSCT. Six ofthese 15 received IVIg or corticosteroids immediately afterHSCT, and were successfully tapered off within 1 year. Twopatients had no change in immunotherapy requirement and7 patients relapsed after HSCT and a treatment-free interval.Relapses occurred at 1 month, 3 months, 4 months (2), 6months, 2 years, and 4 years. Nonmyeloablative autologousstem cell transplant can be performed safely and may bebeneficial for some, but not all, CIDP patients refractory toconventional therapies. Longer follow up is needed beforeconclusions can be made on the ability of this intervention toprovide CIDP patients with durable long term remission.

DIAGNOSIS AND MISDIAGNOSIS OF CIDP: ACAUTIONARY REPORT

Allen JA1,2, Lewis RA3. 1University of Minnesota,Minneapolis, MN, USA; 2Northwestern University, Chicago,IL, USA; 3Cedars-Sinai Medical Center, Los Angeles, CA,USA.

There is no reliable marker that can be used as a CIDPdiagnostic gold standard. The diagnosis weighs heavilyupon individual physician interpretation of data. Althoughnumerous criteria exist to help guide the diagnostic process,they are likely underutilized. The implications of incorrectlylabeling a patient as CIDP are not benign. We sought toexplore the diagnosis/misdiagnosis of CIDP and to exposepitfalls that erroneously lead to misdiagnosis. This retrospec-tive chart review encompassed 18 months of consecutiveCIDP patient referrals (JA). To ensure diagnostic accuracy,all charts were blinded and independently reviewed (RL).Diagnosis was defined by the EFNS/PNS criterion. Fifty-ninecases were identified. In 46% the diagnosis of CIDP wasincorrect. Alternative diagnoses included a heterogeneouscollection of conditions. Age, gender, symptom duration,and time since “CIDP” diagnoses were similar betweengroups. Not surprisingly, the CIDP group was more likely(p<0.01) to meet EFNS/PNS clinical/electrodiagnostic cri-teria, demonstrate CSF cytoalbuminologic dissociation,and show MRI nerve root enhancement or enlargement.However, it is notable that within the not-CIDP group 44%satisfied “atypical” EFNS/PNS clinical criteria, 52% demon-strated some degree (usually mild) of CSF cytoalbuminologicdissociation, and 73% of patients subjectively reportedpossible or definite improvement with immunotherapy(CIDP group 87%). With this broad definition of “subjectiveclinical improvement” there was no statistically signifi-cant difference between the groups. However, when clinicalimprovement was restricted to patients describing unequivo-cal benefit (i.e., definitely improves any symptom rather thana “possible” (or equivalent) response from the patient), only54% of the not-CIDP group responded affirmatively (CIDP87%, p=0.01). When clinical improvement was definedfurther as unequivocal improvement limited to strength orsensation the rate decreased to 27% (CIDP 80%, p< 0.001).

These patients largely had immune-mediated disordersincorrectly diagnosed and treated as CIDP (e.g., MS, SPS,MMN). We demonstrate here that CIDP misdiagnosis iscommon. We urge heightened diagnostic diligence forindividuals with “atypical” CIDP symptoms and for relativelymild CSF protein elevations. Exceptional caution shouldbe applied to interpretation of “clinical improvement afterimmunotherapy”, as most patients will provide a favorablealbeit indeterminate answer but only few will appreciateunequivocal symptom improvement.

RELAPSING GUILLAIN-BARRÉ SYNDROMEACCOMPANIED WITH MEMBRANOUSGLOMERULONEPHRITIS

An JY1, Park MS2. 1Department of Neurology, St. VincentHospital, College of Medicine, The Catholic Universityof Korea, Seoul, Korea; 2Department of Neurology, Collegeof Medicine, Yeungnam University, Daegu, Korea.

Although Guillain-Barré syndrome (GBS) is consideredto be monophasic, recurrences rarely occur. Patients withMiller Fisher syndrome, younger age (<30 years) and milderdisease were more likely to have a recurrence. Althoughmost patients still made a good recovery after recurrence,recurrent GBS is often severe in some cases. GBS can beassociated with renal involvements, ranged from asymp-tomatic proteinuria to overt nephritic syndrome. We reporta 45-year-old man with GBS and membranous glomeru-lonephritis (MGN) who showed more severely relapsed 10days after initial improvement of neurological symptoms.These symptoms did not recover as much as pre-relapse levelin spite of intravenous immunoglobulin and plasmapheresis.Early relapse or treatment-related fluctuation in GBS may bedue to continuous production of pathogenic factors beyondthe time course of the effects of treatments or rebound kinet-ics of antibodies to peripheral nerve myelin after treatment.If MGN, which has a similar immunological mechanism asGBS, is accompanied with GBS, it may influence the clinicalcourse of GBS.

RADICULAR MYOCLONUS IN GUILLAIN-BARRÉSYNDROME (GBS)

Baba M, Miki Y, Ueno T, Haga R, Nishijima H, Arai A,

Suzuki C, Nunomura J, Tomiyama M. Departmentof Neurology, Aomori Prefecture Neurological Centre,Aomori, Japan.

We experienced a GBS patient who presented withmyoclonic jerky movements probably due to severe radi-culitis. A 53-year-old Japanese woman with no history ofneuropsychiatric illness visited us because of proximal limbweakness. She did not have preceding upper respiratoryinfection or diarrhea. Tendon reflexes were totally absent andglove and stocking type hypoesthesia was seen. Motor nerveconduction studies revealed multifocal delay in latencies

251


and absent F-waves in examined limb nerves. CSF exam-ination showed elevated protein level and no cells. Noantiganglioside antibodies were detected in the serum.Contrast-enhanced MRI disclosed enhancement in the spinalroots. We administered IVIg 0.4 g/kg/day for 5 days fromday 1. However, her weakness progressed to tetraparesisand respiratory failure developed on day 4. NCS demon-strated markedly prolonged distal latencies, e.g., 21 ms inthe median nerve, and CSF protein increased up to 695 mg/dlon day 8. On day 17 CSF became coagulated soon after thespinal tap. On day 19, she started to display rhythmic invol-untary movements in the proximal limb muscles and trunkwith variable amplitude between oscillations. The involuntarymovements always started from proximal muscles of theright lower leg, and moved almost simultaneously towardsthe left lower leg and trunk, and finally to the upper extrem-ities lasting for more than 10 minutes. No abnormal move-ment was seen in the head. Palatal myoclonus was absent.Surface EMG recording revealed rhythmic synchronous dis-charges with 100–200 ms duration in the agonist and antag-onist muscles of the thighs at approximately 4 Hz. EEGwas normal. Jerk-locked back averaging EEG showed nopreceding cortical spikes or premovement potentials. Nolong latency reflexes were evoked. SEP study showed noenhanced cortical components. Auditory evoked potentialwas normal. The involuntary movement was slightly relievedby clonazepam, but not by placebo. The involuntary move-ments dramatically disappeared along with improvement ofmuscle weakness and decrease in CSF protein level. Themyoclonus was considered to be radicular origin probably dueto cross-excitation of a large population of neurons throughephaptic transmission at the spinal root levels.

NEUROGENIC CHANGES IN THE BLADDERS OFKETAMINE CYSTITIS PATIENTS

Baker SC, Southgate J. Jack Birch Unit for MolecularCarcinogenesis, Department of Biology, University of York,UK.

Over the last 15 years ketamine has become anincreasingly popular recreational drug for its dissociative andhallucinogenic effects. In 2007, a severe urological syndrome(marked by dysuria, frequency, urgency and haematuria anda thickened, contracted, painful bladder) was first associ-ated with chronic ketamine abuse. We recently discoveredunusual neuropathological features in the bladder wall ofketamine cystitis patients observed by immunohistology.In all cases of ketamine cystitis, the lamina propria wasreplete with fine neurofilament protein (NFP+) nerve fibresthat were not found in other painful bladder syndromes. Inmost patients, we observed prominent peripheral nerve fas-cicle hyperplasia (NFP+, S100+ and the p75 low-affinitynerve growth factor receptor (NGFR+)) that showedparticular resemblance to Morton’s neuroma. The fascicleperineurium was generally well-developed and epithe-lial membrane antigen+ and NGFR+. NGFR is normallyexpressed by basal cells of the urothelium but where thebladder’s epithelium remained present in ketamine cystitis

patients (ulceration is common) NGFR expression wasobserved supra-basally suggesting the urothelium may playa role in these neuropathic changes. The neurogenic changesobserved in the bladder wall of ketamine cystitis patientswere not seen in other painful bladder conditions and likelyaccount for the extreme pain experienced. Nearly half ofpatients who stop using ketamine report no improvement insymptoms and as such, further research is urgently required.

NEUROPATHIES IN HIV INFECTED SOUTH AFRICANSWITH ASSOCIATED CD8 LYMPHOCYTOSIS

Bateman K, Heckmann J. Neurology Division, Departmentof Medicine, Groote Schuur Hospital, University of CapeTown, Cape Town, South Africa.

Polyneuropathy is a frequent complication of HIV infec-tion, typically manifesting as a distal symmetrical sensorypolyneuropathy (DSP). However, in a high HIV prevalenceregion, a wider spectrum of HIV-associated neuropathies areseen, that remain poorly described. Patients were includedwho were seen at the HIV Neuromuscular Clinic, or admit-ted to Groote Schuur Hospital, Cape Town, South Africa,between March 2007 and March 2014 with HIV infection anda suspected inflammatory neuropathy, not characteristic ofHIV-DSP. A retrospective folder review identified 25 cases ofpatients with CD8 lymphocytosis, suggestive of the diffuseinfiltrative lymphocytosis syndrome. We describe the clini-cal phenotype, laboratory and biopsy results and responseto therapy in selected cases. A broad spectrum was iden-tified including both acute and chronic inflammatory radicu-loneuropathies as well as cases with focal or segmentalradiculoneuropathies.

CONSISTENCY OVER TIME OF STRENGTH ANDDISABILITY MEASUREMENTS IN CIDP PATIENTS ONSTABLE IGG THERAPY

Berger M1, Walton TP2, Schaeffer D2, Ney J3, Allen JA4,5.1CSL Behring, LLC, King of Prussia, PA, USA; 2AxelaCare,Lenexa, KS, USA; 3University of Washington, Seattle, WA,USA; 4University of Minnesota, Minneapolis, MN, USA;5Northwestern University, Chicago, IL, USA.

To set the stage for a study to determine the extent towhich the maximal response to IVIG infusion in CIDP patients“wears off” before the next dose is due, we reviewedthe results in the CareExchange® database to assess thevariation in measurements obtained at the time of eachinfusion. CareExchange is an iPAD™ based data systemthat captures and integrates pharmacy data, dosing, infusionnursing assessment data, physician progress notes, patientmeasured outcomes data, and patient response to therapyin a format which can be easily accessed by the patients’physician via the web. CareExchange was developed toimprove chronic disease management and to facilitate theuse of patient-reported outcomes in research. Data was

252


collected on 181 patients over a mean of 14.9 IVIG infusionvisits (excluding induction/loading doses), at a mean intervalof 22.9 days. Patients’ mean age was 57 years and 55%were women. The mean IVIG dose was equivalent to 0.6gr/kg/month, patients on subcutaneous IgG were excluded.Left and right hand grip strength were recorded using Jamardynamometers and Overall Neuropathy Limitations Scale(ONLS) and Rasch-built Overall Disability Scale (R-ODS) wererecorded using standardized forms. The mean left hand gripstrength was 42.5 lbs, with a mean visit to visit variation of0.2 lbs, with an SD of 2.5 lbs and a range of -8 to +20.4lbs. The mean right hand grip strength was 44.8 lbs with amean visit to visit variation of 0 lbs, SD of 2.5 lbs and rangeof -11.8 to +12.0 lbs. The mean ONLS at baseline was 3.9with a visit to visit variation of -0.4, SD of 1.4 and range of-7.5 to +4.4. The mean R-ODS at baseline was 55.9 with amean visit to visit variation of 0, SD of 0.2 and range of -0.8to +1.0. The results, comprising 2,670 visits over nearly 170patient years of follow-up, provide a baseline assessmentof the degree of visit-to-visit variability, which can be usedas a comparator for evaluating the extent of day to dayvariation within dosing intervals in future studies. Disclosureof relationships which could be perceived as conflicts: 1) MelBerger: Employee and stockholder, CSL Behring. 2) TimothyWalton and David Schaeffer: Employees, Axelacare. 3) JohnNey: Consultant, Axelacare and CSL Behring. 4) Jeffrey A.Allen: Consultant, Axelacare; Advisory panel, CSL Behring;Advisory panel, Baxter.

INFLUENCE OF THE SPHINGOSIN 1-PHOSPHATERECEPTOR AGONIST FTY720 ON SCHWANN CELL GENEEXPRESSION RELATED TO DE- AND REDIFFERENTIATIONPROCESSES

Beyer F, Heinen A, Hartung H-P, Küry P. Departmentof Neurology, Medical Faculty, Heinrich-Heine-University,Düsseldorf, Germany.

Diseases of and injury to the nervous system eitherlead to demyelination or loss of axons distal to the injurysite. In contrast to oligodendroglial cells of the central ner-vous system (CNS), Schwann cells as myelinating glial cellsof the peripheral nervous system (PNS) can adapt to thesepathophysiological changes. Remarkably, these cells are ableto dedifferentiate, to generate an axon regeneration per-missive environment and to promote reinnervation of tar-get tissues. Finally, these cells remyelinate growing axons,which leads to efficient functional recovery. However, despitethis high plasticity, regeneration is often incomplete, espe-cially after prolonged, severe disease courses as observed ininflammatory or inherited neuropathies, revealing the neces-sity to uncover new therapeutic interventions to accelerateand improve regeneration by modulation of the Schwanncell transcriptional program. We examined whether the sph-ingosin 1-phosphate (S1P) receptor agonist FTY720 altersSchwann cell gene expression. A number of previous stud-ies showed that FTY720 exerts an immunomodulatory func-tion and ameliorates the disease course of multiple sclerosis.

Apart from this, FTY720 appears to protect oligodendroglialprecursor cells and to promote remyelination associated pro-cesses in the CNS. An amelioration of the disease coursein the PNS was also observed in animals with experimen-tal autoimmune neuritis. However, these studies focused onFTY720’s immunomodulatory function only, but no influenceof FTY720 on regeneration associated gene expression wasinvestigated to date. Interestingly, an influence on p57kip2expression was shown. Since we demonstrated that p57kip2inhibits differentiation of myelinating glial cells (Heinen et al.,PNAS 2008; Heinen et al., Glia 2012), this suggests thatFTY720 may modulate Schwann cell differentiation via reg-ulation of differentiation associated genes. Here, we providea detailed description of transcriptional changes of primarySchwann cells upon FTY720 treatment, taking into accountgene expression related to stemness, de- and redifferentia-tion of the Schwann cell lineage as well as gene signaturesthat have been implicated with its repair conferring pheno-type. This analysis suggests a therapeutic window of oppor-tunity that might be used for a FTY720/Fingolimod/Gilenyaapplication addressing pathological conditions with impairedperipheral nerve regeneration.

PENTRAXIN 3 IN POEMS SYNDROME: A 2-YEARLONGITUDINAL STUDY AND SURAL NERVEIMMUNOHISTOCHEMISTRY FINDINGS

Briani C1, Dalla Torre C1, Cavallaro T2, Ferrari S2, Cabrini

I2, Lessi F3, Scarlato M4, Campagnolo M1, Lucchetta M1,

Ruggero S1, Toffanin E1, Manfredi AA5, Morbin M6,

Lauria G6, Adami F4. 1Department of Neuroscience,SNPSRR, University of Padova; 2Neurological,Neuropsychological, Morphological and MovementSciences, University of Verona; 3Department of Medicine,Haematology Unit, University of Padova; 4Divisionof Neuroscience, Department of Neurology & INSPE, SanRaffaele Scientific Institute, Milan; 5Department of InternalMedicine, San Raffaele Scientific Institute, Milan; 6IRCCSFondazione Istituto Neurologico “Carlo Besta”, Milan, Italy.

Polyneuropathy, organomegaly, endocrinopathy,M-protein, and skin changes (POEMS) syndrome is amultisystem disorder associated with plasma cell dyscra-sia. Elevated serum levels of vascular endothelial growthfactor (VEGF), which strongly promotes neovascularizationand vasopermeability, are considered to be responsible formany of POEMS syndrome’s symptoms. Sural nerves fromPOEMS syndrome patients show increased thickness ofthe basal lamina and despite VEGF reliably mirrors diseaseactivity and response to treatment, anti-VEGF therapy alone,in spite of dramatically reducing VEGF serum levels, is notsufficient for controlling the disease suggesting a more com-plex pathogenesis of POEMS syndrome. Up-regulation ofother inflammatory cytokines has been reported in POEMSsyndrome, but their role has still to be investigated. Theobjective of our study was to assess whether plasma Pen-traxin 3 (PTX3), a marker of vascular pathology, might be acandidate marker for POEMS syndrome. Plasma PTX3 and

253


serum vascular endothelial growth factor (VEGF) levels weremeasured (ELISA) longitudinally (mean follow-up 2 years)in 6 POEMS patients (4 men, 2 women, mean age 56 yrs,42–70 range) and the results correlated with clinical courseand therapy response. Sera from 16 age-matched patientswith inflammatory or paraproteinemic neuropathies wereused as control. PTX3 staining (using rat anti-human PTX3)of sural nerve biopsies from patients with POEMS syndromeand vasculitic neuropathies were performed. Median plasmaPTX3 levels was 1.10 ng/ml (range 0.33–19.94, SD 3.40).Median serum VEGF levels was 733 pg/ml (range 136–2679,SD 573.39). No statistic correlation was found betweenplasma PTX3 levels and VEGF serum levels in POEMS (p0.17; r 0.19) or in controls patients (p 0.56; r 0.16). Theimmunohistochemistry of sural nerve biopsies showed anabundant expression of PTX3 localized around vasculiticvessel walls as compared with samples from patients withPOEMS syndrome, in which the immunopositivity wasvariable from low PTX3 absent PTX3 expression. Our dataconfirms VEGF as a very useful and more specific markerin the diagnostic and monitoring process of POEMS syn-drome, also when compared with other marker of vascularinflammation/damage/injury, such as PTX3.

OXALIPLATIN-INDUCED PERIPHERAL NEUROTOXICITY:RESULTS FROM A TWO-YEAR FOLLOW UP STUDY

Campagnolo M1, Bergamo F2, Cacciavillani M3, Dalla

Torre C1, Lucchetta M1, Lonardi S2, Briani C1.1Department of Neurosciences, SNPSRR, Universityof Padova, Padova, Italy; 2Oncology Unit 1, VenetoOncology Institute - IRCCS, Padova, Italy; 3Data MedicaGroup, EMG Unit, CEMES, Padova, Italy.

Oxaliplatin (OXA)-induced neurotoxicity, both acute andchronic, represents a dose-limiting adverse effect that canlead to severe disability. Whereas several data are availableon OXA neurotoxicity, little is known on the evolution ofOXA-induced chronic neuropathy. The aim of our study wasto evaluate the natural course and presence of residual neu-ropathy in patients treated with OXA-based regimen. Weconvened in a control evaluation a cohort of 52 patients pre-viously treated with capecitabine and OXA (XELOX protocol)for metastatic colorectal cancer who had been prospectivelyneurologically (clinical evaluation with Total Neuropathy Scoreclinical version, TNSc) and neurophysiologically monitoredfrom baseline to the end of therapy. Two years after OXA dis-continuation, 17 (10 men, 7 women, mean age 61.7 yrs, range40-70) of 52 patients were available for neurological evalua-tion (TNSc). Neurophysiological control was performed at dis-cretion of physician provided that the patient was willing to doit. At enrollment, no patients had symptoms or signs of neu-ropathy. At the end of chemotherapy, in 10/17 patients TNScworsened (median TNSc 5, range 3-8). At two-year followup, all patients presented good oncologic response. Amongthe 10 patients who had developed OXA-induced neuropathy(median TNSc 5, range 3-8), 5 patients returned to baselinenormal values, 2 patients remained stable (median TNSc at

the end of OXA 3.5, median TNSc at follow-up 3), 3 patientsshowed an improvement in TNSc that however persisted >4(median TNSc at the end of OXA 7, median TNSc at follow-up4). Regarding neurophysiology, 9 of the 17 had evidence ofsensory axonal neuropathy at the end of chemotherapy. Attwo year follow-up only 4 patients underwent neurophysi-ological examination, that was normal in 3 patients, whilein the remaining patient documented a stable mild sensoryaxonal neuropathy. The preliminary results of our follow-upstudy show that, despite its frequency, OXA-induced periph-eral neuropathy completely reversed in half of the patientsafter 2 years from OXA discontinuation, improved in one-thirdof the cases and persisted stable in 20% of the patients. Theongoing study on a larger population will help better clarifythe long-term course of OXA-induced neurotoxicity.

METHODOLOGICAL VARIATION IN PERFORMINGELECTROPHYSIOLOGICAL STUDIES IN GUILLAIN-BARRÉSYNDROME (GBS) PATIENTS - AN INTERNATIONAL GBSOUTCOME STUDY (IGOS) INITIATIVE

Chavada G1, Verboon C2, Willison HJ1, Jacobs BC2,3;

for the IGOS consortium. 1College of Medical, Veterinaryand Life Sciences, University of Glasgow, Glasgow, UK;Departments of 2Neurology and 3Immunology, ErasmusMedical Centre, Rotterdam, The Netherlands.

Currently, there are no universally accepted standardelectrophysiological (EP) criteria for the diagnosis of GBS andthere is very little information available about methodologicalvariability to guide the development of new standardizedcriteria. Also, the prognostic role of electrophysiologicalstudies (EPS) is debatable. One of the many aims of theInternational GBS Outcome Study (IGOS) is to understandand optimize the diagnostic and prognostic basis for routinelyavailable clinical EPS. The pilot study presented here is thefirst effort to launch a wide range of specialist study groupsformed under the IGOS consortium. The membership andremit of an IGOS-EP subgroup will be opened to interestedresearchers and formulated at INC 2014. The group willbuild on previous efforts to achieve these aims amongst INCmembers and others. Within the IGOS-EP we propose tostudy the methodological variability in performing EPS across131 participating centres from 16 countries, with an aim toevaluate currently available criteria and to propose a newconsensus based international diagnostic criteria of GBS. Aspart of IGOS, each patient undergoes at least one set of EPSand in some centres two, depending on available resources.Currently, 436 patients have been recruited into the study.We propose to analyse EPS of all patients. Reporting datawill be collected including: 1) number of motor and sensorynerves examined; 2) nerves examined for motor nerveconduction velocities; 3) nerves examined for sensory nerveamplitudes and conduction velocities; 4) nerves examined forproximal CMAPs and SNAPs; 5) number of nerves examinedfor F-wave latencies and how many F waves were examinedin each nerve; 6) nerves examined for CMAP durations and% of amplitudes; 7) H-reflex recordings; 8) whether and how

254


an electrophysiological diagnosis was reached; 9) number ofstudies performed and interval; and 10) information regardingstandard technical details such as temperature, filter settings,electrodes and normative values for local laboratories.

INTRAVENOUS CYCLOPHOSPHAMIDE RESPONSIVEMOTOR-DOMINANT CHRONIC INFLAMMATORYDEMYELINATING NEUROPATHY

Cho H-J1, Min J-H1, Kim M-K2, Kim BJ1. 1SungkyunkwanUniversity School of Medicine, Samsung Medical Center,Seoul, Korea; 2Seoul Medical Center, Seoul, Korea.

Motor-dominant chronic inflammatory demyelinat-ing neuropathy (CIDP) is a distinct subtype of CIDP withcharacteristic clinical features, responsiveness to treat-ment, and prognosis. One previous study suggested thattreatment to prevent its recurrence as an alternative tointravenous immunoglobulin (IVIG) therapy is very impor-tant. A 45-year-old man with a 15-year history of psoriasisdeveloped bilateral hand weakness and it progressed to sym-metric distal dominant upper and lower weakness within 6weeks. He met the electrodiagnostic criteria of CIDP, buthad no sensory symptoms. For 2 months he received IVIGtreatment 4 times because he had shown only transientimprovement in weakness and had got worse within 1-2weeks. After one attempt to conduct intravenous methyl-prednisolone pulse therapy, the patient showed quadriplegiaand improved after IVIG treatment. We decided to treat himwith intravenous cyclophosphamide pulse therapy, and hehas been in remission after that. He got worse after thesteroid pulse therapy, showed no sensory symptoms, andin the motor nerve conduction study (NCS), there were con-duction blocks in bilateral median nerves. But sensory NCSshowed decreased conduction velocity in 3 nerves, eventhough the degree was minimal and he showed symmetricdistal dominant weakness. So it is better to consider thispatient as motor-dominant CIDP rather than a multifocalmotor neuropathy with conduction block. Even though hetreated for mild to moderate plaque psoriasis, the diseasecourse of the CIDP and psoriasis seems to have no clinicalrelationship. We report a motor-dominant CIDP patient whohas been in remission with intravenous cyclophosphamide,but not with IVIG therapy.

RESCUE THERAPY WITH CYCLOPHOSPHAMIDE FOR THETREATMENT OF NONSYTEMIC VASCULITIC NEUROPATHY

Cho H-J1, Min J-H1, Kim M-K2, Kim BJ1. 1SungkyunkwanUniversity School of Medicine, Samsung Medical Center,Seoul, Korea; 2Seoul Medical Center, Seoul, Korea.

Nonsystemic vasculitic neuropathy (NSVN) is a local-ized vasculitis of the peripheral nervous system (PNS).NSVN is known to be clinically similar to systemicvasculitis-associated neuropathies except for reducedseverity. One retrospective cohort study suggested that

cyclophosphamide and prednisone combination therapyis effective as in the systemic vasculitis. To evaluate theeffect of cyclophosphamide and steroid combination therapyand identify the clinical features of the NSVN patients, weselected NSVN patients who were diagnostically confirmedby electrodiagnostic testing and nerve biopsy and weretreated by cyclophosphamide and steroid combination ther-apy between January 2000 and February 2014 at SamsungMedical Center. Six patients were identified and the meanfollow up duration was 6.5 years. One patient showed sideeffects of mild leukopenia and hair loss after one intra-venous cyclosphosphamide therapy, and the treatmentswere discontinued since then. The others were treated withcyclophosphamide plus steroid therapy at least for more thanone year. In the nerve conduction study (NCS), five patientsexhibited only sensory nerve involvement, and one patientshowed asymmetric axonal sensorimotor polyneuropathy.Four patients suffered from severe sensory ataxia so muchthat they showed gait disturbance. The neuropathic pain andsensory ataxia have been relieved markedly in two patientsand in remission in four patients since cyclophosphamideand steroid combination therapy. Two patients were treatedwith steroid only and the treatment had no effects, whilethe patients responded to the combination of cyclophos-phamide. Our results showed that NSVN patients tend tobe shown sensory dominant symptoms and NCS findings.Cyclophosphamide and steroid combination therapy may bemore efficient than steroid monotherapy for the neuropathicpain and sensory ataxia in NSVN patients.

NEUROLOGICAL TUBERCULOSIS-ASSOCIATED IMMUNERECONSTITUTION INFLAMMATORY SYNDROME: 4CASES OF LUMBOSACRAL POLYRADICULOPATHY

Cross H, Albertyn C, Heckmann J, Stanley A, Bateman K.

Neurology Division, Department of Medicine, Groote SchuurHospital, University of Cape Town, Cape Town, South Africa.

The phenomenon of tuberculosis-associated immunereconstitution inflammatory syndrome (TB-IRIS) in humanimmunodeficiency virus (HIV) infected individuals after initi-ation of combination antiretroviral therapy (cART) is well doc-umented. Neurological presentations are, however, poorlycharacterised in the literature. Local data have shown thatapproximately 12% of HIV infected patients with paradoxi-cal TB-IRIS have central nervous system involvement. Thismay take the form of meningitis, tuberculoma or more infre-quently, myelo- or polyradiculopathy. The latter presentationhas not previously been well described. We aim to high-light the clinical features, investigation findings and responseto treatment of this condition, by presenting four recentcases seen in the neurology ward at Groote Schuur Hos-pital, Cape Town, South Africa. Three HIV-positive patientswith low CD4 counts, diagnosed with drug-sensitive tubercu-losis (TB) and on appropriate antituberculous therapy, startedcART and experienced new neurological symptoms of lowerlimb weakness and sensory loss, accompanied by sphincterdysfunction in two cases. Cerebrospinal fluid (CSF) proteinwas raised and magnetic resonance imaging (MRI) showed

255


features of an excessive inflammatory response in two ofthree cases. They were assessed as paradoxical TB-IRISmanifesting as myeloradiculopathy (1 case) and lumbosacralpolyradiculoneuropathy (LSR) (2 cases). A third HIV positivepatient with a low CD4 count, was initiated on cART and sub-sequently presented with new drug-sensitive pulmonary TB.He was assessed as having unmasking pulmonary TB-IRIS.Two months after starting appropriate TB therapy, he deteri-orated clinically, presenting with new leg weakness, numb-ness and loss of bladder and erectile function. Clinicalexamination revealed a lumbosacral polyradiculopathy sec-ondary to paradoxical TB-IRIS. Spinal MRI was normal. CSFprotein was raised. All four cases responded well to corticos-teroids. Lumbosacral polyradiculoneuropathies, with or with-out spinal cord involvement, presenting as TB-IRIS may occurmore frequently than is recognised in the literature. It shouldbe considered in the differential diagnosis of new lower limbsymptoms (±sphincter dysfunction) occurring shortly afterinitiation of cART, especially in those with lower nadir CD4count and disseminated TB. Therapy with corticosteroidsshould be commenced as soon as drug resistance andother conditions have been excluded, to improve chances ofneurological functional recovery.

A DOUBLE BLIND, RANDOMISED CONTROLLED PHASE IITRIAL OF COMPLEMENT INHIBITION INGUILLAIN-BARRÉ SYNDROME

Davidson AI1,2, Chavada G1,2, Overell JR2, Willison HJ1,2;

on behalf of the ICA-GBS Trial Study Group. 1Instituteof Infection, Immunity and Inflammation, Collegeof Medical, Veterinary and Life Sciences, Universityof Glasgow, Glasgow, UK; 2Department of Neurology,Institute of Neurological Sciences, Southern GeneralHospital, Glasgow, UK.

Guillain-Barré syndrome (GBS) is the most frequentcause of acute flaccid paralysis worldwide. Current treat-ment comprises immunomodulation via plasma exchange orintravenous immunoglobulin. Nevertheless 1/5 of patientsrequire artificial ventilation and 1/5 have significant residualdisability at 1 year, indicating that there is an unmet need fornovel treatment approaches. There is a growing body of evi-dence to suggest that GBS is an antibody-mediated disorderin which complement fixing IgG1/3 subclass anti-gangliosideantibodies play a major role in pathogenesis, with this beingbest defined in the axonal variants. Ex vivo and in vivo stud-ies show the presence of the terminal membrane attackcomplex (MAC) in affected nerves. The complement cas-cade has thus become an attractive target for novel thera-pies. Eculizumab (Soliris, Alexion Pharmaceuticals) is a fullyhumanized monoclonal recombinant antibody (mAb) derivedfrom a murine anti-human C5 antibody that specifically neu-tralises the complement cascade at C5, preventing MAC for-mation and thereby abrogating the MAC-dependent cytotoxiceffects. Here, we are undertaking a single centre, 2:1 ran-domised, double blinded, prospective study of 30 patientsdiagnosed with GBS, with the aim to evaluate the safetyand efficacy of Eculizumab as a potential treatment for GBS.

Patients with motor symptoms for 2 weeks or less, and aGBS disability score of 3 or greater will potentially be eligiblefor inclusion and randomisation. Patients will all be treatedwith standard dose IVIg therapy, and will be randomised toreceive weekly boluses of Eculizumab (initial dose 1200 mgand subsequent doses 900 mg) or placebo over 4 weeks.The primary efficacy outcome is an improvement of 1 pointon the GBS disability score at 4 weeks, with the secondaryoutcomes involving improvements in Rasch-Built LinearlyWeighted Overall Disability Scale (R-ODS) and Overall Neu-ropathy Limitation Scale (ONLS) from baseline to 6 months.Safety data will be recorded throughout. The Trial SteeringCommittee and Independent Data Safety Monitoring Com-mittee are chaired by Pieter van Doorn and David Corn-blath, respectively. The study is financially supported by Alex-ion Pharmaceuticals, with recruitment scheduled to begin inJune 2014, and results due to be reported in 2016.

IMMUNOLOGICAL CAUSES IN A POPULATION WITHSMALL FIBER NEUROPATHY

de Greef BTA1, Pruppers MHJ1, Hoeijmakers JGJ1,

Merkies ISJ1,2, Faber CG1. 1Department of Neurology,Maastricht University Medical Center, The Netherlands;2Department of Neurology, Spaarne Hospital, Hoofddorp,The Netherlands.

Small fiber neuropathy (SFN) is a disorder of the thinlymyelinated A𝛿-fibers and the unmyelinated C-fibers. Sev-eral diseases are associated with SFN, such as metabolicdiseases (diabetes mellitus), inherited diseases (sodium-channelopathy, Fabry’s disease), toxic and drugs (alcoholabuse). In addition it is conceivable that immunological mech-anisms play a role in patients with SFN, since severalimmune-mediated diseases, such as sarcoidosis, Sjogren’sdisease and auto-antibodies are found in patients with SFN.There are indications that both the activation of the immunesystem at the peripheral level and the change in process-ing of sensory information in the central nervous system(CNS) have a role in pain associated with peripheral neuropa-thy. Some case studies in patients with SFN have reportedan effect of immunomodulating therapy. We will give anoverview of associated immunological disorders in a cohortof 568 patients diagnosed with SFN.

SCHWANN CELLS ACT AS FACULTATIVE ANTIGENPRESENTING CELLS IN THE INFLAMED PERIPHERALNERVE

Derksen A1, Kühl G1, Hagenacker T2, Kindermann D2,

Meyer zu Hörste G1, Kieseier BC1. 1Departmentof Neurology, Research Group for Clinical and ExperimentalNeuroimmunology, Heinrich-Heine University, Düsseldorf,Germany; 2Department of Neurology, University HospitalEssen, University of Duisburg-Essen, Germany.

In the peripheral nervous system (PNS) glial cells, theso-called Schwann cells (SCs) have trophic functions and

256


form the insulating myelin sheath that enables rapid saltatorypropagation of nerve impulses in axons. In the context ofvarious peripheral nerve pathologies, SCs become targetsof an immune response, but can also actively modulateinflammatory processes. In particular, some studies suggestthat SCs express antigen-presenting molecules via whichthey directly interact with T cells. Thus, SCs may activelyparticipate in local immune responses in the PNS, althoughin vivo evidence for such mechanisms is still lacking. Toaddress the role of SCs as antigen-presenting cells (APCs)in vivo, we used a genetically engineered animal model.By cross-breeding genetically modified Cre-loxP-bearingmice we produced mice whose myelin-forming SCs donot express the major-histocompatibility-complex (MHC)II (P0CreIab−/− mice). In these animals we performed achronic constriction injury of the sciatic nerve which triggersperipheral nerve infiltration by various immunocompetentcells, contributing to the generation and maintenance of neu-ropathic pain. To determine the level of clinical impairment,von Frey hair as well as hot plate tests were performedto assess allodynia as wells as thermal hyperalgesia. Toanalyze the number of infiltrating CD4+ T-cells in distaldegenerating nerve segments, immunohistochemistrywas performed. Furthermore, the number of re-extendingaxons were quantified in semithin sections. After chronicconstruction injury, P0CreIab−/− mice presented with areduction of thermal hyperalgesia compared to wild typeanimals. This was associated with a significant reductionof intraneural CD4+ T-cells as well as a reduction of myelindestruction in the sciatic nerve. Furthermore, we coulddemonstrate a significant decrease of nerve fibres loss inP0CreIab−/− mice compared to controls. Our data identifiedthe specific contribution of SCs in the inflamed peripheralnerve as facultative antigen presenting cells. This mighttranslate into new therapeutic avenues supporting repair orpreventing further damage in patients with peripheral nervepathology.

DELETION OF ADAM10 IN AXONS IMPAIRS AXONALOUTGROWTH AND REMYELINATION IN THE PNS

Derksen A1, Stassart R2, Stettner M1, Meyer zu Hörste

G1, Kieseier BC1. 1Department of Neurology, ResearchGroup for Clinical and Experimental Neuroimmunology,Heinrich-Heine University, Düsseldorf, Germany;2Department of Neurogenetics, Research Group Molecularand Translational Neurology, Max-Planck-Instituteof Experimental Medicine, Göttingen, Germany.

An emerging body of evidence suggests that disintegrinand metalloproteinases (ADAMs) play an essential role inprimary development and myelination of the peripheralnervous system (PNS). ADAM10 is a membrane-anchoredmetalloproteinase with both proteolytic and disintegrincharacteristics. Previous in vitro studies propose that dur-ing the process of myelin formation, ADAM10 is highlyupregulated and appears to be critically involved in axonaloutgrowth that is a requirement for myelination in theperipheral nerve. To further address the importance of

ADAM10 in these processes in vivo, we generated a cellspecific Cre-loxP-mediated knockout model of ADAM10either in myelin-forming Schwann cells (P0-cre, ADAM10−/−)or in motor neurons (Mnx-cre, ADAM10−/−). In these ani-mals we performed a sciatic nerve crush, which is widelyaccepted as a valid model for peripheral nerve regeneration.To determine the level of clinical impairment, continuousclinical and electrophysiological examination was con-ducted. To quantify the degree of post-traumatic axonaldegeneration and remyelination, semi-thin sections weregenerated 4 weeks after crush. Under physiological condi-tions, P0-cre, ADAM10−/− as well as Mnx- cre, ADAM10−/−

did not present with any clinical, electrophysiological orhistological phenotype when compared to wildtype mice.However, traumatic peripheral nerve lesion by sciatic nervecrush revealed a significant reduction of nerve fibres, espe-cially of small calibre fibres in Mnx-cre, ADAM10−/− mice.Our data suggest that axonal ADAM10 is important forneuronal outgrowth and thus represents a prerequisitefor successful regeneration and consecutively remyelina-tion. ADAM10 might play a crucial role in the interactionbetween axons and Schwann cells during the process ofremyelination.

THE USE OF SKIN BIOPSY TO STUDY NODALARCHITECTURE IN PATIENTS WITH PERIPHERALNEUROPATHY WITH AND WITHOUT CONDUCTIONBLOCK

Doppler K, Kilgué A, Wilhelmi K, Sommer C. UniversityHospital Würzburg, Department of Neurology, Würzburg,Germany.

The node of Ranvier is supposed to play a major roleas the site of initiation of demyelination in inflammatoryperipheral neuropathy. Changes of nodal architecture havebeen detected in patients with inflammatory demyelinat-ing neuropathy, and animal studies give evidence that thenode of Ranvier is the site of attack of anti-gangliosideantibodies leading to conduction block (CB). The conceptof nodo-paranodopathy has been suggested in this context.In the present study we aimed to elucidate the morpho-logical background of nodo-paranodopathy by investigatingnodal architecture in skin biopsies from patients withdemyelinating neuropathy with and without CB. Twelvepatients with inflammatory neuropathy with CB (7 withmultifocal acquired demyelinating sensory and motorneuropathy (MADSAM), 3 with chronic inflammatorydemyelinating polyneuropathy (CIDP), 2 with Guillain-Barrésyndrome (GBS)), 13 with inflammatory neuropathy withoutCB (2 GBS, 11 CIDP) and eight patients with hereditarydemyelinating neuropathy (2 HNPP, 8 other CMT) wereincluded. All patients underwent skin biopsy of the lateralindex finger. Double-immunofluorescence staining withanti-myelin basic protein (MBP, myelin marker) and anti-casprand anti-neurofascin was performed to study nodal archi-tecture. Seven patients with complete loss of myelinatedfibers (2 with CIDP, MADSAM and hereditary neuropathy

257


each, one with GBS) were not included in evaluation of nodalarchitecture. Dispersion of caspr staining was more oftenfound in patients with CB compared to patients withoutdetection of CB (p=0.048). Dispersion of caspr and elon-gated nodes were detectable in almost all patients withinflammatory neuropathy with CB (elongated nodes 8/10,dispersion of caspr 9/10), but also in half of the patientswith inflammatory neuropathy without detection of CB (5/10each) and hereditary demyelinating neuropathy (4/8 each).Assuming that nodo-paranodopathy is the pathogenetic con-cept underlying inflammatory neuropathy with CB, our datagive evidence of a high concordance of pathological findingsin nodes of dermal nerves and CB. However, nodal disruptionwas also found in cases of classical demyelinating neuropa-thy, like CMT, CIDP and GBS without CB. With the caveatthat CB may have been missed by incomplete recordingfrom proximal nerves, we tentatively conclude that disrup-tion of nodes can also be found in demyelinating neuropathywithout CB.

DOES THE ABILITY TO WALK MATTER?

Draak THP1, Vanhoutte EK1, Faber CG1, Merkies ISJ1,2;

on behalf of the PeriNomS study group. 1MaastrichtUniversity Medical Centre, Maastricht; 2Spaarne Hospital,Hoofddorp, The Netherlands.

Simplifying function assessment to only one item, e.g.,the ability to walk or not, has been applied in variousfields including inflammatory neuropathy studies. Althoughthis approach seems clinically appealing for trial designs,dichotomizing an outcome may have major concerns: its con-tent may lead to data reduction, causing relevant informationbeing lost through neglect of the real spectrum of the qual-ity of interest being assessed. In addition, dichotomizationleads to a reduction of scale’s increments, by for examplereducing the thresholds seen in a wider ruler to only onecut-off point. We determined whether the ability to walk(or not) would reflect patient’s Functional Acceptable Clini-cal Threshold (FACT) in inflammatory neuropathies. A totalof 137 patients with newly diagnosed (or relapsing pattern)Guillain-Barré syndrome (GBS: 55), chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP: 59), and IgMmonoclonal gammopathy related polyneuropathy (MGUSP:23) were serially examined (GBS/CIDP at T0, T1, T3, T6,and T12 months; MGUSP: T0, T3, T12). The percentage ofpatients being able to walk that reached a postulated cut-offon the inflammatory Rasch-built Overall Disability Scale(inflammatory-RODS) at 50th, 75th, and 90th percentile wasdetermined. The inflammatory RODS has recently demon-strated to be the best surrogate outcome measure to specif-ically assess functional outcome in GBS, CIDP, and MGUSP.Patients were treated to the discretion of their own physi-cian and the ability to walk outside or not plus the RODSwere assessed, as part of the international multi-centreinflammatory PeriNomS study. The findings in the currentstudy will be presented at the meeting determining whether“the ability to walk would reflect a FACT” in inflammatoryneuropathies.

COMPARING THE NIS VERSUS THE MRC AND INCATSENSORY SCALE IN INFLAMMATORY NEUROPATHIESTHROUGH RASCH ANALYSES

Draak T1, Vanhoutte EK1, van Nes SI2, Gorson KC3, Cats

EA4, Van der Pol WL4, Notermans NC4, Gallia F5,

Bombelli F6,7, Van den Bergh PYK8, Léger J-M6,

Nobile-Orazio E5, Lauria G9, Bril V10, Lunn MPT11, Pouget

J12, van der Kooi AJ13, Raaphorst J13, Hahn AF14, van

Doorn PA2, Cornblath DR15, van den Berg LH4, Faber

CG1, Merkies ISJ1,16; on behalf of the PeriNomS study

group. 1Department of Neurology, University MedicalCentre Maastricht, Maastricht, The Netherlands;2Department of Neurology, Erasmus Medical CentreRotterdam, Rotterdam, The Netherlands; 3Departmentof Neurology, St. Elizabeth’s Medical Center, TuftsUniversity School of Medicine, Boston, MA, USA;4Department of Neurology, Rudolf Magnus Instituteof Neuroscience University Medical Centre Utrecht, TheNetherlands; 5Department of Neurological Sciences, MilanUniversity, Humanitas Clinical Institute, Rozzano, Milan,Italy; 6Department of Neurology, Hopital de la Salpêtrière,Paris, France; 7San Camillo-Forlanini Hospital, UOCof Neurology and Neurophysiopathology, Rome, Italy;8Department of Neurology, Catholique Universityof Louvain, Belgium; 9Department of Neurology,Neuromuscular Diseases Unit National NeurologicalInstitute “Carlo Besta”, Milan, Italy; 10Departmentof Neurology, Toronto General Hospital, Toronto, Canada;11Department of Neurology, Centre for NeuromuscularDisease, National Hospital for Neurology and Neurosurgery,London, UK; 12Department of Neurology, Centre deRéférence des Maladies Neuromusculaires et de la SLA,Hôpital de La Timone, Marseille, France; 13Departmentof Neurology, Academic Medical Centre, Amsterdam, TheNetherlands; 14Department of Neurology, London HealthScience Center, London, Ontario, Canada; 15Departmentof Neurology, Johns Hopkins School of Medicine, Baltimore,MD, USA; 16Department of Neurology, Spaarne Hospital,Hoofddorp, The Netherlands.

In neuromuscular disorders, sensory/motor deficitsare generally evaluated using the Neuropathy Impair-ment Scale (NIS) sensory/motor subsets (NISs/ NISm),the modified-INCAT sensory scale (mISS), or Medi-cal Research Council (MRC) grades. A head to headcomparison between these measures has never beenperformed. The objective of this study was to com-pare NISs versus the mISS, and NISm versus theMRC in patients with Guillain-Barré syndrome (GBS),chronic-inflammatory-demyelinating-polyradiculoneuropathy(CIDP), and gammopathy-related polyneuropathy (MGUSP).Since selected scales are ordinal-based, collected datain GBS/CIDP/MGUSP patients were subjected to Raschanalyses, creating Rasch-transformed (RT)-interval mea-sures. Comparison between measures was based onvalidity/reliability with emphasis on responsiveness (usingpatient’s level of change related to the individually-obtainedvarying standard errors (MCID-SE)). Eighty (GBS: 30, CIDP:

258


30, MGUSP: 20) stable patients were assessed twice (entry:2-observers; 2-4 weeks later: 1-observer) and 137 newly diag-nosed/relapsing patients (GBS: 55, CIDP: 59, IgM-MGUSP:23) were serially examined (follow-up 12-months). For allmeasures data modifications (e.g., rescoring response cat-egories eliminating disordered thresholds) were needed toimprove model fit. Overall, the sensory/motor scales demon-strated ∼equal and acceptable validity/reliability scores.Responsiveness scores were slightly higher in RT-mISSversus RT-NISs, but remained poor in both. Moderate equalresponsiveness scores were seen for the RT-motor scales,being higher in GBS>CIDP, and hardly seen in MGUSP. Thecurrent study demonstrates deficiencies of ordinal-basedsensory/motor scales needing translation into interval mea-sures. Sensory measures showed poor responsiveness. Themotor (MRC sum-score/NIS-motor) scales had moderateresponsiveness, with higher values in GBS versus CIDP.Additional studies in MGUSP are suggested since hardly anychanges were seen in this condition.

MOTOR NERVE EXCITABILITY AFTER CHILDHOODGUILLAIN-BARRÉ SYNDROME

Drenthen J, Roodbol J, Maathuis EM,

Catsman-Berrevoets CE, van Doorn PA, Blok JH, de Wit

M-CY, Jacobs BC. Erasmus MC, University Medical CenterRotterdam, The Netherlands.

Guillain-Barré syndrome (GBS) may affect children aswell as adults and, at least in adults, age is the main predictorof clinical recovery in the first 6 months of disease. Previousstudies have shown that the long term prognosis of GBS inchildren is better than in adults, although approximately 20%of these patients may still suffer from residual complaints,including fatigue and reduced quality of life. However, studiesinvestigating residual neurophysiological deficits are scarce.The aim of this study was to determine residual motor nervedysfunction after pediatric GBS (GBS). In this observationalcross-sectional cohort study, 37 patients with GBS in child-hood were included. Motor ulnar nerve dysfunction wasdefined by compound motor action potential (CMAP) scanin patients after a follow-up of at least one year comparedwith age-matched healthy controls, in relation to clinicalcourse and outcome. The key parameters of the CMAP scanare S0 and S100 (stimulus intensities that excites the firstmotor unit and all motor units, respectively), the stimulusintensity range (difference between S0 and S100) and thepresence of steps. Steps appear in the CMAP scan as gapsand they result from the firing of large motor units. Also,residual clinical symptoms and complaints were defined indetail in these patients. Motor nerve dysfunction was foundin 25 (68%) of the patients. It was present in all patientswith residual clinical weakness, but also in the majority ofpatients with complete clinical recovery. The most com-mon abnormalities were found in the stimulus intensityparameters. CMAP scan characteristics were not relatedto prognostic factors. In conclusion, paediatric GBS resultsin residual motor nerve excitability disturbances, even in

completely recovered patients, possibly reflecting thephysiology of regenerated peripheral nerves.

INTRAVENOUS IMMUNOGLOBULIN OVERTREATMENT INCHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY: A RANDOMIZED CONTROLLEDNON-INFERIORITY TRIAL (IOC-TRIAL)

Eftimov F1, Adrichem ME1, de Haan RJ1, Dijkgraaf

MGW1, Merkies ISJ2, Notermans NC3, Faber CG2, van

Doorn PA4, van Schaik IN1. 1Academic Medical Center,Amsterdam; 2Maastricht Academic Medical Center,Maastricht; 3University Medical Center, Utrecht; 4ErasmusMedical Center, Rotterdam, The Netherlands.

Intravenous immunoglobulin (IVIg) is an efficacious treat-ment for chronic inflammatory demyelinating polyradicu-loneuropathy (CIDP). However, CIDP runs different andunpredictable disease courses including spontaneous remis-sions. Prognostic factors for individual disease courses andbiomarkers for disease activity are lacking, making it difficultto assess requirements for ongoing IVIg treatment. Success-ful IVIg withdrawal will reduce adverse events, discomfort ofregular infusion and high health care costs in treatment forCIDP. The objectives of the trial are to determine whethersubjects with CIDP are overtreated with maintenance IVIgtreatment and to reduce overtreatment-associated subjects’burden and health care costs. The secondary objective isto search for possible predictive factors for ongoing needof IVIg treatment. To study these objectives, we havedesigned a multicenter, randomized, double-blind, standardIVIg treatment-controlled non-inferiority trial. We will includesixty adult subjects with clinically stable CIDP who are cur-rently receiving maintenance IVIg treatment. Subjects willbe randomized to either IVIg withdrawal or continuation ofIVIg treatment. Those randomized to IVIg withdrawal willstart with a tapering phase consisting of 3 infusions (75%,50% and 25%, respectively, of the subjects’ pre-study IVIgdose combined with placebo), followed by 100% placeboinfusions. Those randomized to continuation of treatmentwill receive the same IVIg brand, doses and interval priorto the study. The primary outcome is the change betweenbaseline and endpoint Rasch-Overall Disability Scale (R-ODS)score, a patient self-reported linearly weighted scale thatmeasures activity and social participation limitations. Anendpoint will be reached at the final 24 weeks visit or incase of a predefined deterioration on the R-ODS duringfollow-up. Secondary outcomes will include change in qual-ity of life, muscle strength, grip strength, sensory impair-ment and costs of health care use. Blood samples will betaken to enable biomarker exploration including changes inIgG levels and clonal composition of lymphocytes. Partici-pants who deteriorate will enter a predefined restabilizationprotocol. The study has been approved by the AMC EthicsCommittee and is awaiting approval in other Dutch neuro-muscular centers. The study is funded by ZonMw/RationalPharmacotherapy and Sanquin Blood Supply. Start of study isApril 2014.

259


DEVELOPMENT AND APPLICATION OF AN ALGORITHMTO INDIVIDUALISE IMMUNOGLOBULIN DOSING INNEUROPATHIES

Ellis L, Reilly M, Lunn M. National Hospital for Neurologyand Neurosurgery, London, UK.

Immunoglobulin (IgG) treatment is indicated forchronic inflammatory demyelinating polyneuropathy (CIDP),multifocal motor neuropathy (MMN) and Guillain-Barrésyndrome; investigations are ongoing for other peripheralneuropathies. Current dosing guidelines in neurologicaldisorders of 2 g/kg/month are outdated and do not considervariations in the half-life of IgG or between patients. Individ-ualisation of IgG therapy could optimise clinical outcomesand help control costs. We have developed an algorithm tooptimise the IgG dose based on the patient’s response asfollows. Patients are treated with an initial dose of 2 g/kg,and their response is assessed after 3 weeks. After 6 weeks,if the patient has fully normalised, a second dose is givenand the response is assessed after a further 3 weeks. A thirddose is not administered until the patient informs the doctorthat their condition has deteriorated, allowing the doseinterval to be set according to the duration of effectivenessof the IgG therapy. The patient is then stabilised with 2 fulldoses at the new dosing interval, following which the doseis reduced by 20% until relapse, allowing the optimal doseto be determined. Interval attempts at withdrawal are madeannually over the first three years. Using this algorithm wehave individualised IVIG doses for 71 inflammatory neuropa-thy patients (48 male, 23 female), with a mean±SD age of56.9± 13.9 years and weight of 77.8± 16.6 kg over five years.The majority are CIDP (n= 39) or MMN (n=24) patients;the remaining neuropathies are sensory ganglionopathy(n= 3), chronic immune sensory polyradiculopathy (n= 2),demyelinating neuropathy and IgM paraproteinaemic neu-ropathy (n=3; 2 anti-MAG [one with Waldenström’s], 1MAG negative). The mean±SD dose of IgG administeredis 1.39± 0.56 g/kg, with a mean dosing interval of 4.3 weeks(range 0.5-10 weeks). We conclude that IgG dose and dosingfrequency in peripheral neuropathies should be individualiseddepending on the disease subset and patient outcomes.Use of this algorithm has allowed us to optimise IgG dosingin inflammatory neuropathy patients to maintain a stablecondition, maximise effectiveness and minimise costs.

SERUM ALBUMIN AS PREDICTOR OF OUTCOME INGUILLAIN-BARRÉ SYNDROME TREATED WITH IVIMMUNOGLOBULIN

Fokkink W-JR1,2, Walgaard C2, Kuitwaard K2, Tio-Gillen

AP1,2, Huizinga R1, van Doorn PA2, Jacobs BC1,2.

Department of 1Immunology and 2Neurology, Erasmus MC,University Medical Center Rotterdam, The Netherlands.

At present there are no serum biomarkers avail-able to monitor treatment efficacy or predict outcome inGuillain-Barré syndrome (GBS). Previous studies indicated

that the increase in serum IgG level after treatment with IVimmunoglobulin (IVIg) was related to disease severity andprognosis in GBS. IgG has a unique long half-life in serumbecause it is saved from degradation by binding to theneonatal Fc receptor (FcRn). The only other serum proteinrescued by binding to FcRn is albumin, which is used as abiomarker for overall health status and to monitor the effectsof IVIg in other diseases. The aim of the current study wasto define the prognostic value of albumin in GBS patientstreated with IVIg. Firstly, we determined albumin levelsbefore and 2 weeks after start of IVIg treatment (2 g/kg)in 174 GBS patients by routine diagnostic turbidimetry.Secondly, we assessed whether these albumin levels wererelated to a set of pre-defined clinical outcome measuresduring 6 months follow-up. Thirdly, we evaluated the valueof albumin as additional predictor in the clinical prognosticmodels currently used for GBS. The median pre-treatmentalbumin levels were 42 g/L (IQR 38-45), with only 13% ofpatients being hypoalbuminemic (<35 g/L). Post-treatmentlevels were lower with a median of 37 g/L (IQR 32-41)(p< 0.001), with 33% of patients being hypoalbuminemic.Low albumin levels were related with a higher probabilityand longer duration of mechanical ventilation, more severelimb weakness at nadir (lower MRC sum score) and a morefrequent poor outcome (GBS-disability at 6 months). Theaddition of albumin as a categorical predictor variable tocurrent clinical prognostic, multivariable logistic regressionmodels, resulted in a further improvement of the accuracyin which respiratory failure and disability at 4 weeks and6 months could be predicted. In conclusion, this studyshows that a proportion of GBS patients after IVIg developshypoalbuminemia, which is associated with respiratoryfailure and poor outcome. Further studies are required todemonstrate whether measuring serum albumin can beused as a biomarker in clinical practice to monitor GBSpatients treated with IVIg.

GANGLIOSIDE COMPLEX ANTIBODIES DETERMINENEUROLOGICAL FEATURES IN ANTI-GQ1B ANTIBODYSYNDROME

Fukami Y1, Funakoshi K2, Wong AHY3, Yanuar A4, Yuki

N1. 1Department of Medicine, Yong Loo Lin Schoolof Medicine, National University of Singapore, Singapore;2Department of Neurology, Dokkyo Medical University,Tochigi, Japan; 3Department of Medicine, Queen ElizabethHospital, Hong Kong Special Administrative Region, China;4Department of Neurology, University of Indonesia, Jakarta,Indonesia.

We aim to identify the mechanism how anti-GQ1b and-GT1a antibodies produce various clinical presentations inFisher syndrome and its related conditions. Clinical featuresof 915 patients who carried IgG anti-GQ1b antibodies werereviewed. Antibodies to complex of GQ1b or GT1a with GM1,GD1a, GD1b or GT1b were tested in sera with optical densityvalues of 0.5 or more with IgG anti-GQ1b (n= 708) or -GT1a(n= 696) antibodies, which contained neither antibodies to

260


GM1, GD1a, GD1b or GT1b. Optical densities of IgG antibod-ies to single GQ1b or GT1a were used as standard (100%),and those of the antibodies to each ganglioside complexwere expressed in antibody activity (%). Complex-enhancedand -attenuated antibodies were respectively defined morethan 120% and less than 80%. Each antibody activity wascompared with various clinical features to identify any sig-nificant relationship. Patients who had IgG antibodies toGQ1b or GT1a antibodies as well as to GM1, GD1a, GD1bor GT1b were significantly associated neck and limb weak-ness. The anti-GQ1b or -GT1a antibody-positive patientswho had none of the other anti-ganglioside antibodies pre-sented had an increased risk of ataxia, being associatedwith enhanced anti-GQ1b/GD1b, GQ1b/GT1b, GT1a/GM1and GT1a/GT1b antibodies. An increased risk of hypersom-nolence was associated with attenuated anti-GQ1b/GT1b,GT1a/GD1b and GT1a/GT1b antibodies, that of bulbar palsywith enhanced anti-GT1a/GD1a antibodies, that of neckweakness with enhanced anti-GQ1b/GD1a and -GT1a/GD1aantibodies, and that of limb weakness was associated withattenuated anti-GQ1b/GT1b and GT1a/GT1b antibodies. Inconclusion, (i) oculomotor nerves and reticular formationmay express an isolated GQ1b, but not GQ1b complex withother gangliosides, and the attenuated anti-GQ1b antibod-ies may produce ophthalmoplegia and hypersomnolence andinduce the development of Bickerstaff brainstem encephali-tis. (ii) Spinal anterior roots may express an isolated GM1,GD1a, GD1b, GT1b, but not GQ1b or GT1a complex, andattenuated anti-GQ1b/GT1b and GT1a/GT1b antibodies mayproduce limb weakness. (iii) Muscle spindle may expressGQ1b/GD1b, GQ1b/GT1b, GT1a/GM1 and GT1a/GT1b, andenhanced anti-ganglioside complex antibodies may pro-duce ataxia. (iv) Glossopharyngeal and vagal nerves mayexpress GT1a/GD1a, and enhanced anti-GT1a/GD1a antibod-ies may produce bulbar palsy and induce the development ofpharyngeal-cervical-brachial weakness.

GD1B-SPECIFIC ANTIBODIES MAY BIND TO COMPLEXOF GQ1B AND GM1, CAUSING ATAXIA

Fukami Y1, Yanaka C2, Koike S3, Hirata K2, Yuki N1.1Department of Medicine, Yong Loo Lin School of Medicine,National University of Singapore, Singapore; 2Departmentof Neurology, Dokkyo Medical University, Tochigi, Japan;3Institute for Medical Science, Dokkyo Medical University,Tochigi, Japan.

Monospecific IgG antibodies to GD1b ganglioside(GD1b-specific antibodies) have been found in patientswith acute ataxic neuropathy and Guillain-Barré syn-drome. We aim to elucidate the clinical features andanti-ganglioside complex antibodies that may be associatedwith GD1b-specific antibodies. We also aim to investi-gate whether the GD1b-specific antibodies recognize anew conformational epitope formed by two gangliosidesor ganglioside-like lipo-oligosaccharides of Campylobacterjejuni. Serum samples with the GD1b-specific antibodieswere chosen, in which antibodies to ganglioside complexes

were assayed. Whether the GD1b-specific antibodiesrecognize ganglioside complex was tested by absorp-tion study. Binding of the GD1b-specific antibodies toC. jejuni lipo-oligosaccharides with GT1a and GM1 epi-topes were investigated. Six patients had the GD1b-specificIgG antibodies, all of whom had acute ataxia and IgGantibodies to complex of GQ1b and GM1 (GQ1b/GM1)and GT1a/GM1. GD1b-specific antibodies recognizedGQ1b/GM1 or GT1a/GM1 complex as well as C. jejunilipo-oligosaccharides bearing GT1a and GM1 epitopes. Inconclusion, the GD1b-specific antibodies are associated withacute ataxia. Micro-organisms, such as C. jejuni expressingboth GT1a and GM1 epitopes, may induce the production ofthe GD1b-specific antibodies, which may bind to GQ1b/GM1complex at the muscle spindle and cause ataxia.

LONG-TERM PROGNOSIS AND HEALTH-RELATEDQUALITY OF LIFE (HRQol) IN MULTIFOCAL MOTORNEUROPATHY (MMN)

Galassi G1, Ariatti A1, Tondelli M1, Benuzzi F1, Stefani

M2, Miceli P2, Nichelli P1, Valzania F1. 1Departmentof Biomedical, Metabolic and Neural Sciences,2Oncohaematology, University of Modena and ReggioEmilia, Italy.

MMN evolves with asymmetric weakness, conductionblocks (CB), and antibodies to glycolipid GM1. The purposeof our study was to assess if demographic, clinical, andneurophysiological variables could be useful to identify dis-ease progression in MMN. Forty-one Caucasian patients (34males and 7 females, median age of onset 47 yrs) werefollowed for median duration of 92 months (range 12-264).Eight patients (19.5%) had GM1 IgM antibodies at diagno-sis, 36.5% became positive during the study frame. Upperextremity (UE) tremor was observed in 60% of patients.Strength was assessed separately in UE and in LE withMedical Research Council Scale (MRC), disability with Over-all Disability Sum Score (ODSS) and Ranking scale. Effectsof IVIg treatment on progression were included in analy-ses conducted at 1, 3, 5, 10, 15 yrs since onset by sepa-rate Mann-Whitney U test and Wilcoxon matched pair test.Human leukocyte antigen (HLA) distribution was comparedbetween patients and 3,528 controls. Health-related qualityof life (HRQol) was assessed using Short-Form Health Survey(SF-36). At 1 and 3 years, total MRC score and the subscorerelated to lower extremities significantly decreased (T= 113;p= 0.009 and T= 70.5; p= 0.002, respectively) without ben-efit from periodic IVIg courses. At 10 years, overall MRC sub-scores significantly decreased (p= 0.003 and 0.001). Therewas no significant difference of demographic variables (ageof onset, gender), number of definite CBs, or disability out-come measures. Analysis of distribution of 9 selected HLAallelles with frequency ≥15% either in patients and controlsshowed that DQB1*06 prevailed in anti GM1-positive MMN(p= 0.02) .Our results provide evidence that MRC grading isa reliable prognostic marker. The finding of HLA DQB1*06prevalence in patients with detectable anti GM1 confirmsthat HLA locus may contribute to immune response in MMN.

261


PROGNOSTIC FACTORS AND HEALTH-RELATED (HRol)QUALITY OF LIFE IN POLYNEUROPATHIES WITH IgMANTIBODIES TO MYELIN-ASSOCIATED GLYCOPROTEIN(MAG)

Galassi G1, Tondelli M1, Ariatti A1, Stefani M2, Miceli P2,

Benuzzi F1, Nichelli P1, Valzania F1. 1Departmentof Biomedical, Metabolic and Neural Sciences,2Oncohaematology, University of Modena and ReggioEmilia, Italy.

Polyneuropathies with IgM antibodies to MAG areimmunologically mediated disorders. The purpose of thiscohort study was to assess the effects on disease progres-sion of demographic (age of onset, gender), clinical andneurophysiological variables, such as the electrophysiologi-cal type of neuropathy at diagnosis. Forty Caucasian patients(25 males, 15 females, median age 70.5 yrs) were followedfor a median duration of 91 months (range 12-225). Mediananti-MAG titer determined by ELISA was 17,452 U. The elec-trophysiological type of neuropathy (classified either demyeli-nating, axonal or mixed), muscle strength (assessed withMedical Research Council Scale (MRC)), disability (assessedwith Overall Disability Sum Score (ODSS) and Ranking scale),type of treatment, and serum IgM levels were included inthe analyses. Worsening was considered significant if MRCdifference between first and last examination was at leastof 12 points. Survival analysis with Cox regression modelwas performed. Human leukocyte antigen (HLA) distribu-tion was compared between patients and to 3,528 controls.Health-related quality of life (HRQol) was assessed usingShort-Form Health Survey (SF-36). Survival analysis showedthat patients with higher IgM level (p= 011), electrophysiolog-ical signs of demyelinating damage (p=0.05), and absence ofeither immunomodulating or immunosuppressive during dis-ease course (p.0021) had significantly higher risk of clinicalworsening. Analysis of distribution of 9 selected HLA allelleswith frequency ≥15% either in patients or controls showedthat the B44 and DRB1*07 prevailed significantly in patients(p= 0.004 and p= 0.03, respectively). Variations of clinicalmeasures did not affect HRQol in our patients. In conclusion,the IgM level and electrophysiological type of neuropathy atonset/diagnosis could be considered as prognostic markersin polyneuropathies with IgM antibodies to MAG. The findingof HLA B44 and DRB1*07 prevalence in patients could pointto possible association of anti-MAG antibody production withthis molecule.

ANTI-SULFATIDE IgM ANTIBODIES IN PERIPHERALNEUROPATHY: TO TEST OR NOT TO TEST?

Giannotta C, Di Pietro D, Gallia F, Balducci C,

Nobile-Orazio E. Humanitas Clinical and Research Center,Milan University, Rozzano, Milan, Italy.

Anti-sulfatide IgM antibodies have been associatedwith different neuropathies and are often associated withserum IgM monoclonal gammopathy and antibodies to

the myelin-associated glycoprotein (MAG). This heteroge-neous association has induced some skepticism on thepathogenetic relevance of this reactivity. We reviewed theclinical association of high titers of anti-sulfatide IgM anti-bodies in 570 patients with neuropathy and related disordersexamined in our laboratory since 2004. Sera were testedby ELISA at the initial serum dilution of 1:32,000 and sub-sequently titrated by serial two-fold dilution. In all positivepatients IgM antibodies to MAG were also measured andtitrated by western blot. High titers of anti-sulfatide IgMantibodies (1:32,000 or more) were found in 39 patients,including 19 patients with titers up to 1:64,000, and 20 withtiters of 1:128,000 or more. In 33 of the 39 positive patients(85%) increased titers of anti-MAG IgM antibodies were alsofound. In these patients the neuropathy had the typical fea-tures of a chronic demyelinating sensory ataxic neuropathyassociated with anti-MAG antibodies. Six patients did nothave increased titers of anti-MAG antibodies. Five of themhad moderately increased anti-sulfatide titers (1:32,000 to1:64,000) that were associated in one each with chronicsensory axonal neuropathy and IgG monoclonal gammopa-thy, POEMS syndrome, transthyretin amyloid neuropathy,minimal and asymptomatic neuropathy and paraneoplas-tic subacute sensory neuropathy. Only one patient with ademyelinating neuropathy associated with IgM monoclonalgammopathy had markedly increased anti-sulfatide titers(1:256,000). Increased titers of anti-sulfatide IgM antibodiesare not infrequent in patients with neuropathy even if theyare often associated with a concomitant reactivity to MAG. Aselective reactivity to sulfatide is rarely found and is associ-ated with different forms of neuropathy indicating that test-ing for these antibodies may rarely help in the diagnosis ofpatients with neuropathy.

EVALUATING THE DIAGNOSTIC UTILITY OF THESURAL-SPARING PATTERN DERIVED USING RADIALVERSUS MEDIAN OR ULNAR NERVES IN THE INITIALDIAGNOSIS OF GUILLAIN-BARRÉ SYNDROME

Goh EJH1, Umapathi T2, Verma K2, Yuki N1. 1Yong LooLin School of Medicine, National University of Singapore,Singapore; 2National Neuroscience Institute, Singapore.

The “sural sparing” pattern, the relative sparing of suralsensory nerve action potential (SNAP) over that of medianand ulnar nerves, is useful in the diagnosis of Guillain-Barrésyndrome (GBS). However, both median and ulnar nervesare commonly affected by entrapment neuropathy. We there-fore studied the diagnostic utility of a sural-sparing pat-tern, derived using radial SNAP, in the early diagnosis ofGBS. We defined sural-sparing as a greater decrease in theSNAP of the upper limb nerves compared to that of thesural nerve, adjusted to age and height matched norms.We excluded patients with co-existent carpal tunnel syn-drome and polyneuropathy. Out of 30 GBS patients, 11had the sural-sparing pattern, derived using median or ulnarSNAPs. Of the 11, 4 had sural-sparing when the radial SNAPwas used. Four other patients did not have radial-derived

262


sural-sparing pattern. Radial sensory nerve recordings werenot done for the remaining 3 patients. Out of 30 patients withFisher Syndrome (FS), 6 had the sural-sparing-pattern derivedfrom median or ulnar nerves. Of the 6, 5 patients also hadthe pattern when radial SNAP was used in the computation.The radial nerve was not studied in a single patient. How-ever, in one other FS patient, the radial SNAP at day 7 wasabnormal in the presence of normal median, ulnar and suralSNAPs. At day 15 the median and ulnar SNAPs decreasedto abnormal values while sural SNAP remained normal. Thisis the only case of isolated radial-derived sural-sparing in ourcohort. Among 18 patients that were initially diagnosed asGBS or FS but later had alternative diagnoses (GBS mim-ics), median or ulnar derived sural-sparing pattern was seenin 1 patient with neurosyphillis and in the second study(done on day 8) of another patient with sensory neuronopa-thy. The radial-derived sural-sparing pattern was present inboth patients as well. Radial sensory data was unavailablein 6 GBS mimics. In conclusion, our overall findings suggestthat a radial derived sural-sparing pattern may not be supe-rior to one derived from median or ulnar nerves in the earlydiagnosis of GBS.

CIDP AND TREMOR: POSSIBLE RELATIONSHIPBETWEEN ELECTROPHYSIOLOGICAL DATA, PRESENCEOF AUTO ANTIBODIES AND RESPONSE TO TREATMENT

Guimarães-Costa R1, Iancu Ferfoglia R1, Viala K2, Querol

L5, Musset L3, Apartis E4, Illa I5, Léger J-M1. 1Centre deRéférence de Maladies Neuromusculaires, UniversityHospital Pitié-Salpêtrière, Paris, France; 2Département deNeurophysiologie Clinique, University HospitalPitié-Salpêtrière, Paris, France; 3Départementd’Immunologie, University Hospital Pitié-Salpêtrière, Paris,France; 4Département de Physiologie, HôpitalSaint-Antoine, Université Pierre et Marie Curie, Paris,France; 5Department of Neurology, Hospital de la SantaCreu i Sant Pau, Barcelona, Spain.

It has been recently reported that chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP) patients pre-senting a tremor might have antibodies to neufascin 155 iso-type IgG4 (NF155), with a possible correlation with a severephenotype and a poor response to intravenous immunoglob-ulin (IVIg). Though, scarce data are available regarding tremorin CIDP, mainly considering neuropathic tremor (NT). Wereport on 5 patients with tremor and CIDP (aged 40 to 84),one having a purely sensory form. Surface polymyographicrecordings coupled to accelerometry were performed in allpatients. One CIDP patient had bilateral distal tremor in upperlimbs (3.5 Hz in interossei and 5 Hz in extensor carpi radialis)typical of NT. Three others had essential-like tremor (ELT):one with a bilateral distal tremor in upper limbs (6 Hz inextensor carpi radialis), another with a severe bilateral distaland proximal upper limbs tremor (4.5 Hz in all simultane-ously recorded muscles) and the third one with a postu-ral and action tremor in upper limbs (6 Hz in proximal and6.5 Hz in interossei muscles). The last patient had postural

and orthostatic myoclonus (brief arythmic 40 ms) in only thelower limbs. In the CIDP NT patient, treatment with IVIgwas followed by improvement of both CIDP symptoms andtremor. The same result was observed in the first patient withan ELT, after treatment with IVIg/steroids. In the two otherpatients with an ELT, CIDP symptoms improved with severalimmunomodulators and a transient or a secondary improve-ment of tremor was observed. All patients were tested forNF155 antibodies by immunocytochemistry. Results will beavailable at the meeting. Overall, the study of these correla-tions should contribute to better define subtypes of CIDP inorder to select their best treatment.

ANTI-GalNAc-GD1a ANTIBODIES IN MULTIFOCAL MOTORNEUROPATHY AND RELATED DISORDERS

Hamada Y, Samukawa M, Kuwahara M, Mitsui Y,

Kusunoki S. Department of Neurology, Kinki UniversityFaculty of Medicine, Japan.

GalNAc-GD1a is a minor ganglioside that is locatedon the paranodal regions of ventral roots and intramuscu-lar nerves in the human peripheral nervous system. It isknown that anti-GalNAc-GD1a antibodies are detected inthe sera from a subset of patients with Guillain-Barré syn-drome, mainly in AMAN type. In this study, we examinedthe clinical profiles of patients with tentative diagnosis ofmultifocal motor neuropathy (MMN) and motor neuron dis-ease (MND) associated with the anti-GalNAc-GD1a antibod-ies. Anti-GalNAc-GD1a antibodies were examined by ELISAas described previously (Kusunoki et al., Ann Neurol 1994).A sample was considered positive when the optical density(OD) was greater than 0.3. Among 294 patients with ten-tative MMN and 227 patients with tentative MND, whosesera were examined between October 2012 and September2013, anti-GalNAc-GD1a antibodies were positive in twelvepatients with tentative MMN (IgM 5, IgG 7), and in tenpatients with tentative MND (IgM 6, IgG 4). The electrophysi-ological findings and detailed clinical status could be obtainedfrom ten of the twelve patients with tentative MMN (IgM 3,IgG 7) and seven of the ten patients with tentative MND (IgM4, IgG 3). Among ten tentative MMN patients, five patientswere categorized as definite MMN, one patient as probableMMN, and the other 4 patients as non-MMN by EFNS/PNScriteria. Among seven tentative MND patients, one patientwas categorized as probable, but the other six patients didnot fulfill MMN criteria. Seven of ten tentative MMN patientswith anti-GalNAc-GD1a antibodies were treated with intra-venous immunoglobulin therapy (IVIg), while no such treat-ment was performed in tentative MND patients. Amongthe seven patients treated with IVIg, four showed excel-lent response, and two showed moderate response. Notablyone of the excellent responders and one of the moderateresponders were categorized as non-MMN by EFNS/PNS cri-teria. These results suggested that the positive status ofanti-GalNAc-GD1a antibody could be not only a diagnosticmarker of MMN but also an independent marker to detectthe responder to immune-modulating therapy.

263


HUMAN STEM CELL DERIVED MOTOR NEURONS TOMODEL MULTIFOCAL MOTOR NEUROPATHY

Harschnitz O1,2, Jansen M1, Vlam L1,4, Kling S1,

Jongbloed BA1,3, Pasterkamp RJ2, van den Berg LH1, van

der Pol WL1. 1Department of Neurology and Neurosurgery,UMC Utrecht Brain Center Rudolf Magnus, Utrecht, TheNetherlands; 2Department of Translational Neuroscience,UMC Utrecht Brain Center Rudolf Magnus, Utrecht, TheNetherlands; 3Department of Neurology, St. ElisabethHospital, Tilburg, The Netherlands; 4Departmentof Neurology, Erasmus MC, Rotterdam, The Netherlands.

Multifocal motor neuropathy (MMN) is animmune-mediated pure motor neuropathy, associatedwith IgM antibodies against GM1 gangliosides in the serumof approximately 50% of patients. There is indirect evidencethat anti-GM1 IgM antibodies cause damage to neurons,but their pathogenicity remains controversial, due to thefact that in approximately 50% of patients these antibodiescannot be detected by ELISA. We have developed an in vitrodisease model for MMN using induced pluripotent stemcell (iPSC)-derived motor neurons. After reprogramming ofhealthy control fibroblasts into iPSCs, we differentiate iPSCsinto motor neurons that express GM1 in vitro using estab-lished motor neuron differentiation techniques. We show forthe first time that IgM antibodies in serum from patients withMMN, but not healthy or disease controls, bind to humanmotor neurons, irrespective of the presence of anti-GM1 IgMantibodies according to ELISA. IgM reactivity of so-called‘sero-negative’ samples again underlines the methodologicalissues associated with the ELISA technique, and highlightsthe importance of IgM antibodies in the pathogenesis ofMMN. This model allows us to examine stress pathways inthese iPSC-derived motor neurons triggered by IgM antibod-ies. The described disease model may be a significant stepforward in elucidating the exact pathogenesis of MMN andestablishing which role IgM antibodies play in MMN.

TRACKING THE INTERACTIONS BETWEEN TLYMPHOCYTES AND THE PERIPHERAL NERVE – A NEWIN VITRO LIVE IMAGING MODEL

Hattenhauer ST, Mausberg AK, Wolffram K, Stettner M,

Kieseier BC. Department of Neurology, Research Groupfor Clinical and Experimental Neuroimmunology,Heinrich-Heine-University, Düsseldorf, Germany.

Immune-mediated inflammatory disorders of the periph-eral nervous system (PNS) are characterized by cellular infil-tration, demyelination and axonal loss in the affected part ofthe PNS. Most of our current understanding on the role ofT cell immunology affecting the peripheral nerve has beengathered from studies in an animal model, experimentalautoimmune neuritis (EAN). However, it still remains elu-sive how. CD4+ and/or CD8+ T lymphocytes precisely con-tribute to the destructive process of demyelination and axonaldamage in the peripheral nerve, to shed further light on theprecise interactions between T cells, myelin sheaths and

axons we established a live imaging in vitro model. Myeli-nated fibres of rat dorsal root ganglia (DRG) served as amodel for the peripheral nerve. DRGs of embryonic (E16)Lewis rats were prepared and cultured, myelination was initi-ated after one week in vitro and proceeded for two additionalweeks. T lymphocytes were obtained from diseased animalswith EAN: Lewis rats immunized with P2 or with peripheralnerve myelin were sacrificed to obtain T cells of the lymphnodes after immunization After magnetic separation of CD4+vs CD8+ T cells, we studied the specific effect of neurito-genic T lymphocytes. Control T cells were prepared fromhealthy rats. For vital tracking T lymphocytes were stainedusing Orange Cell Tracker. Myelin detection in vital cultureswas assed by incorporation of C16 fatty acids conjugatedwith a flurophore into the myelin layer. Experiments wereperformed in a conditioned microscope chamber, dyed T cellswere added to the DRG-culture and continuously followed-upfor up to 16 hours. We were able to successfully establisha model system in which DRGs and T lymphocytes remainvital and can be followed by live imaging. The dyes for fattyacids and for T cells exhibited no bleaching. First experimentsallowed to monitor T cell migration in the myelinated cul-tures and revealed close proximity of several T cells to themyelin sheaths. This new model system may represent auseful tool to better understand the interactions between Tlymphocytes and Schwann cells forming the myelin sheathas well as axons. In addition, it may be useful in the develop-ment of new therapies for inflammatory diseases affectingthe peripheral nerve.

HISTONE METHYLTRANSFERASE ENHANCER OF ZESTEHOMOLOG 2 REGULATES SCHWANN CELLDIFFERENTIATION

Heinen A1, Tzekova N1, Graffmann N2, Torres KJ1,

Uhrberg M2, Hartung H-P1, Küry P1. 1Departmentof Neurology, Medical Faculty, Heinrich-Heine-University,Düsseldorf, Germany; 2Institute for TransplantationDiagnostics and Cell Therapeutics, Medical Faculty,Heinrich-Heine-University, Düsseldorf, Germany

Epigenetic control is crucial for the differentiation of avariety of cells including oligodendrocytes, the myelinatingglial cells of the central nervous system. However, stud-ies about the implication of epigenetic factors in peripheralnervous system maturation are just emerging and includemicro-RNAs (activity of the DICER enzyme), the role ofhistone deacetylation (HDAC1/2) and of DNA methylation(S-adenosylmethionine) in peripheral nerve myelination. Herewe demonstrate the impact of a histone methyltransferase,encoded by the enhancer of zeste homolog 2 (EZH2) gene,on Schwann cell differentiation. In sciatic nerves, EZH2 post-natal expression was found in Schwann cells and expressionpeaks perinatally. Suppression of EZH2 expression in cul-tured Schwann cells induced morphological changes whichwere accompanied by widespread alterations in the geneand protein expression pattern, including downregulationof myelin genes and induction of p57kip2, an intrinsicinhibitory regulator of Schwann cell maturation (Heinen

264


et al., PNAS 2008). ChIP analysis revealed binding of EZH2at the p57kip2 promoter and reduction of histone H3K27trimethylation and hence reduced EZH2 activity upon genesuppression. EZH2 suppression dependent effects on mor-phology and myelin genes could be reversed by concomi-tant suppression of p57kip2, indicating that p57kip2 is adownstream effector of EZH2. In addition, we show thatEZH2 suppression in DRG cocultures interferes with invitro myelination. Furthermore, we describe Hes5 as tran-scriptional repressor of myelin genes in Schwann cells,which was induced upon EZH2 suppression and downreg-ulated in p57kip2-suppressed Schwann cells. Hes5 suppres-sion induced myelin gene and protein expression. We havetherefore identified a molecular link between histone methy-lation and control of Schwann cell differentiation and demon-strate that this epigenetic mechanism is crucial for glialdifferentiation to proceed (Heinen et al., GLIA 2012). Ourcurrent investigations focus on the in vivo function of H3K27trimethylation regarding Schwann cell maturation and periph-eral nerve regeneration using Schwann cell specific condi-tionally ablated mice. Here we describe first results analysingEZH2fl/fl mice, suggesting a compensatory role for EZH1in EZH2 deficient nerves. We therefore suppose a crucialfunction for H3K27 trimethylation during peripheral nervedevelopment and are at present expanding our studies usingEZH1/EZH2 double knockout mice.

EFFECT OF INTRAVENOUS IMMUNOGLOBULINS ONNATURAL KILLER CELLS

Heininger MK1, Meyer zu Horste G2, Cordes S3, Stettner

M1, Mausberg AK1, Kieseier BC1. 1Departmentof Neurology, Heinrich-Heine-University, Düsseldorf,Germany; 2Center for Neurologic Diseases, Brigham &Women’s Hospital, Harvard Medical School, Boston, MA,USA; 3Department of Hematology Oncology &Tumorimmunology, Charite Berlin, Germany.

Natural killer (NK) cells are part of the innate immunesystem with regulatory and effector functions playing animportant role in early reactions in anti-viral and anti-tumourdefences. NK cells are known for their regulatory potential tomodulate immune reactions under autoimmune conditions.Different studies suggest that treatment with intravenousimmunoglobulins (IVIg) has an immunomodulatory effect onNK cells. IVIg is a first-line treatment for various autoimmunediseases, in particular in chronic inflammatory demyelinat-ing polyneuropathy (CIDP). However, the exact mechanismof action still remains unknown. Using flow cytometry basedassays, we analysed the effects of IVIg on isolated peripheralblood lymphocytes, NK cell activity and cytotoxicity, as wellas on cell surface marker expression. By measuring degranu-lation and intracellular cytokine staining after stimulation withtarget cells, we found that IVIg reduces both cytotoxic andregulatory potential of NK cells in a dose dependent manner.Incubation with IVIg also alters expression levels of functionalNK receptors, such as CD161 or NKG2A. IVIg-treatment hasan approximate 70% efficiency in patients with CIDP. Thelack of a predictive marker for IVIg-responsiveness avoids

the preservation of not responding patients from a treat-ment period of up to several months before discriminationinto responders and nonresponders is possible. With hightreatment costs and potential undesirable side effects, abiomarker for treatment response would be of high patientand economic interest. Further experiments are warrantedto prove if differences in the NK cell status of patients withCIDP represent a potential surrogate marker in predicting theoutcome of IVIg-treatment.

A SIMPLIFIED PROTOCOL FOR THE GENERATION OFANTI-GANGLIOSIDE ANTIBODIES IN MICE USINGLIPOSOMES

Huizinga R1, Meehan G2, Cunningham M2, van Rijs W1,

Yao D2, Jacobs B1, Willison H2. 1Erasmus MC, UniversityMedical Center Rotterdam, Rotterdam, The Netherlands;2Institute of Infection, Immunity and Inflammation, Collegeof Medical, Veterinary and Life Sciences, Universityof Glasgow, Glasgow, UK.

Induction of anti-ganglioside antibodies in mice requiresthe use of strong adjuvants and multiple booster immuniza-tions owing to the low inherent antigenicity of carbohydratescombined with tolerance to self antigens. These cumber-some immunization regimens, although effective, are lesssuitable to study the mechanism by which Campylobac-ter jejuni induces acute phase antibodies that cross-reactwith gangliosides as a model for studying Guillain-Barrésyndrome. Therefore, we aimed to develop a simpleimmunization protocol without adjuvants for the induc-tion of anti-ganglioside antibodies in mice. GD3 synthaseknockout mice (lacking GD3 ganglioside) were injectedintra-peritoneally with liposomes containing either C. jejunilipo-oligosaccharides (LOS), the ganglioside GD3, or both.LOS containing GD3/GD2/GM2 ganglioside mimics wasderived from C. jejuni strain MF7, isolated from a MillerFisher syndrome patient. LOS from a Penner O:3 strain,without ganglioside mimics, was used as control. To investi-gate whether the liposomes could activate innate immunity,we assessed cytokine expression by qPCR. One hour afterintraperitoneal injection of MF7-LOS-liposomes, TNF-𝛼, IL-6and type I interferon were upregulated in the liver, the spleenand in peritoneal cavity cells. Cytokines were only inducedwith LOS-liposomes, but not with GD3-liposomes. No dif-ferences were found between MF7 and O:3 LOS-containingliposomes. IgM and IgG antibody responses were measuredwith combinatorial glycoarray and ELISA using serum col-lected on day 5 and 21. Antibody responses to liposomeswere only observed when LOS was present. MF7-LOS andO:3-LOS-liposomes induced an IgM response on day 5 toliposome components including cholesterol and the complexof dicetylphosphate and sphingomyelin, but no IgG responseto GD3 was detected. In contrast, liposomes containing bothLOS and GD3 induced antibodies to GD3 of both IgM andIgG3 isotype. The presence of ganglioside mimics on theLOS structure was not required. In conclusion, we showthat anti-GD3 antibodies can be readily induced in transgenicmice lacking GD3, using only two injections with liposomes.This response requires the presence of both LOS and

265


ganglioside-mimicking structures that are incorporated in theliposomal membrane in sufficient quantities. These resultssuggest that toll-like receptor activation is an important ampli-fier in the induction of anti-ganglioside antibodies in mice.

LONG-TERM EFFICACY OF RITUXIMAB IN IGMANTI-MYELIN-ASSOCIATED GLYCOPROTEINNEUROPATHY: RIMAG STUDY FOLLOW-UP

Iancu Ferfoglia R1, Guimarães-Costa R1, Viala K1,

Musset L2, Neil J2, Léger J-M1. 1Department of Neurology,2Department of Immunology, University HospitalPitié-Salpêtrière, Paris, France.

Immunoglobulin M (IgM) anti-myelin associated gly-coprotein (MAG) neuropathy is an immune mediatedneuropathy that might lead to severe disability due to pro-gressive ataxia and marked sensory symptoms. The RIMAGstudy failed to show any improvement at one year usingthe inflammatory neuropathy cause and treatment (INCAT)sensory score (ISS) in rituximab patients when compared toplacebo. This new study aimed to determine the long-termeffects of rituximab in a subset of patients included in theRIMAG study. Twenty patients from our center participatedin the RIMAG study between March 2006 and November2008 (10 received placebo and 10 rituximab). Two of the rit-uximab patients were excluded because of adverse events.In follow-up, 8 of the 10 placebo patients were retreatedwith rituximab because of disease progression. Only one outof the 8 rituximab patients needed a new rituximab infusion.Three patients could not be included in follow-up. Dataconcerning outcome measures were available in 7 rituximaband 8 placebo. The mean follow-up was 5.7 years (SD 0.82).There was a significant difference in the ISS score betweenthe two groups (p= 0.045), which contrasted with absenceof any difference using the ISS in the RIMAG study. A similarsignificant difference was observed in the 10-meter walktest between the two groups (p=0.044) in the follow-up.On the other hand there was no significant difference usingthe INCAT score. In conclusion, these results may indicatea possible improvement of the ISS in patients treatedwith rituximab in long-term follow-up. In addition, all but twopatients in the placebo group had to be treated with rituximabduring follow-up, versus only one in the rituximab group.

HIGH MORTALITY OF GUILLAIN-BARRÉ SYNDROME INBANGLADESH

Ishaque T1, Islam MB1,2, Ara G1, Endtz HP1,2,

Mohammad QD3, Jacobs BC4,5, Islam Z1. 1EmergingDiseases and Immunobiology Research Group, CFWD,International Centre for Diarrheal Disease Research(icddr,b), Dhaka, Bangladesh; 2Department of MedicalMicrobiology and Infectious Diseases, Erasmus MC,Rotterdam, The Netherlands; 3National Instituteof Neurosciences, Agargaon, Dhaka, Bangladesh;Departments of 4Neurology and 5Immunology, ErasmusMC, Rotterdam, The Netherlands.

Guillain-Barré syndrome (GBS) is an acutepost-infectious immune mediated neuropathy with highlyvariable clinical course and considerable morbidity andmortality. In Bangladesh, previous study on GBS patientsreported a high mortality compared to developed countries,but risk factors for fatal GBS have not been defined. The aimof the current study was to determine the frequency, timing,and risk factors of fatal GBS in Bangladesh. We conducteda prospective study on 491 subsequent cases of GBS whowere admitted at Dhaka Medical College Hospital, Dhaka,Bangladesh. We compared patients who died and survivedto identify risk factors. Confounding effects were adjusted byfitting into a Cox regression model. Survival probability after6 months was assessed by Kaplan Meijer survival analysis.Sixty-one (12.4%) of 491 GBS patients died and mediantime interval between onset of weakness and death was 17days (IQR 9.5 to 31 days, range 4 to 152 days). Among thefatal cases, 44% were above 40 years age, 75.4% had anMRC sum score ≤20 at entry, 31% had a progressive phase≥8 days and 54% were ventilated. Twelve patients (20%)died because mechanical ventilation was not available. Thestrongest risk factor for dying was the shortage of ventilatorsupport in patients with respiratory failure (OR: 26; 95% CI:11.2-60.3). Other risk factors for dying were age ≥40 years(OR: 6.8; 95% CI: 2.8-16.2), mechanical ventilation (OR: 4.5;95% CI: 2.2-8.9), severity at entry (OR: 2.2; 95% CI: 1.1-4.5)and involvement of III, IV, VI cranial nerve (OR: 3.6; 95% CI:1.7-7.5). Survival probability in the general population was86.9% after 5 months, but the chances decreased to 73.5%(p< 0.001) if the patient needed mechanical ventilation, andfurther decreased to 50% if the facilities for artificial respi-ration were unavailable. Median survival time for this groupof GBS patients was only 31 days. The mortality rate of GBSis much higher in Bangladesh compared to the developedworld. The high mortality rate in part is related to shortageof ventilator support, age and disease severity.

CLINICAL SPECTRUM OF GUILLAIN-BARRÉ SYNDROMEIN LOW-INCOME COUNTRIES – A PROSPECTIVECOHORT STUDY AND VALIDATION OF BRIGHTONCRITERIA

Islam MB1,2, Islam Z1, Farzana KS1, Sarker SK1,

Ahammad RU1, Jahan I1, Endtz HP1,2, Mohammad QD3,

Jacobs BC4,5. 1Emerging Diseases and ImmunobiologyResearch Group, CFWD, International Centre for DiarrhoealDisease Research (icddr,b), Dhaka, Bangladesh;2Department of Medical Microbiology and InfectiousDiseases, Erasmus MC, Rotterdam, The Netherlands;3National Institute of Neuroscience, Agargaon, Dhaka,Bangladesh; Departments of 4Neurology and 5Immunology,Erasmus MC, Rotterdam, The Netherlands

Guillain-Barré-syndrome (GBS) is the most commonform of acute flaccid paralysis worldwide, but few infor-mation is available about patients from low income coun-tries. Initial studies have shown that the incidence of GBSis high in Bangladesh, which might be related to the highexposure to infections triggering GBS. To be able to define

266


back ground incidence rates of GBS, accurate case defini-tions are required. Recently case definitions for GBS weredeveloped by the Brighton Collaboration and validated onlyin a cohort of Dutch patients. GBS in low-income countriesmay have a different phenotype than GBS in The Netherlands,considering the younger population, precipitation by othertype of preceding infections, predominance of axonal sub-types and the lack of specific therapy. In the current study,we described in detail the core diagnostic features of GBSand evaluated the performance of the Brighton criteria in awell-defined cohort of GBS patients from the Dhaka area ofBangladesh. A prospective study was conducted enrolling344 adult patients in Dhaka Medical College Hospital, thelargest tertiary hospital in Bangladesh. All included cases ful-filled the NINDS diagnostic criteria for GBS. Standardizeddata were collected regarding to demography, clinical fea-tures important for diagnosis, and results of cerebrospinalfluid (CSF) and nerve conduction studies (NCS). Includedpatients had a median age of 33 year (IQR 25-45 year) and50% had preceding diarrhea. The progressive phase lastedless than 2 weeks in 96%, but 88% of patients was admit-ted after reaching nadir. Symmetrical limb weakness andreduced reflexes were found in 98%. Increased CSF pro-tein level and normal cell count was found in 84% and evi-dence for poly(radiculo)neuropathy in NCS in 98%, whichwas axonal in 57%. Only 8% patients received intravenousimmunoglobulin or plasmapheresis and 15% patients died.Patients met the criteria for Brighton level 1 in 57%, level 2in 31%, level 3 in 11% and level 4 in 1%. In conclusion, GBSin Bangladesh is variable with respect to diagnostic features,but most patients meet the Brighton criteria. The currentdata can be used to further improve the diagnostic criteriafor patients from low-income countries.

SMALL VOLUME PLASMA EXCHANGE FORGUILLAIN-BARRÉ SYNDROME IN LOW-INCOMECOUNTRIES

Islam MB1,2, Mohammad QD3, Islam Z1, van Doorn PA5,

Endtz HP1,2, Rahman AKMS4, Jacobs BC5,6. 1EmergingDiseases and Immunobiology Research Group, Centrefor Food and Waterborne Diseases, International Centrefor Diarrhoeal Disease Research (icddr,b), Dhaka,Bangladesh; 2Department of Medical Microbiologyand Infectious Diseases, Erasmus MC, Rotterdam, TheNetherlands; 3National Institute of Neuroscience, Agargoan,Dhaka, Bangladesh; 4Uttara Adhunik Medical CollegeHospital, Bangladesh; Departments of 5Neurologyand 6Immunology, Erasmus MC, Rotterdam, TheNetherlands.

In low-income countries, most patients withGuillain-Barré syndrome (GBS) cannot afford treatment withintravenous immunoglobulin (IVIg) or plasmapheresis (PE).More than 77% of GBS patients in Bangladesh thereforedo not receive IVIg or PE, possibly explaining the high rateof mortality (14%) and disability at 6 months (29% unableto walk independently). Hereby, we propose small volumeplasma exchange (SVPE) for GBS patients who cannot afford

IVIg or plasmapheresis and currently receive supportive careonly. In SVPE the exchanged plasma volume is similar toplasmapheresis (23 ml/kg/day for 8 days), yet this amountis reached by daily exchange of small volumes of plasma(generally in adults 1.0 L/day). Potential advantages of SVPEare that the treatment requires no advanced equipment, ischeap (approximately 200 USD) and can be performed inonly 8 days. We present the design of a planned phase IItrial establishing the feasibility and safety of SVPE in DhakaMedical College Hospital. This open study, funded by theGBS-CIDP Foundation International, will use the infrastruc-ture of the International GBS Outcome Study group (IGOS).We aim to include 25 patients who fulfill the diagnosticcriteria for GBS, cannot afford IVIg or plasmapheresis, are≥12 years of age, have a GBS disability score of ≥3, presentwithin 2 weeks of onset of weakness, and do not havecontraindications for SVPE. Whole blood will be drawntransvenously according to body weight (7 ml/kg), and aftersedimentation for 2.5 hours, blood cells will be returned tothe patient. Supernatant plasma (4 ml/kg) will be exchangedwith equal volumes of fresh frozen plasma and colloidsolution alternately. Primary endpoints will be feasibility toreach the exchanged plasma volume of 185 ml/kg within 8days and safety as determined by the absence of infections,clotting problems or other major complications potentiallyrelated to SVPE. Secondary endpoints concern improvementof clinical outcome, defined as change in GBS disability scoreand reaching independent walking at 4 weeks after startof treatment. Standardized clinical and laboratory data willbe collected and compared with non-SVPE treated patientsincluded in IGOS with respect to secondary endpoints.

MANNOSE-BINDING LECTIN GENE-2 POLYMORPHISMSASSOCIATED WITH SUSCEPTIBILITY AND SEVERITY OFGUILLAIN-BARRÉ SYNDROME: NEW EVIDENCE ANDMETA-ANALYSIS

Islam Z1, Khalid MM1, Ahammad RU1, Farzana KS1,

Sarker SK1, Islam MB1,2, van Rijs W3, Geleijns K3,

Mohmmad QD4, Endtz HP1,2, Jacobs BC3. 1EmergingDiseases and Immunobiology Research Group, CFWD,International Centre for Diarrheal Disease Research(icddr,b), Dhaka, Bangladesh; Departments of 2MedicalMicrobiology and Infectious Diseases, 3Neurologyand Immunology, Erasmus University Medical Centre,Rotterdam, The Netherlands; 4National Instituteof Neuroscience, Agargaon, Dhaka, Bangladesh.

Complement activation plays a crucial role in the patho-genesis of Guillain-Barré syndrome (GBS), especially inpathogen recognition and nerve damage. Previous studiesindicated that severity in GBS is associated with geneticpolymorphisms of mannose binding lectin (MBL). This pat-tern recognition receptor of the innate immune system bindsto repetitive sugar moieties on both pathogens and apop-totic cells leading to complement activation via the lectinpathway and subsequent killing or clearance. We aimed toconfirm if MBL2 genotypes and MBL levels are associatedwith the GBS susceptibility and severity in patients from

267


Bangladesh and conducted a meta-analysis. Polymorphismsin the promoter region and exon 1 of the MBL2 gene wasdetermined in 322 GBS patients and 320 healthy controlsusing high throughput melt curve genotyping by real timePCR. GBS patients had significant higher frequency of theHH genotype, HY haplotype, and HYA haplotype comparedto healthy controls (p< 0.004). Two H-alleles or two HYAhaplotypes compared to a single H-allele or HYA haplotypefurther increased the risk of developing GBS. H-alleles andHYA haplotypes were associated with more severe GBS(MRC-sumscore <40) (p< 0.05). HY genotypes were alsofound associated with increased risk of developing GBS(p< 0.002). The frequency of the H-allele, the HY promoterhaplotype and the HYA haplotype were all associated withan increased MBL production. Serum levels of MBL werehigher in severely affected patients compared to mildlyaffected patients (P< 0.001). Presence of anti-GM1 antibodywas also associated with high serum concentration of MBL(p< 0.05). MBL2 gene polymorphisms were not associatedwith the presence of axonal or demyelinating subtypes ofGBS. Meta-analysis of the combined Dutch and Bangladeshidataset including 591 GBS patients and 530 healthy controlsrevealed that HYA-allele and H-allele were associated withthe occurrence and severity of GBS. HYA-allele and H-allelewas associated with high level of MBL production in bothstudies. In conclusion, MBL2 gene polymorphisms related tohigh levels of serum MBL are associated with disease sus-ceptibility and severity in GBS.

ELECTROPHYSIOLOGICAL SUBTYPES AND PROGNOSISOF CHILDHOOD GUILLAIN-BARRÉ SYNDROME INBANGLADESH

Islam Z1, Sarker SK1, Islam MB1, Ara G1, Jahan I1,

Ahammad RU1, Farzana KS1, Jacobs BC3,4, Endtz HP1,2,

Mohmmad QD5. 1Emerging Diseases and ImmunobiologyResearch Group, CFWD, International Centre for DiarrhealDisease Research (icddr,b), Dhaka, Bangladesh;2Department of Medical Microbiology and InfectiousDiseases, Erasmus MC, Rotterdam, The Netherlands;Departments of 3Neurology and 4Immunology, ErasmusMC, University Medical Centre, Rotterdam, TheNetherlands; 5National Institute of Neuroscience, Agargoan,Dhaka, Bangladesh.

Guillain-Barré syndrome (GBS) is the most commoncause of acute flaccid paralysis (AFP) in children. Thoughnumerous studies on GBS have been carried out, there is apaucity of data on clinical phenotype of childhood GBS acrossthe world. We aimed to identify preceding events, demo-graphic, clinical characteristics, electrophysiological featuresand prognostic factors of childhood GBS in Bangladesh.We conducted a prospective hospital based study enrolling133 childhood GBS patients from Dhaka Medical CollegeHospital, Dhaka, Bangladesh. Detailed clinical, electrophys-iological, and follow up data were collected at differenttime points. Clinical and electrophysiological features werecorrelated with prognosis. GBS affected children werepredominantly males (M/F=3.2:1) and the median age was

13 years (IQR 8-15, 25%-75% percentile). The antecedentevents were recorded in 81% of patients; the most frequentevents being gastroenteritis (42%) and upper respiratorytract infection (22%). The majority (85%) of the children hada pure motor variant of GBS with 58% cranial nerve involve-ment. Sixty percent (60%) of patients were bed-boundat entry and 20% of patients required a mechanical ven-tilator. Electrophysiological studies showed that childrenwere classified as having axonal (58%) or AIDP (20%), orwere unclassified (16%). Sixty three percent (74/118) of thepatients had a positive serology for Campylobacter jejuni.Preceding diarrheal illness was more common in AMANsubtype as compared to AIDP subtype (46% vs. 25%). Sen-sory symptoms were more common in AIDP subtype thanin AMAN subtype (p<0.01). Distal motor latencies (DML)were much longer and motor nerve conduction velocities(MCV) were slower for AIDP than for AMAN patients. Motorcompound muscle action potential (CMAP) amplitude wassignificantly higher in AIDP compared to AMAN (p< 0.05).Sensory nerve conduction velocity (SCV), sensory nerveaction potential (SNAP) amplitudes were significantly greaterfor patients with AMAN than AIDP (p<0.05). Eleven (8%)patients died and 13% remained severely disabled duringthe follow-up of 6 months. Axonal variant accounted for asignificant proportion of childhood GBS in Bangladesh. Thepresence of severe disability at entry, C. jejuni infection,axonal variant and the need for mechanical ventilator werefound to be significant predictors for poor outcome.

FUNCTIONAL RECOVERY OF DENERVATED SKELETALMUSCLE WITH SENSORY OR MIXED NERVEPROTECTION: A PILOT STUDY

Jiang B, Li Q, Zhang P, Yin X, Kou Y. Departmentof Trauma and Orthopedics, Peking University People’sHospital, Beijing, China.

Functional recovery is usually poor following peripheralnerve injury when reinnervation is delayed. Early innervationby sensory nerve has been indicated to prevent atrophy ofthe denervated muscle. It is hypothesized that early protec-tion with sensory axons is adequate to improve functionalrecovery of skeletal muscle following prolonged denerva-tion of mixed nerve injury. In this study, four groups of ratsreceived surgical denervation of the tibial nerve. The proximaland distal stumps of the tibial nerve were ligated in all animalsexcept for those in the immediate repair group. The experi-mental groups underwent denervation with nerve protectionof peroneal nerve (mixed protection) or sural nerve (sensoryprotection). The experimental and unprotected groups hada stage II surgery in which the trimmed proximal and distaltibial nerve stumps were sutured together. After 3 monthsof recovery, electrophysiological, histological and morpho-metric parameters were assessed. It was detected that thesignificant muscle atrophy and a good preserved structureof the muscle were observed in the unprotected and pro-tective experimental groups, respectively. Significantly fewernumbers of regenerated myelinated axons were observedin the sensory-protected group. Enhanced recovery in the

268


mixed protection group was indicated by the results ofthe muscle contraction force tests, regenerated myelinatedfiber, and the results of the histological analysis. Our resultssuggest that early axon protection by mixed nerve maycomplement sensory axons which are required for promot-ing functional recovery of the denervated muscle nativelyinnervated by mixed nerve.

ULTRASOUND/ELECTROPHYSIOLOGICALCORRELATIONS IN MULTIFOCAL MOTOR NEUROPATHY

Katzberg HD, Ebadi H, Breiner A, Bril V. Universityof Toronto, Toronto, Canada.

Ultrasound (US) has been used increasingly in theassessment of patients with neuropathy. Multifocal motorneuropathy (MMN) is a multifocal, demyelinating motor neu-ropathy. Few studies have evaluated the correlation betweennerve conduction studies and findings on ultrasound inpatients with MMN. Patients diagnosed with MMN with orwithout conduction block were included in this prospectivestudy. Clinical evaluation included neurological examina-tion and grip strength with dynamometry. Patients hadstandardized, high-resolution ultrasonography of bilateralmedian, ulnar, peroneal and tibial motor and sural sensorynerves, and nerve conduction studies of the most involvedlimbs. Distal latency (DL), amplitude and proportion ofpatients with conduction block >50% on NCS and enlargedcross-sectional area (mm2) on ultrasound were evaluatedacross corresponding proximal and distal upper and lowerextremity segments. Eleven patients (3 women, 8 men) witha diagnosis of MMN (mean age 53.2 years) were included inthe study. The proportion of patients with thickened nerveswas higher in proximal compared to distal segments inthe upper extremity median motor (50% at the wrist, 50%wrist to elbow, 81.3% elbow to axilla, p= 0.03) and ulnarmotor (50% at the wrist, 68% wrist to elbow, 85% elbowto axilla, p=0.03) nerves. Neither thickening on ultrasoundnor conduction block on NCS was associated with reducedgrip strength. There was no correlation between thickenednerves on US and conduction block on NCS (p=0.25). Motornerve ultrasound in patients with MMN shows abnormalnerve thickening, particularly in proximal nerve segment, buta correlation between US and NCS is not observed. Further,neither ultrasound nor NCS show a correlation to weaknessas measured by grip strength.

HIGH-DOSE SUBCUTANEOUS IMMUNOGLOBULIN(HIZENTRA 20%) FOR TREATMENT OF MULTIFOCALMOTOR NEUROPATHY

Katzberg HD, Rasutis V, Bril V. University of Toronto,Toronto, Canada.

Intravenous immunoglobulin is an established treatmentfor multifocal motor neuropathy. Subcutaneous immunoglob-ulin (SCIG) 10% and 16%, given after IVIG, has been reported

to have efficacy in small case series. Our study objec-tive was to transition patients with MMN from intravenousimmunoglobulin (IVIG) to SCIG using a 20% formulation.Weekly 20% SCIG dose was calculated by dividing themonthly IVIG dose by four and multiplying by 1.53 as perNorth American product monograph, or a maximum of 2 g/kgper month. Training occurred immediately within a week aftereach patient’s last IVIG infusion and patients did 2-3 train-ing sessions to teach correct SCIG technique. A mechanicalpump was used for administration in the abdomen or thigh.Dose and volume determined whether patients self-infusedfor 1 or 2 days for approximately one hour per infusion, usinga 3-4 site infusion needle set. Patients were evaluated withan interim visit at 3 months to ensure patient safety andmaintenance of strength and the duration of the study was 6months. Fourteen patients (10 males, 4 females, mean age57 years) have been transitioned. Most patients experiencedonly mild erythema and edema at the injection sites, whichimproved with modification of technique, rate and site rota-tion. Five out of 14 patients have completed the 24-weekprogram and 5 out of 14 have maintained strength to month3. Three out of 14 patients tolerated SCIG but were res-cued with IVIG due to deterioration in strength at 3 months.Deterioration in one of these 3 patients was associated withan unexplained drop in immunoglobulin levels. An additionalpatient experienced intolerable skin reactions and elevationof liver enzymes at 2 months, which resolved after discon-tinuation of SCIG. Final results are expected by the time ofpresentation. Our results show that most patients with MMNtolerate transition from IVIG to high-dose SCIG, and maintainstrength for 3-6 months after SCIG initiation. Close moni-toring is needed as some patients experience neurologicaldeterioration or intolerable local or systemic reactions.

TREATMENT OF CHRONIC INFLAMMATORYDEMYELINATING POLYRADICULONEUROPATHY WITHIVIg - A NON-INTERVENTIONAL TRIAL CONDUCTED INGERMANY

Kieseier BC1*, Klehmet J2*, Haas J3*, Trautmann M4,

Tackenberg B5*; *for the GAMEDIS study group.1Heinrich Heine University, Düsseldorf; 2Charité UniversityHospital, Berlin; 3Jewish Hospital, Berlin; 4GrifolsDeutschland GmbH; 5Philipps University, Marburg,Germany.

Chronic inflammatory demyelinating polyradiculoneu-ropathy (CIPD) is an immune-mediated disorder of theperipheral nervous system, with broad clinical variety in itspresentation. Clinically, CIDP is characterised by motor and/orsensory symptoms in more than one limb, developing overat least two months. In addition, patients suffer from addi-tional symptoms such as fatigue and depression as in otherchronic diseases. Furthermore, quality of life (QoL) in affectedpatients is reduced due to the impairment in daily livingand social activities. The current non-interventional study(NIS) investigated efficacy, tolerability and safety of IVIg(Gamunex® 10%) in CIDP patients under real life conditions.

269


Patients ≥18 years, diagnosed with CIDP, who gave informedconsent, either drug-naive or pretreated, received IVIg for upto 48 weeks. The functional impairment was assessed atbaseline by the Inflammatory Neuropathy Cause and Treat-ment (INCAT) disability scale. The Hughes score was appliedto evaluate the effect on neurological limitations. Depression(Beck Depression Index) and Fatigue (Fatigue Severity Scale)were documented at baseline and quarterly by the patient.Health economic data were collected. Adverse events (AE)were reported during the course of the study. ThroughoutGermany, 60 centres participated. 97 patients were recruitedand treated with IVIg. This study has investigated for the firsttime the effect of IVIg (Gamunex® 10%) treatment on CIDPpatients’ fatigue and depression. This study has completedits recruitment and observational phase. The data shown inthis abstract reflect the current evaluation status. The finalresults will be presented at this meeting.

COMPARISON OF ULTRASONOGRAPHIC FEATURESBETWEEN CIDP AND AIDP: A PILOT STUDY

Kim B-J1, Kim JK2, Nam T-S3, Shin KJ4, Bae J-S5, Shin

HY6, Suh BC7, Oh J8. 1Department of Neurology, KoreaUniversity Medical Center, Seoul; 2Departmentof Neurology, Dong-A University College of Medicine,Busan; 3Department of Neurology, Chonnam NationalUniversity Medical School, Gwangju; 4Departmentof Neurology, Haeundae Paik Hospital, Inje University,Busan; 5Department of Neurology, College of Medicine,Hallym University, Seoul; 6Department of Neurology, YonseiUniversity College of Medicine, Seoul; 7Departmentof Neurology, Kangbuk Samsung Hospital, SungkyunkwanUniversity School of Medicine; 8Department of Neurology,Konkuk University Medical Center, Seoul, South Korea.

The diagnosis of acute inflammatory demyelinatingpolyneuropathy (AIDP) and chronic inflammatory demyelinat-ing polyneuropathy (CIDP) is based on clinical features andelectrophysiological studies. Especially, the time course isa key point of distinguishing these two diseases. However,acute or subacute forms of CIDP are hard to distinguishfrom a fluctuating AIDP. Some studies have reported thatultrasonography may be another valid tool for evaluation ofdemyelinating peripheral neuropathies. We compared ultra-sonographic findings between patients with AIDP and CIDPto investigate the possibility that ultrasonography could dif-ferentiate both diseases. Six patients with CIDP (who werefirst ever diagnosed), 3 patients with AIDP and 2 patientswith ALS for case controls were enrolled in this study. Demo-graphic data such as height, weight, and body mass indexwere collected at the time of the study. Ultrasonography wasperformed bilaterally using a 5-12 MHz linear array transducer(HD15 system, Philips Ultrasound, Bothell, WA, USA). Thecross-sectional area (CSA) at the relevant point of each nervewas measured by tracing just inside the hyperechoic rim ofthe nerve. For each nerve, CSA measurements were takenat multiple points with anatomical or clinical significanceas follows: median nerve (outlet and inlet of carpal tunnel,mid-forearm, elbow, mid-upper arm); ulnar nerve (wrist,

mid-forearm, outlet and inlet of cubital tunnel, retrocondy-lar area); sciatic nerve (thigh); tibial nerve (popliteal fossa,ankle); common peroneal nerve (popliteal fossa, fibular head).Demographic data and CSAs were compared between thepatients with AIDP and CIDP using Mann-Whitney test. Inaddition, the statistical comparison of three groups (AIDP,CIDP, and ALS) was performed with Kruskal-Wallis test.Height, weight, and BMI did not differ significantly among thethree groups. Mean CSAs of CIDP patients revealed largerthan AIDP patients. Particularly, the CSAs of nerves at varioussites–median nerve at mid-forearm (p= 0.013) and mid-upperarm (p=0.013), ulnar nerve at mid-forearm (p=0.003), cubitaloutlet (p=0.010) and retrocondylar level (p=0.001)–weresignificantly larger in the CIDP patient. Additionally, meanCSAs of AIDP and CIDP patients were significantly largerthan ALS patients at various sites, both proximal and distal.We suggest that nerve ultrasonography may have value asa supportive diagnostic criterion for CIDP that could poten-tially differentiate acute or subacute forms of CIDP from AIDPthrough this pilot study. Further studies with more subjectnumbers are needed to support the results of this study.

ACUTE BULBAR PALSY WITHOUT LIMB WEAKNESS AS AVARIANT OF GUILLAN-BARRÉ SYNDROME

Kim JK1, Kim B-J2, Nam T-S3, Shin KJ4, Bae J-S5, Shin

HY6, Suh BC7, Oh J8. 1Dong-A University, Busan; 2KoreaUniversity, Seoul; 3Chonnam National University, Gwangju;4Inje University, Busan; 5Hallym University, Seoul; 6YonseiUniversity, Seoul; 7Sungkyunkwan University, Seoul;8Konkuk University, Seoul, Korea.

Acute bulbar weakness with swallowing difficulty can bea presenting manifestation of various kinds of neurologicaldisease such as stroke, myasthenia gravis, Guillain-Barrésyndrome (GBS) or botulism. Pharyngeal-cervical-brachialvariant (PCB) is the representative example of GBS withprominent bulbar manifestations though PCB also hasbrachial weakness. We analyzed the cases of acute bulbarpalsy without limb motor weakness those was diagnosedwith anti-ganglioside antibody positivity. Eleven cases agedfrom 18 to 65 (mean 33.8 years old) were included. Present-ing symptom of all patients was acute onset bulbar palsy.Eight had history of preceding infection, including five withgastrointestinal problems such as diarrhea. Mean durationfrom infection to initial neurological symptom was 9.5 days.Though all patients suffered from bulbar weakness, initialsymptoms varied. The most common was dysarthria (6).Gait disturbance, diplopia, dizziness and tingling limb were 2,1, 1 and 1, respectively. Sensory abnormalities were foundfrequently (8) in neurological examination also, and mostof them were deep sensory loss (6). The most frequentfinding from examination was a/hypo-reflexia (10), sensorytype ataxia (9) and ophthalmoplegia (8). Unilateral or bilateralfacial nerve palsies was 5. From the ophthalmoplegia, 4 werecomplete. Nine of the studied ten patients showed normalfindings in nerve conduction study during the acute stage.Mean CSF protein was 35.7 mg/dL and none of the casesexceeded 50 mg/dL. In enzyme linked immunosorbent assay

270


study against ganglioside GM1, GM2, GD1a, GD1b, GD3,GT1a, GT1b and GQ1b using serum from acute stage, themost frequent positive was IgG type anti-GT1a antibody(10 from 11), and the next was IgG anti-GQ1b antibody(6). We propose that acute bulbar palsy without neck orlimb weakness is a representative variant of GBS otherthan PCB. It is highly associated with other kinds of cra-nial neuropathy (especially ophthalmoplegia) and sensoryataxia. IgG anti-GT1a antibody can be an explanation ofthe relationship between clinical distinction and underlyingpathomechanisms.

THE UTILITY OF CYTOALBUMINOLOGIC DISSOCIATION,AS DEFINED BY BRIGHTON CRITERIA, FOR THEDIAGNOSIS OF GUILLAIN-BARRÉ SYNDROME

Koh OSQ1, Yuki N1, Umapathi T2. 1Yong Loo Lin Schoolof Medicine, National University of Singapore, Singapore;2National Neuroscience Institute, Singapore.

The Brighton Collaboration criteria for Guillain-Barré syn-drome (GBS) specify various clinical and laboratory diagnosticfeatures. Cytoalbuminologic dissociation is defined as cere-brospinal fluid (CSF) cell-count of less than 50 cells/μl withelevation of CSF protein above the laboratory normal. How-ever, in practice, many clinicians use the upper limit of normalCSF cell-count to define pleocytosis, which is approximately5 cells/μl at most laboratories. We asked if the greater cut-offfor spinal fluid cells in the Brighton criteria would lead tolesser specificity. We studied the CSF of 41 patients withGBS and 27 patients with Fisher syndrome (FS), includingFS overlapping with GBS and acute ophthalmoparesis. Wedefined common clinical-practice cytoalbuminologic dissoci-ation as an elevation of CSF protein above 0.4 g/L in thepresence of not more than 5 cells/μl. 39 of the 41 GBS and24 of the 27 FS patients had lumbar puncture. The timeinterval between onset of weakness and lumbar puncturewas median 6 days (range, 1-21 days) for GBS patients andmedian 5 days (range, 1-11 days) for the FS patients. 16GBS patients had cytoalbuminologic dissociation. Using theBrighton criteria for cytoalbuminologic dissociation, this num-ber increased to 21. Eight FS patients had cytoalbuminologicdissociation, which increased to 9 with the Brighton crite-ria. We identified 18 patients that were initially diagnosedas GBS or FS but subsequently had an alternative diagnosis.Fifteen of these patients with GBS mimics had CSF exami-nation, at a median of 11 days. Four had cytoalbuminologicdissociation. Using the Brighton criteria, 3 other patients hadcytoalbuminologic dissociation; a man with leptomeningealmetastasis from B-cell lymphoma and 2 patients with acuteonset chronic inflammatory demyelinating polyneuropathy (1of whom had HIV seroconversion). In conclusion, our find-ings suggest that allowing up to 50 cells/μl of CSF, as inthe Brighton criteria, may be more sensitive at detectingGBS but not FS cases. This is accompanied by not insignif-icant compromise on specificity. Therefore, due considera-tion should be given to modifying the Brighton criteria forcytoalbuminologic dissociation, at least for FS.

MORPHOLOGY OF NONMYELINATING SCHWANN CELLSIN CHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY

Koike H, Takahashi M, Ohyama K, Kawagashira Y, Iijima

M, Sobue G. Department of Neurology, Nagoya UniversityGraduate School of Medicine, Nagoya, Japan.

Electron microscopic examination was performed toexamine morphologic changes in nonmyelinating Schwanncells and unmyelinated axons in chronic inflammatorydemyelinating polyneuropathy (CIDP). Morphometric indicesof 21 CIDP patients were investigated and compared to 14age-matched normal control subjects. Eighteen of thesepatients were conventional CIDP without conspicuousonion-bulb formation, while the other 3 patients werehypertrophic variant of CIDP with marked onion-bulb forma-tion. Complete transverse sural nerve cross-sections wereobtained, and the total number of axons and Schwann cells ineach cross-section was estimated. The total number of myeli-nated axons in entire cross-section of the sural nerve wasnot reduced in patients with conventional CIDP. In patientswith hypertrophic CIDP, the number of myelinated axonsassessed by light microscopy was extensively reduced, butin electron microscopy, demyelinated axons, supposed tobe remnants of myelinated fibers, were present in most ofthe center of the onion bulbs. The number of unmyelinatedaxons in patients with conventional CIDP did not differ fromthat of control subjects. In hypertrophic CIDP, reduction ofunmyelinated axons was not apparent, too. The numberof myelinating Schwann cell nuclei per nerve cross-sectionin conventional CIDP patients was not increased, whilenonmyelinating Schwann cell nuclei seemed to be slightlyincreased, but not to a significant extent as compared to nor-mal controls. Hypertrophic CIDP patients showed markedincrease of myelinating Schwann cell nuclei (p<0.01 forcontrols). Nonmyelinating Schwann cell nuclei also wereincreased (p<0.01 for controls). The number of Schwanncell profiles per axon in an unmyelinated axon-containingSchwann cell subunit and the number of axons per unmyeli-nated axon-containing subunit were not significantly differentamong the conventional CIDP, hypertrophic CIDP, and controlgroups. These findings indicate the preservation of non-myelinating Schwann cell morphology in patients with CIDP.

EPIMEDIUM EXTRACT PROMOTES PERIPHERAL NERVEREGENERATION IN RATS

Kou Y, Yin X, Zhang P, Han N, Jiang B. Departmentof Trauma and Orthopedics, Peking University People’sHospital, China.

In this study, effects of epimedium extract and its con-stituent icariin on peripheral nerve repair were investigatedin a crush injury rat model. Animals were divided into fourgroups: sham, control, epimedium extract and icariin groups.At postoperative weeks 1, 2, 4, and 8, nerve regeneration andfunctional recovery were evaluated by sciatic functional index(SFI), nerve electrophysiology, nerve pinch test and muscle

271


wet weight. Results showed at 2 and 4 weeks after surgery,rats in the epimedium group displayed a better recovery ofnerve function than that in the icariin and control groups, withbetter recovery in the icariin group than in the control group.The nerve pinch test showed nerve regeneration was greaterin the epimedium group and the icariin group, as comparedto the control group. In addition, the muscle wet weight inthe epimedium group was significantly improved when com-pared with the icariin group, and the improvement in theicariin group was better than that in the control group at 8weeks post operation. Our findings suggest that epimediumextract effectively promotes peripheral nerve regenerationand improves the function of damaged nerves.

SMALL GAP SLEEVE BRIDGING CAN IMPROVE THEACCURACY OF PERIPHERAL NERVE SELECTIVEREGENERATION

Kou Y, Yin X, Zhang P, Han N, Jiang B. Departmentof Trauma and Orthopedics, Peking University People’sHospital, China.

Peripheral nerve injury is a serious health problem intoday’s society that can lead to lifelong disability and per-manent disfigurement Peripheral nerves generally consistof both motor and sensory fibers. One important factor inpost-operative functional recovery is the correct routing ofthe proximal sensory and motor tracts to their correspond-ing tracts in the distal stumps during regeneration. We haveattempted to improve the nerve regenerative effect by deter-mining the optimal conditions for axonal regeneration overa surgically induced short, empty space between the prox-imal and distal nerve ends. Previous experiments confirmthe benefit of using a conduit small gap sleeve bridging tosubstitute traditional epineurium neurorrhaphy. In this studythe pure motor peripheral nerves animal model, obtained byablating the dorsal root ganglions (DRGs), was used to inves-tigate the accuracy of peripheral nerve selective regenerationusing small gap sleeve bridging compared to epineurium neu-rorrhaphy. The results showed that the number of improperlyregenerated motor axons in the distal stump and the misrout-ing ratio were significantly lower when the nerve transectionwas treated by small gap sleeve bridging. This suggests thatmore accurate reinnervation may be achieved by small gapsleeve bridging than by traditional epineurium neurorrhaphy.

ELECTROPHYSIOLOGICAL SUBTYPES OF GBS WITHANTI-GAL-C ANTIBODIES AND OTHER ANTI-GLYCOLIPIDANTIBODIES

Kusunoki S1, Samukawa M1, Hamada Y1, Kuwahara M1,

Takada K1, Hirano M1,2, Mitsui Y1. 1Departmentof Neurology, Kinki University Faculty of Medicine,Osaka-sayama, Japan; 2Department of Neurology, SakaiHospital Kinki University Faculty of Medicine, Sakai, Japan.

Galactocerebroside (Gal-C) is a major component ofmyelin. Demyelinating neuropathy was induced in rabbits

by sensitization with Gal-C, and anti-Gal-C antibody wasshown as a demyelinating factor. We previously reportedthat anti-Gal-C antibodies are frequently observed in theacute-phase sera from patients with Guillain-Barré syn-drome (GBS) subsequent to infection by Mycoplasmapneumoniae. We recently reported that GBS patients withanti-Gal-C antibodies mostly have demyelinating neuropa-thy. In contrast, antibodies to such gangliosides as GM1are reported to be associated with axonal neuropathy.We therefore investigated electrophysiological features ofanti-Gal-C antibody-positive GBS patients who also hadother anti-glycolipid antibodies. Antibodies against glycol-ipids (GM1, GM2, GD1a, GD1b, GalNAc-GD1a, GT1b andGQ1b) in serum samples from 47 consecutive anti-Gal-Cantibody-positive GBS patients were examined with ELISA.We then assessed the electrophysiological findings based onHadden’s criteria (Ann Neurol, 1998) and Ho’s criteria (Brain,1995). Results showed that 12 patients with anti-Gal-Cantibodies also had antibodies to other glycolipids. One ofthem had IgM anti-GM1 antibody, three had IgG anti-GM1antibodies, two had IgG anti-GD1a antibodies, two hadIgG anti-GD1b antibodies, one had IgG anti-GD3 antibody,two had IgG anti-GT1b antibodies, four had IgG anti-GQ1bantibodies, and one had IgG anti-GalNAc-GD1a antibody(some had multiple antibodies). The electrophysiologicaldata could be obtained in nine patients. Five patients (56%)were categorized as demyelinating, four (44%) as equivocal,and none as axonal or normal by Hadden’s criteria. Fivepatients (56%) had AIDP, four (44%) had unclassified, andnone had AMAN, normal or inexcitable according to Ho’scriteria. In this study, none of GBS patients with anti-Gal-Cantibodies who had antibodies to other glycolipids werecategorized as axonal neuropathy. It indicates that antibodiesto Gal-C, a myelin antigen, may be a demyelinating factor andpredominantly be associated with demyelinating neuropathyeven when antibodies to other glycolipids also are presentin patients’ sera.

THE ANTI-GLYCOLIPID ANTIBODIES BINDING TO BOTHGQ1B AND GM1/GD1A COMPLEX IN GUILLAIN-BARRÉSYNDROME AND FISHER SYNDROME

Kuwahara M1, Hamada Y1, Samukawa M1, Takada K1,

Sonnino S2, Kusunoki S1. 1Department of Neurology, KinkiUniversity Faculty of Medicine, Osaka, Japan; 2Departmentof Medical Chemistry, Biochemistry and Biotechnology,University of Milan, Italy.

Previously, we reported that anti-GM1/GD1a complexIgG antibodies in GBS sera mostly recognize the artificialGM1-GD1a hybrid dimer. It suggested that the carbohydratestructure of GM1-GD1a hybrid dimer was similar to that ofthe GM1/GD1a complex. But the anti-GM1/GD1a complexantibodies in sera which also had anti-GQ1b activities didnot react with the GM1-GD1a hybrid dimer. It indicated thata difference exists between the antigenic epitope of theGM1/GD1a complex and that of the GM1-GD1a hybrid dimerand that some of the IgG anti-GQ1b antibodies could bind

272


to the GM1/GD1a complex but not to the GM1-GD1a hybriddimer. We therefore investigated the relation of anti-GQ1b,anti-GM1/GD1a complex and anti-GM1-GD1a hybrid dimerantibodies in larger number of patients. We collected 167GBS and 100 FS sera with anti-GQ1b IgG antibodies, andexamined whether anti-GM1/GD1a complex IgG antibod-ies were detected in those sera. Then, we prepared 8patients’ sera containing the antibody activities to bothGQ1b and GM1/GD1a complex and 8 patients’ sera con-taining those to GM1/GD1a complex but not to GQ1b, andexamined the antibody activities to the GM1-GD1a hybriddimer. We performed the immunoabsorption test using anti-gens of GQ1b and GM1/GD1a complex for 5 patients’ serawith the antibody activities to both GQ1b and GM1/GD1acomplex. The IgG antibodies to GM1/GD1a complex weremore frequently observed in anti-GQ1b-positive GBS sera(11%) than in anti-GQ1b-positive FS sera (3%) (p<0.05). Theanti-GM1-GD1a hybrid dimer activities were detected in only2 of the 8 (25%) sera that have both anti-GM1/GD1a com-plex and anti-GQ1b activities, whereas those were detectedin all 8 sera containing the antibody activities to GM1/GD1acomplex but not to GQ1b. In the immunoabsorption test, theantibody activities to both GQ1b and GM1/GD1a complexdecreased by absorption using either GQ1b or GM1/GD1acomplex antigen in 3 of the 5 sera. This study shows thata part of steric structure of GQ1b is similar to that ofGM1/GD1a complex, and such antibodies may be one of thefactors to develop limb weakness in some GBS patients withanti-GQ1b antibody.

DIAGNOSTIC UTILITY OF THE SURAL SPARING PATTERNIN GUILLAIN-BARRÉ AND FISHER SYNDROMES

Li Z1, Umapathi T2, Verma K2, Yuki N1. 1Yong Loo LinSchool of Medicine, National University of Singapore,Singapore; 2National Neuroscience Institute, Singapore.

Electrodiagnosticians routinely look for a “sural-sparing”pattern in patients with suspected Guillain-Barré syndrome(GBS). We analyzed the utility of the “sural-sparing” pat-tern, defined as a decrease in sural sensory nerve actionpotential (SNAP) that is less than median and or ulnarSNAPs when compared to age and height matched norms,in the electrodiagnosis of GBS. Eleven of 30 GBS and6 of 20 Fisher syndrome patients had sural-sparing.One GBS and 1 FS patient had the pattern on secondstudy on days 21 and 15, respectively. Only 1 of the 50patients had decreased sural SNAP without reduction ofthe ulnar or median SNAPs at presentation. Among 18GBS mimics, patients initially diagnosed as GBS or Fishersyndrome but subsequently had an alternative diagnosis,sural-sparing was seen in only 1 patient who had neu-rosyphillis. Another patient with sensory neuronopathy hadnormal study on day 3 but showed sural-sparing on day8. It was not present in the 2 patients with acute-onsetchronic inflammatory demyelinating polyneuropathy. Usingserial electrodiagnostic studies, we sub-classified the GBSpatients. The sural-sparing pattern was seen in 3 of 8 acuteinflammatory demyelinating polyneuropathy, 5 of 13 acute

motor axonal neuropathy and 3 of 9 unclassified cases atpresentation. Sequential studies uncovered covertsural-sparing in 4 other patients. One GBS and 1 FS patienthad normal initial SNAPs, based on age-height matched con-trols. Subsequently the median and ulnar SNAPs increasedby 50% and 48%, respectively, whereas the sural did notincrease significantly, indicating covert sural-sparing at pre-sentation. Two patients had absent SNAPs initially. Duringconvalescence, the sural nerve showed quicker and greaterrecovery than median and ulnar nerves, which suggestscovert sural-sparing. In conclusion, an abnormal sural withnormal median or ulnar SNAP is rare in the initial study of apatient with GBS. The sural-sparing pattern occurs in bothaxonal and demyelinating subtypes and is uncommon inGBS mimics. These features make sural-sparing a usefuldiagnostic tool in the initial electrodiagnosis of GBS.

SENSORY NERVE ACTION POTENTIALS ELICITED BYINTRA-EPIDERMAL STIMULATION

Maiser S, Walk D, Raabe W. University of Minnesota,Minneapolis, MN, USA.

The epidermis contains the terminations of nociceptivefibers. These fibers can be electrically stimulated with anintra-epidermal electrode and have a conduction velocity inthe A-𝛿 fiber range as measured indirectly by recording theP2 potential from Cz (Inui et al., 2002, Pain 96:247-252).This study explores the feasibility of recording A-𝛿 fiberaction potentials from cutaneous nerves with intra-epidermalstimulation (IES). For IES, a subdermal needle electrode,modified to partially penetrate (by 0.2 mm) the epidermis(thickness 0.4-5 mm), was placed in the area innervated by acutaneous nerve and served as cathode. The anode was anadhesive ground electrode placed 6-15 mm distal to the IESelectrode. IES was done at 1-2x of the perception threshold(PT) (0.2-0.5 ms duration, 0.12-0.84 mA, 1-30 Hz). For record-ing, three subdermal needle electrodes were placed alongthe superficial radial or sural nerve ≥50 mm proximal to theIES electrode. The recording electrodes were separated by10 mm and used for 2-channel recording (G1-G2, G2-G3) withcommercial EMG equipment. Hand temperature was ≥32 ∘C,foot temperature ≥29 ∘C. Sensory nerve action potentials(SNAPs) were identified by (i) an amplitude ≥2x backgroundnoise, (ii) a duration ≥0.40 ms, (iii) the presence in both chan-nels, (iv) the SNAP in the more proximal channel occurringlater than in the distal channel, with the delay correspond-ing to the time required to travel an additional 10 mm, and (v)≤1 m/s difference in conduction velocity between SNAPs inthe two channels. IES at 1x PT (0.12-0.39 mA, 0.2 ms dura-tion) elicited SNAPs of 46-100 nV (averages N=1500-3000)with conduction velocities of 17-25 m/s, identifying theseSNAPs as generated by A-𝛿 fibers. IES at ≥1.5x PT and/or0.5 ms duration recruited SNAPs with conduction velocities>40 m/s, identifying these as generated by A-𝛽 fibers. IES atPT elicited the sensation of a minimal pin-prick and was welltolerated. IES (i) at PT selectively elicits SNAPs with conduc-tion velocities characteristic of A-𝛿 fibers, (ii) is well tolerated,

273


and (iii) deserves further exploration as a technique to studyA-𝛿 fibers in peripheral nerves.

SIMULTANEOUS COMBINED MYOSITIS, INFLAMMATORYPOLYNEUROPATHY AND MYASTHENIC SYNDROME

Mathis S1, Magy L2, Corcia P3, Ghorab K2, Richard L2,

Vallat J-M2. 1Service de Neurologie, CHU Poitiers; 2Servicede Neurologie, CHU Limoges; 3Service de Neurologie, CHUTours, France.

Immune-mediated neuromuscular disorders include dis-orders of the peripheral nervous system, the neuromuscularjunction and muscles. Most patients develop only one ofthese organ-specific autoimmune diseases. If overlap syn-dromes (or the association of almost two autoimmune disor-ders) are well known, the simultaneous occurrence of threeautoimmune neuromuscular disorders is rare. We describetwo patients (a 67-year-old woman and a 79-year-old man)presenting the simultaneous occurrence of inflammatoryneuropathy, polymyositis and myasthenia gravis (with posi-tive acetylcholine receptor antibodies). For each patient, weobtained a detailed clinical history and full clinical examina-tion, and we performed a complete electrodiagnostic studyand pathological analysis (nerve and muscle). To our knowl-edge, this is the first pathological description of such atriple immune-mediated neuromuscular syndrome. We havecompared our observations with the other few cases ofsimultaneous diagnosis of two inflammatory neuromusculardisorders that have been previously published, and discussthe pathogenesis of this peculiar association.

LOCALISATION AND KINETICS OF NEURITOGENIC TCELLS IN EXPERIMENTAL AUTOIMMUNE NEURITIS

Mausberg AK1, Stettner M1, Dehmel T1, Odoardi F2,

Flügel A2, Kieseier BC1. 1Department of Neurology,Medical Faculty, Heinrich-Heine-University, Düsseldorf,Germany; 2Department of Neuroimmunology, UniversityMedical Centre, Göttingen, Germany.

Autoimmune polyneuropathies are acquired inflam-matory disorders of the peripheral nervous systemcharacterized by demyelination, inflammation and axonaldegeneration. Although the precise pathogenesis remainsuncertain, T cells recognizing self-antigens are believedto trigger the inflammatory reaction in the peripheralnerves and roots. However, the route and time of entryinto the peripheral nervous system as well as autoag-gressive targets are still not described properly. In thisstudy we analysed time kinetics as well as tissue distribu-tion of retrovirally transfected neuritogenic T lymphocytesin experimental autoimmune neuritis (EAN). T lympho-cytes obtained from rats with EAN, immunized withperipheral nerve protein peptide P255-78, were retrovirallytransduced in cell culture to express green fluorescentprotein (GFP). Non specific T cells were negativelyselected during culture period, whereas GFP-expressing

neuritogenic T cells (reactive against P255-78) were adoptivelytransferred into healthy rats and animals were monitoredfor seven days for clinical signs of EAN. Tissue distributionlocalization of T cells were analysed by flow cytometry andhistology. We were able to transfer autoimmune neuritiswith P255-78 reactive, GFP+ T lymphocytes. These cells weredetectable in liver, spleen, lymph nodes, blood and the sciaticnerves with distinct kinetics. A significant amount of GFP+

T cells appeared early in the lung with a peak at day fourafter disease induction. In the peripheral nerve a substantialnumber of GFP+ T lymphocytes was detectable already atday four after disease induction. In the following days thenumber of GFP− T cells rapidly increased and exceededthose of GFP+ cells. T cell inflammation within the peripheralnerve reached its maximum at day six post-disease inductionand correlated with clinical disease severity. T cell localisa-tion in the peripheral nervous system was not restricted tothe proximal roots and distributed homogenously within thenerve. Our findings suggest that after an initial priming periodof neuritogenic GFP+ T lymphocytes, a secondary wave ofunspecific T cells is established propagating the inflamma-tory reaction within the peripheral nerve. Understanding thepathophysiological role of autoaggressive T cells in the PNSmay help to improve therapeutic strategies.

MINIMUM CLINICALLY IMPORTANT DIFFERENCEANALYSIS CONFIRMS THE EFFICACY OF IVIG(PRIVIGEN®) IN CIDP: THE PRIMA TRIAL

Merkies ISJ1, Edelman JM2, Lawo J-P3, Mielke O3, De

Bleecker JL4, Sommer C5, Robberecht W6, Saarela M7,

Kamienowski J8, Stelmasiak Z9, Tackenberg B10,

Bauhofer A3, Zenker O3, Léger J-M11. 1Spaarne Hospital,Hoofddorp and Maastricht University Medical Centre,Maastricht, The Netherlands; 2CSL Behring LLC, Kingof Prussia, PA, USA; 3CSL Behring GmbH, Marburg,Germany; 4AZ St-Lucas, Gent, Belgium; 5Departmentof Neurology, Universitätsklinikum Würzburg, Würzburg,Germany; 6UZ Leuven, Leuven, Belgium; 7Departmentof Neurology, Helsinki University Central Hospital, Helsinki,Finland; 8Dolnoslaski Szpital Specjalistyczny, Wrocław,Poland; 9Samodzielny Publiczny Szpital Kliniczny, Lublin,Poland; 10Department of Neurology, Philipps University,Marburg, Germany; 11Hôpital Pitié-Salpêtrièreand University Paris VI, Paris, France.

The PRIMA trial was a single-arm, open-label trial aimingto assess the efficacy and safety of Privigen® (IgPro10,10% proline-stabilized intravenous immunoglobulin, [IVIG]) inpatients with chronic inflammatory demyelinating polyneu-ropathy (CIDP). The primary endpoint was the responderrate, defined as an improvement in adjusted InflammatoryNeuropathy Cause and Treatment (INCAT) score ≥1 point.The preset success criterion of responder rate of ≥35%was met. To confirm the clinical relevance of this result,we reanalyzed the responder rates based on minimal clin-ically important difference (MCID) values. MCID valuesare defined as the smallest difference in a clinical scorethat patients perceive as beneficial. Merkies et al. (2010)

274


determined the MCID values for the INCAT, MedicalResearch Council (MRC) scores in CIDP and grip strengthusing the results of Immune Globulin Intravenous CIDPEfficacy (ICE) trial, the only placebo-controlled trial assessingthe efficacy of IVIG in patients with CIDP. The most conser-vative MCID estimates were 0.72 for INCAT score, 3.6 forMRC score and 8 kPa for grip strength (Merkies et al., 2010).The INCAT MCID value was rounded to 1, as only integerincrements are possible. Thus, the results of the reanalysisconfirmed that the primary endpoint used in the PRIMA trialwas clinically relevant. Based on the MCIDs for the MRCscore and grip strength, the response rates in the PRIMAtrial were 60.71% [95% confidence interval: 42.41–76.43%]and 35.71% [20.71–54.17%], respectively; above the presetsuccess criterion by INCAT score. Under even more stringentconditions, i.e., only considering patients who maintainedMRC score or grip strength higher than MCID throughoutthe study, the response rates were 39.29% [23.57–57.59%]and 28.57% [15.25–47.06%], respectively. Similar resultswere obtained with a different IVIG product in the ICE trial,where the response rates were 42.4% [30.61–55.07%] byMRC MCID, which was higher than the value of 10.34%[4.82–20.79%] obtained for the placebo arm, and 25.86%[16.35–38.38%] by grip strength MCID. In conclusion, thisMCID analysis confirmed that Privigen® produces a clinicallyrelevant improvement in patients with CIDP. Merkies et al.J Neurol Neurosurg Psychiatry 2010;81:1194. Disclosure ofpotential conflicts of interest: I.S.J. Merkies received fund-ing for research from the Talecris Talents program and theGBS-CIDP Foundation International; furthermore, a researchfoundation at the University of Maastricht received honorariaon his behalf for participation in steering committees ofthe Talecris ICE Study, CSL Behring, Novartis, LFB andOctapharma. J.M. Edelman, J-P. Lawo, and O. Mielke areemployees of CSL Behring and have no other conflicts.

REFERENCE VALUES OF THE DISTAL COMPOUNDMUSCLE ACTION POTENTIAL DURATION FORDIAGNOSIS OF CIDP: A JAPANESE-EUROPEANMULTICENTER PROSPECTIVE STUDY

Mitsuma S1, Van den Bergh P2, Sonoo M3, Rajabally Y4,

Inaba A5, Kokubun N6, Komori T7, Shimizu T8, Misawa

S1, Kuwabara S1; and The Tokyo Metropolitan

Neuromuscular Electrodiagnosis Study Group.1Department of Neurology, Chiba University, Chiba, Japan;2Catholic University of Louvain, Belgium; 3Departmentof Neurology, Teikyo University School of Medicine, Tokyo,Japan; 4University Hospital of Birmingham, UK;5Department of Neurology, Kanto Central Hospital, Tokyo,Japan; 6Department of Neurology, Dokkyo MedicalUniversity, Tochigi, Japan; 7Department of Neurology,National Hakone Hospital, Kanagawa, Japan; 8Departmentof Neurology, Tokyo Metropolitan Neurological Hospital,Tokyo, Japan.

The distal compound muscle action potential (DCMAP)duration is a useful parameter to detect demyelinationin the distal nerve segments, and currently employed in

the electrodiagnostic criteria of CIDP (EFNS/PNS, 2010).However, the cut-off values in the criteria are provided usingonly 20 Hz low-cut filtering, whereas DCMAP durations aresubstantially influenced by low-cut filter settings. We aimedto establish widely-available reference values of DCMAPduration with a number of low-cut filters. We prospectivelymeasured DCMAP duration of the median, ulnar, peronealand tibial nerves in 59 typical CIDP patients and 147 normalcontrols in a multicenter population of Europe (Belgium, UK)and Japan. The low-cut filter setting was set as 2 Hz, 5 Hz,10 Hz, and 20 Hz. The cut-off values were calculated as thepoint with 98% specificity by plotting ROC curves betweenCIDP patients and normal controls. Low cut filter settingssignificantly affected DCMAP durations both in CIDP andnormal controls; the use of lower filters was associated withthe shorter DCMAP duration in all 4 nerves. We provided thecut-off values of each nerve under each low-cut filter settings.Using these cut-off values, the sensitivity was 56-77% andthe specificity was 95-98%. We confirmed the effects of thelow cut filters on DCMAP duration, and established, in thefour nerves tested, the cut-off values for each low-cut filtersetting; 2 Hz, 5 Hz, 10 Hz, and 20 Hz. The reference values canbe widely used for diagnosis of CIDP.

SIGNAL CHANGE ON SPINAL MRI AND LONG DURATIONFOR DIAGNOSIS OF UNDERLYING CANCER MAY BEPOOR PROGNOSTIC FACTORS IN PARANEOPLASTICSENSORY NEURONOPATHY

Nam T-S1, Kim JK2, Kim B-J3, Shin KJ4, Bae J-S5, Oh J6,

Shin HY7, Suh BC8. 1Chonnam National University MedicalSchool, Gwangju; 2Dong-A University College of Medicine,Busan; 3Korea University College of Medicine and KoreaUniversity Medical Center, Seoul; 4Haeundae Paik Hospital,Inje University, Busan; 5College of Medicine, HallymUniversity, Seoul; 6Konkuk University Medical Center,Seoul; 7Yonsei University College of Medicine, Seoul;8Kangbuk Samsung Hospital, Sungkyunkwan UniversitySchool of Medicine, Seoul, South Korea.

Paraneoplastic sensory neuronopathy (PSN) may becaused by underlying cancer indirectly at the level of dorsalroot ganglia sensory neurons, which result in the degen-eration of both central- and peripheral-sensory projections.In general, the neurologic symptoms may precede byseveral months or years before the diagnosis of cancer,and thus PSN may be frequently overlooked. A 42-year-oldwoman with neuropathic limb pain for 4 months visited ourneurologic clinic for the evaluation of progressive gaitinstability. She has been treated under the provisionaldiagnosis of sensory dominant polyneuropathy. Neurologicexamination showed wide-based gait, positive Rombergsign, loss of position and vibration sense. Breast cancerwas also diagnosed through ultrasonography-guided biopsyat the same time. Unfortunately, mastectomy has beendelayed by 3 months due to preoperative chemotherapy forreducing size and treating metastatic lymph nodes, but herneurologic deficits have not been ameliorated. A 63-year-old

275


man complained of asymmetric sensory symptoms fortwo weeks, who was initially diagnosed with mononeuritismultiplex. Neurologic examination showed mild abnor-mality in tandem gait. He was diagnosed with small celllung carcinoma through bronchoscopy-guided lung biopsy.Besides concurrent chemoradiation therapy, high-dosemethylprednisolone and intravenous immunoglobulin havebeen administrated under the diagnosis of PSN. With time,his neuropathic pain and gait unsteadiness more improvedthan before. Both patients showed similar electrophysiologicfindings in nerve conduction studies, quantitative sudomotoraxon reflex tests, and somatosensory evoked potentials.However, MRI of the spinal cord showed clear distinction.That is, T2-hyperintensity within posterior aspect of thoraciccord was observed in the female patient, but not in the malepatient. In cases with PSN, early detection and treatment ofunderlying cancer should be needed for reducing neurologicdeficits including gait disturbance and neuropathic pain. Thesignal changes on spinal MRI as well as the time durationfrom the onset of neuropathic symptoms to diagnosis ofunderlying cancer may be useful for predicting prognosisof PSN.

MUSCLE ATROPHY IN CHRONIC INFLAMMATORYDEMYELINATING POLYNEUROPATHY: A COMPUTEDTOMOGRAPHY ASSESSMENT

Ohyama K, Koike H, Katsuno M, Takahashi M,

Hashimoto R, Kawagashira Y, Iijima M, Adachi H,

Watanabe H, Sobue G. Department of Neurology, NagoyaUniversity Graduate School of Medicine, Nagoya, Japan.

Muscle atrophy is generally mild in patients with chronicinflammatory demyelinating polyneuropathy (CIDP) com-pared with the severity and duration of the muscle weakness.We evaluated muscle atrophy using computed tomography(CT) in patients with CIDP. In this study, 31 patients with typ-ical CIDP who satisfied the diagnostic criteria for the definiteCIDP classification proposed by the EFNS/PNS criteria wereassessed. Clinical, electrophysiological, and pathological find-ings in patients with muscle atrophy were also comparedwith those in patients without atrophy. For the assessment ofCT, marked muscle atrophy with findings suggestive of fattydegeneration was found in 11 of the 31 patients with CIDP.CT-assessed muscle atrophy was in the lower extremities,particularly in the ankle plantarflexor muscles. Muscle weak-ness, which reflects the presence of muscle atrophy, tendedto be more pronounced in the lower extremities than in theupper extremities in patients with muscle atrophy, whereasthe upper and lower limbs tended to be equally affected inpatients without muscle atrophy. Nerve conduction studiesrevealed significantly greater reductions in compound mus-cle action potential amplitudes in the tibial nerves of patientswith muscle atrophy. Findings of sural nerve biopsy speci-mens were similar in both groups. The functional prognosesafter immunomodulatory therapies were significantly poorerin patients with muscle atrophy. Muscle atrophy was presentin a subgroup of patients with CIDP, including patients witha typical form of the disease. These patients tended to

demonstrate predominant motor impairments of the lowerextremities and poorer functional prognoses.

A STUDY OF BIOLOGICAL PROGNOSTIC FACTORS FORIgM PARAPROTEINAEMIC anti-MAG ASSOCIATEDPERIPHERAL NEUROPATHY

Pihan M1, Chou MKL2, Manji H1, Reilly MM1, D’Sa SP3,

Decaux O4, Lunn MP1. 1MRC Centre for NeuromuscularDiseases, Department of Molecular Neurosciences, UCLInstitute of Neurology, London, UK; 2Departmentof Neuroimmunology, Institute of Neurology, Queen Square,London, UK; 3Department of Haematology, UniversityCollege London Hospitals NHS Foundation Trust, London,UK; 4Internal Medicine Department, University HospitalHopital Sud, Rennes, France.

Anti-MAG neuropathies are of variable severity. Somehave insignificant responses to immunotherapies, but allhave significant risks of severe adverse effects from them.The identification of predictive factors to determine whichpatients are at high risk of evolution to severe disability andthose who will respond to treatment so that treatment can betargeted is important. The objective was to determine serumbiomarkers that can predict of severity of anti-MAG neu-ropathies in a retrospective study. This included moleculesthat regulate the monoclonal IgM secreting B-cells (BAFF,inflammatory cytokines) and molecules that modulate thealteration of the blood-nerve barrier (inflammatory cytokines,VEGFs, angiopoietins). 40 patients were included andcomprehensively re-evaluated between January 2013 andFebruary 2014. All fulfilled the EFNS-PNS criteria for IgManti-MAG neuropathy. Retrospective clinical and electrophys-iological data were also collected at the time of the bankedserum sampling. Banked serum was available for 38 of 40patients which enabled retrospective biomarker correlativedata. The retrospective follow-up duration was 3.2±2.7 [0.5;11.5] years. Five groups of clinical evolution were determined:A. 28.2% of patients were stable with mild or moderateimpairment, B. 10.3% stable with severe impairment,C. 20.5% progressive with mild or moderate impairment, D.28.2% progressive with severe impairment and E. 12.8%improved (4/5 related to treatment). 12/31 (38.7%) treatedpatients responded to at least one pharmacological treat-ment. However, neither the clinical severity nor the clinicalevolution were significantly different between previouslytreated and untreated patients. The walk scale, sensory sumscore (and vibration sensation sub-score), distal-MRC scoreand the ataxia score progression rates over the follow-upperiod were significantly different between the different evo-lution groups. To the contrary, the INCAT sensory sum score,MRC score, 10 meter walk time, ONLS and RODS progres-sion rates did not distinguish groups. Multiplex biomarkertesting was performed in retrospective and prospectivesamples and compared to controls (healthy, CIDP, diabeticneuropathy, auto-immune diseases, POEMS syndrome andIgM dysglobulinemia without neuropathy). The clinical andelectrophysiological evolution as well as the response

276


to treatment was correlated with the biomarker testsin order to establish the predictive value of the studiedmolecules.

RAISED VEGF: ITS USEFULNESS IN THE DIAGNOSIS OFPOEMS SYNDROME

Pihan M1, D’Sa SP2, Church AJ3, Yong KL4, Reilly MM1,

Lunn MP1. 1MRC Centre for Neuromuscular Diseases,Department of Molecular Neurosciences, UCL Instituteof Neurology, London, UK; 2Department of Haematology,University College London Hospitals NHS Foundation Trust,London, UK; 3Department of Neuroimmunology, Instituteof Neurology, Queen Square, London, UK; 4Departmentof Haematology, University College London Hospitals NHSFoundation Trust, London, UK.

Vascular endothelial growth factor (VEGF) is markedlyelevated in the majority of patients with POEMS syndromeand is thought to be a useful biomarker for its management.However, VEGF can be elevated in many other illnesses,and thus relying on a raised VEGF might be misleading. Westudied the specificity of serum VEGF (sVEGF) in 195 con-secutive patients with a neuropathy tested for sVEGF in theDepartment of Neuroimmunology, including 25 untreatedPOEMS syndrome patients. Then, we analysed 238 consec-utive patients without POEMS syndrome (170 patients witha neuropathy and 68 patients with other diseases) testedfor sVEGF and explored these for causes of raised sVEGF.In patients with a neuropathy, very elevated sVEGF (>1000𝜌g/ml, normal range <771 𝜌g/ml) had a sensitivity (Se) of100% and a specificity (Sp) of 92% for the diagnosis ofPOEMS syndrome, with positive (PPV) and negative (NPV)predictive values of 66% and 100%. In patients presentingwith a neuropathy and paraproteinaemia (the likely scenariogenerating a request to make a diagnosis of POEMS), Spwas 90% and PPV 76% (Se and NPV both 100%). sVEGFwas much higher in POEMS syndrome patients than anyothers. When POEMS patients were excluded, sVEGF washighest in patients with CIDP and anti-MAG neuropathy.However, none of the neuropathy groups were found tobe predictive factors for raised sVEGF when co-morbidconditions were controlled for in multiple logistic regressionmodels. Multiple logistic regression identified anaemiawith low iron as the most significant predictor for ele-vated sVEGF. There was a tendency for cancers andWaldenström’s macroglobulinaemia to be predictors ofelevated sVEGF (>771 𝜌g/ml). When considering onlyvery elevated sVEGF (>1000 𝜌g ml), COPD/obstructivesleep apnoea syndrome was the only significant predictoralongside anaemia with low iron. These results are sup-ported by piecemeal data from previous studies. Otherpotential factors for VEGF elevation have been describedbut not found in this cohort. We confirmed the highsensitivity and specificity of elevated VEGF for POEMS

syndrome diagnosis. However, when VEGF is sustainablyelevated, anaemia with low iron, cancers, haematologicalmalignancies, OSAHS, COPD and chronic inflammatorydiseases should be excluded.

GUILLAIN-BARRÉ SYNDROME SUBTYPE: A NEW SET OFCRITERIA FOR EARLY AND ACCURATEELECTRODIAGNOSIS

Rajabally YA1, Durand M-C2, Mitchell J1, Orlikowski D3,

Nicolas G4. 1Regional Neuromuscular Clinic, QueenElizabeth Neurosciences Centre, University Hospitalsof Birmingham, Birmingham, UK; 2Departmentof Neurophysiology, 3Medical Intensive Care Unit,and 4Department of Neurology, Hôpital Raymond-Poincaré(AP-HP), Université Versailles-Saint-Quentin-en-Yvelines,Garches, France.

Serial electrophysiology has been suggested as essen-tial for accurate diagnosis in Guillain-Barré syndrome (GBS).However, whether more adapted electrophysiological crite-ria may allow a single study to be sufficient, is unknown. Weretrospectively reviewed records of 365 consecutive patientswith GBS from Birmingham, U.K. and Garches, France, admit-ted between 1998-2013. Electrophysiology was first analyzedusing existing criteria (Hadden et al., 1998). We developedin addition a new set of modified criteria, utilizing sensi-tive and specific cut-off values for demyelination (Van denBergh and Piéret, 2004) of proven sensitivity and specificityin chronic inflammatory demyelinating plyradiculoneuropa-thy, and incorporating new knowledge on electrophysiologyof axonal GBS. We compared diagnostic rates and classi-fication changes using modified criteria with published lit-erature relating to serial studies. With existing criteria, wefound similar proportions of acute inflammatory demyelinat-ing polyradiculoneuropathy (AIDP) (71.5% vs. 72%; p=1),axonal GBS (17.5% vs. 14.7%; p=0.62) and equivocal forms(9.9% vs. 13.3%; p=0.41), to the previous studies consid-ered. With modified criteria, we identified comparable ratesof AIDP (56.2% vs. 58.7%; p= 0.70), axonal GBS (35.1% vs.36%; p=0.89) and equivocal forms (7.7% vs. 5.3%; p= 0.63)with a single nerve conduction study, as compared to whenserial electrophysiology was used in previous analyses. Weobserved an identical diagnostic shift from AIDP to axonalGBS with modified criteria as that described with serial stud-ies (21.5% vs. 18.5%; p=0.72). Classification changes withmodified criteria correlated significantly with performing ofelectrophysiology ≤7 days after symptom-onset (p= 0.045),indicating their greater usefulness in earlier disease stages.In conclusion, our findings indicate that our proposed mod-ified electrodiagnostic criteria are adequate for early andaccurate electrodiagnosis of GBS. Furthermore they impor-tantly demonstrate that a single electrophysiological studymay suffice to establish the ultimate electrodiagnosis ofGBS subtype.

277


DEFINING THE PERIPHERAL NERVE ENVIRONMENT INAMYOTROPHIC LATERAL SCLEROSIS AND MOTORNEUROPATHIES: MORPHOLOGICAL AND WGEXPRESSION STUDIES IN HUMAN MOTOR NERVEBIOPSIES

Riva N1, Domi T1, Clarelli F2, Dina G1, Cerri F1, Podini P1,

Gallia F3, Nobile-Orazio E3, Martinelli-Boneschi F2, Comi

G1, Quattrini A1. 1Neuropathology Unit, Departmentof Neurology and Institute of Experimental Neurology(INSPE), San Raffaele Scientific Institute, Milan, Italy;2Laboratory of Complex Genetic Disorders, Departmentof Neurology and Institute of Experimental Neurology(INSPE), San Raffaele Scientific Institute, Milan, Italy;3Department of Neurological Sciences, University of Milan,2nd Neurology, IRCCS Humanitas Clinical Institute,Rozzano, Milan, Italy.

The causes and pathogenesis of amyotrophic lateralsclerosis (ALS) remain poorly understood. To date, only afew treatments can prolong survival of ALS patients, and anidentified biomarker is still lacking for the diagnosis of thisdisease. Therefore, the characterization of pathways involvedin the pathogenesis of this disease could help in the iden-tification of new biomarkers and to provide insight into thedevelopment of new therapeutic strategies. As the first step,we demonstrated specific alterations in human ALS motornerves, supporting the utility of the biopsy of the motorbranch of the obturator nerve for an early differential diag-nosis of selected cases of lower motor neuron disease. Spe-cific histopathologic diagnostic criteria have been establishedfor proper interpretation of motor nerve biopsies. To investi-gate the molecular changes underlying ALS, we performeda whole genome expression (GE) profiling study on motorand sural nerve biopsies. Based on pathologically-validateddiagnosis, the following groups of patients have been stud-ied: Group 1, ALS (N:10); Group 2, Motor Neuropathy (N:8);Group 3, controls (normal sural nerves, N:4); Group 4, heredi-tary demyelinating neuropathy (CMT1, N:5); Group 5, chronicaxonal neuropathy of undetermined origin (CIAP) withoutsigns of inflammation (N:5); Group 6, vasculitic neuropathy(N:10); Group 7, chronic inflammatory demyelinating periph-eral polyradiculoneuropathy (CIDP, N:5). Total RNA was iso-lated from nerves, and the RNeasy kit (Qiagen) was used.RNA was quantified using the Nanodrop-2000 spectropho-tometer (Celbio), the Agilent 2100 Bioanalyzer was used toassess the RNA integrity. GE study was performed using theIllumina Beadchips. For each experimental condition, 4 upto 10 biological replicates were analysed. Sample clusteringanalysis based on the absolute correlation metric parame-ter was also generated with GenomeStudio software. Thedendrograms showed a good segregation of our group sam-ples. Differentially expressed genes (DEGs) were identified.Subsequently, we carried out a pathway analysis, in orderto assign biological meaning to the group of differentiallyexpressed genes. Our preliminary data suggest similar gene

expression profiles in the different diagnostic groups andstimulate further analyses in order to unravel the patho-genetic pathways underlying the development of ALS andother PNS disorders.

REFERENCE VALUES OF CSF PROTEIN LEVEL INCHILDREN

Roodbol J1,2, Kahlmann V1,2, van Leeuwen N4,

Ramakers CRB5, van Pelt D1,2, Neuteboom RF2, de Wit

M-CY2, Jacobs BC1,3. Department of 1Neurology,2Paediatric Neurology, 3Immunology, 4Public Health,and 5Clinical Chemistry, Erasmus MC – Sophia Children’sHospital, University Medical Center Rotterdam, TheNetherlands.

Cerebrospinal fluid (CSF) protein level is frequently usedas diagnostic test, but this level changes with age and vali-dated reference values for children are unavailable. This limitsthe current diagnostic use for immune-mediated diseasesincluding Guillain-Barré syndrome (GBS), acute disseminatedencephalomyelitis (ADEM) and multiple sclerosis (MS). Theaim of this study was to define age-specific reference val-ues for CSF protein levels for children and validate these forchildren with GBS, ADEM and MS. We conducted a retro-spective cohort study on 1218 children (<18 years) seen atSophia children’s hospital (2006-2013) who underwent a lum-bar puncture for routine diagnostic work-up. Excluded werepatients with a traumatic puncture (>500 erythrocytes/μL),leukocytosis (>50 white blood cells/μL), a history of pre-maturity (age at birth <37 weeks) and aged under one yearor patients with a confirmed diagnosis associated withincreased protein level, resulting in a cohort of 378 patients.The median CSF protein level in the reference group was0.20 g/l (IQR 0.16-0.29, range 0.08-2.25). In the first 6 monthsafter birth, the CSF protein level was exceptionally variable(median 0.42 g/l, IQR 0.25-0.65, range 0.12-2.25). The low-est CSF protein levels are reached between the first andsixth year (median 0.17 g/L IQR 0.14-0.20, range 0.08-0.63).Hereafter the protein level increased gradually to adult lev-els. The median CSF protein level between 12-18 years was0.21 g/L (IQR 0.17-0.26, range 0.12-0.56). Patients with GBS(N= 52) had a median CSF protein level of 0.74 g/L, (IQR:0.41-1.76). Children with MS (N=39) showed a median pro-tein level of 0.28 g/L (IQR 0.24-0.34). Patients with ADEM(N= 41) showed a median CSF protein level of 0.32 g/L (IQR0.24-0.47). Based on our new reference values, the CSF pro-tein level was elevated in 92% of GBS, 78% of ADEM and74% of MS children. In conclusion, CSF protein reference lev-els are highly dependent on the age of the patient. Below 6months the range is too large to be of diagnostic value. Over6 months we found age-specific reference values which areconsiderable lower than commonly used in clinical practice.These new values have a much higher sensitivity for the diag-nosis of GBS, ADEM and MS in children.

278


IMMUNOGLOBULINS THERAPY IN CHRONICINFLAMMATORY DEMYELINATINGPOLYRADICULONEUROPATHY: WHY SUBCUTANEOUSROUTE?

Schirinzi E, Lucchesi C, Piazza S, Siciliano G. Departmentof Clinical and Experimental Medicine, Instituteof Neurology, University of Pisa, Italy.

Intravenous immunoglobulins (IVIg) are awell-recognized effective therapy in patients affected bychronic inflammatory demyelinating polyradiculoneuropathy(CIDP), often a first choice treatment compared to long-termsteroids or plasma exchange. A recent alternative strategyin CIDP therapy is represented by Ig administered subcu-taneously (SCIg), based on the demonstrated biologicalefficacy equivalence with the advantage of more stableblood level of Ig administered by that route compared tointravenously. We report clinical data concerning 4 CIDPpatients, diagnosed according to EFNS/PNS clinical andelectrophysiological criteria, successfully treated with IVIgand then shifted to SCIg 20% (Hizentra®, CSL Behring); in allthe cases the shift was justified by the scarce level of patientcompliance to the IVIg treatment regimen. The followingparameters were monitored before and after the shift fromIVIg to SCIg: muscle strength assessed by means of MRCscale, somatosensory perception assessed by neurologicalbedside examination, clinical relapse rate, life quality usingLQI (Life Quality Index) and functional limitations by OverallNeuropathy Limitations Scale (ONLS). All patients (69-78years), on stable IVIg dosing, received weekly SCIg at amonthly cumulative dose equivalent to previous IVIG using.Two patients had both motor and sensory impairment,whereas two subjects at the time of the switching fromIVIg to SCIg only referred subjective sensory symptoms, likepainful sensations, paresthesias and dysesthesias, distallyat all extremities. The mean follow up for all patients was 9months (4-17 months). In the observational period, consid-ering overall, patients clinical course remained stable andno relapses were verified. Our data support the evidencesof at least similar efficacy profile of SCIg compared to IVIgin CIDP patients; in addition, treatment was well toleratedin all patients, without either significant side effects orcompliance issues with at home auto-infusion system. Inour view, additional reasons for selecting SCIg over IVIgin CIDP include individual dose adjustment flexibility, poorvenous access, independence from hospital-based infusionsettings and ease of administration, all factors that increasethe compliance to treatment and contribute to improvepatient’s quality of life.

FORCIDP–FINGOLIMOD ORAL IN CHRONICINFLAMMATORY DEMYELINATINGPOLYRADICULONEUROPATHY (CIDP) – DESIGN OF APHASE III STUDY

Schmidt J1, Sobue G2, Dalakas M3, Latov N4, Leger

J-M5, Merkies I6, Nobile-Orazio E7, Häring DA8,

Zhang-Auberson L8, von Rosenstiel P8, Pepe C9,

Vormfelde SV9, Hughes R10, Hartung H-P11.1Universitätsmedizin Göttingen, Georg-August-Universität,Göttingen, Germany; 2Nagoya University Hospital, Nagoya,Japan; 3Medizinische Fakultät der Universität von Athen,Athens, Greece; 4Weill Cornell Medical College, New York,NY, USA; 5Boulevard de l’Hopital, Paris, France; 6SpaarneZiekenhuis, Hoofddrop, und Medizinisches Zentrum derUniversität von Maastricht, Maastricht, The Netherlands;7Universität Mailand, Klinik und ForschungszentrumHumanitas, Rozzano, Milan, Italy; 8Novartis Pharma AG,Basel, Switzerland; 9Novartis Pharma GmbH, Nürnberg,Germany; 10National Hospital for Neurologyand Neurosurgery, London, UK; 11UniversitätsklinikumDüsseldorf, Heinrich-Heine-Universität, Düsseldorf,Germany.

Fingolimod is effective and an approveddisease-modifying drug in relapsing-remitting multiplesclerosis. Fingolimod modulates sphingosine 1-phosphatereceptors, what results in the retention of lymphocytesin lymph nodes and reduces the number of circulatingautoreactive T-cells. Chronic inflammatory demyelinat-ing polyradiculoneuropathy (CIDP) is a disease of theperipheral nervous system, which is similarly an acquiredimmune-mediated inflammatory demyelinating disorder.In a T-cell-mediated disease model for CIDP, experimentalautoimmune neuritis, fingolimod completely suppressedparaparesis and significantly decreased T-cell, B-cell andmacrophage infiltration into and demyelination of sciaticnerves. Fingolimod could thus help in CIDP. Here we presentthe design of a trial called Fingolimod ORal in CIDP (FOR-CIDP). FORCIDP compares fingolimod 0.5 mg daily withplacebo in CIDP patients. It is a double-blind, randomized,multicenter parallel-group study. Depending on the numberof events, 156-200 adult CIDP-patients, who are treatedwith intravenous immune globulins of corticosteroids dueto recent disease activity, shall be randomized. Treatmentwith fingolimod 0.5 mg daily or placebo will start followingthe last infusion of intravenous immune globulins or withthe beginning of the corticoid tapering period. The primaryoutcome is the time to the first event defined as disabilityprogression by one score on the adjusted InflammatoryNeuropathy Cause And Treatment (INCAT) disability scale.Secondary endpoints include grip strength, and total disabil-ity (assessed by the Rasch-Built Linearly Weighted OverallDisability Scale; R-ODS), safety and tolerability. FORCIDPhas 90% power at 2.5% level of significance to detect ahazard ratio of 0.51, assuming 30% of fingolimod-treatedand 50% of placebo patients worsen within six months.Study duration is flexible. FORCIDP will be stopped when:(1) the minimum required number of patients have met thedisability event criterion - with the required number adjustedstarting from n= 111, (2) an interim analysis after 50 eventsdeems the study cannot meet its goals, or (3) a maximumof 3 years after the first patient enrollment. In conclusion,FORCIDP will provide evidence for whether and how goodCIDP can be treated with fingolimod. Disclosure: Theseresults were presented at the congress of the American

279


Academy of Neurology 2014 (26 April-3 May, Philadelphia,USA). Novartis Pharma supports FORCIDP.

FUNCTIONAL OUTCOME FOLLOWING ANTERIORSUBMUSCULAR TRANSPOSITION OF THE ULNAR NERVEWITH Z LENGTHENING OF THE FLEXOR-PRONATORORIGIN IN SEVERE CUBITAL TUNNEL SYNDROME

Sekiguchi Ya, Kikuchi S, Konno S, Handa J, Sekiguchi M.

Department of Orthopaedic Surgery, Fukushima MedicalUniversity School of Medicine, Fukushima, Japan.

Cubital tunnel syndrome (CuTS) is one of the commoncompression neuropathies in neurology. However, there area lot of surgeries which are simple decompression, ante-rior transposition (subcutaneous, submuscular, or intramus-cular), and medial epicondylectomy. However, there is nogold standard for surgery. The aim of this study was to showthe functional outcome of anterior submuscular transposi-tion for severe CuTS. There were 18 men with average ageof 60 years (rage, 40-75 years). The average follow-up timewas 20 months. 15 patients had elbow arthritis. All patientsunderwent surgery for anterior submuscular transpositionand humerus spur removal. Factors evaluated included upperextremity range of motion, grip strength, pre and postopera-tive nerve conduction, and pain scores were assessed usingvisual analog scales. Range of elbow motion improved in 15patients. Quantitative grip analysis revealed 30% improved,50% with little improvement, or the same, and 20% worse.The average ulnar motor conduction velocity across theelbow was 20 m/sec preoperative and 40 m/sec postopera-tively. 15 of 18 patients were completely free of signs andsymptom. In 3 patients, slight residual hypesthesia or pares-thesia were observed. Anterior submuscular transpositionof the ulnar nerve provided satisfactory subjective outcome,relief of symptoms and adequate decompression of the ulnarnerve at the elbow. In especially elbow arthritis patients, rageof elbow motion were improved by removing anterior spurof humerus bone with anterior submuscular transposition ofulnar nerve.

CLINICAL COURSE OF FISHER SYNDROME ANDFISHER/GUILLAIN-BARRÉ OVERLAP SYNDROME

Sekiguchi Yu, Misawa S, Shibuya K, Mitsuma S, Iwai Y,

Watanabe K, Beppu M, Kuwabara S. Departmentof Neurology, Chiba University, Chiba, Japan.

Fisher syndrome (FS) is characterised by the clinical triadof ophthalmoplegia, ataxia and areflexia and considered avariant of Guillain-Barré syndrome (GBS). FS patients usuallyshow good recovery without treatment; however, in certaincases, the syndrome progresses to GBS (FS/GBS overlapsyndrome), thereby requiring immunological treatment. Toinvestigate the clinical features that help predict the devel-opment of FS/GBS overlap syndrome, we reviewed 52 FSpatients who were seen at our hospital between 1990 and

2013. FS/GBS overlap syndrome was defined as FS withdefinite limb weakness or respiratory failure (%VC<80%).Approximately 60% of MFS patients started with diplopia,20% started with ataxia and 20% started with both. Themedian duration between the onset of diplopia and ataxiawas 1 day. Twelve of 52 patients showed limb weakness(92%) or respiratory failure (33%) and developed FS/GBSoverlap syndrome. Among FS/GBS patients, 68% startedwith diplopia, 28% started with both diplopia and ataxia,whereas 8% started with dysesthesia. Facial nerve palsyand bulbar palsy were observed more frequently in FS/GBS(42% and 50%) than FS (8% and 15%, respectively, p<0.05)patients, as were dysesthesia and decrease in pinprick sen-sation at first examination (83% versus 33%, p< 0.05). Themedian duration from onset to the appearance of thesesymptoms was 3 (1-12) days, and 95% of the symptomsappeared within 7 days after onset. The median duration fromonset to nadir was 6 (4-7) days in MFS and 7 (4-19) days inFS/GBS patients, with no significant differences. AlthoughFS/GBS patients were more often unable to walk without aidcompared with MFS patients at first visit (75% versus 28%,p< 0.01) and at nadir (92% versus 30%, p<0.01), signifi-cant differences in the duration from onset to recovery werenot observed between the groups. This study revealed thatFS/GBS patients frequently showed facial nerve palsy, bul-bar palsy and sensory symptoms besides the triad of MFS.Because these symptoms primarily appeared within 7 daysand reached nadir, MFS patients should be carefully observedduring this period.

THE ROLE OF NERVE CONDUCTION STUDY ANDULTRASONOGRAPHY IN ASSESSING INTERDIGITALNEUROPATHY OF THE FOOT

Shin KJ1, Nam T-S2, Kim JK3, Kim B-J4, Bae JS5, Oh JY6.1Department of Neurology, Haeundae Paik Hospital, InjeUniversity, Busan; 2Department of Neurology, ChonnamNational University Medical School, Gwangju; 3Departmentof Neurology, Dong-A University College of Medicine,Busan; 4Department of Neurology, Korea University Collegeof Medicine and Korea University Medical Center, Seoul;5Department of Neurology, College of Medicine, HallymUniversity, Seoul; 6Department of Neurology, KonkukUniversity School of Medicine, Seoul, South Korea.

Interdigital neuropathy (IDN) of the foot, called Morton’sneuroma, is one the common causes of metatarsal pain.Diagnosis of IDN is basically made by clinical features suchas localized pain and/or numbness or diminished sensation inthe interdigital nerve territory. Nerve conduction study (NCS)and ultrasonography could be ancillary tests in the diagnosisof IDN. However, the comparative study of NCS and ultra-sonography in assessing IDN has not yet reported. Thirty-oneIDN patients (52.9± 15.9 years old, 28 females) were enrolledin the study. Fourteen patients had symptoms in the rightfoot, 13 in the left foot, and 4 in both feet. The III-IV inter-digital nerve was affected in 19 cases, the II-III interdigitalnerve in 14 cases, the I-II interdigital nerve in 3 cases, and

280


the IV-V interdigital nerve in 2 cases. All patients were per-formed the interdigital NCS by Oh’s method and ultrasonog-raphy in the symptomatic foot. Twenty-seven patients exhib-ited the abnormal dip phenomenon in interdigital NCS and23 patients exhibited the thickening of the interdigital nervewithin the web space in ultrasonography. All patients whoshowed abnormal findings in ultrasonography exhibited theabnormal dip phenomenon in interdigital NCS. InterdigitalNCS and ultrasonography could be good tools in assessingthe IDN.

SOMATIZATION DISORDER MASQUERADING ASPERIPHERAL NEUROPATHY

Smith BE, Cortez MM, Goodman BP, Ross MA. MayoClinic College of Medicine, Scottsdale, AZ, USA.

A significant diagnostic challenge in diagnosing individu-als referred for subspecialty peripheral neuropathy evaluationis that a wide variety of disorders of peripheral, central and/orpsychogenic origin may ultimately be documented, highlight-ing the importance of considering a broad differential diagno-sis in peripheral nerve clinical practice. This series presentsthe range of final diagnoses in a series of consecutive out-patients referred for tertiary center subspecialty peripheralneuropathy (PN) evaluation. Data were collected retrospec-tively on 60 consecutive outpatients referred to one examinerfor subspecialty evaluation of PN on 40 consecutive clinicdays. All patients had detailed history, quantitative neurologicexamination and neurophysiologic testing. Of the 60 consent-ing patients (mean age 57.3 years, range 19-90; M:F ratio 3:2),one or more neurologic diagnoses were made in 34 (56.7%),a diagnosis of somatization disorder in 17 (28.3%) and diag-nosis of a neurologic condition plus somatization disorderin 2 (3.3%); the combination of neither a neurologic nor asomatization disorder diagnosis was concluded in 10 (16.7%)individuals. A significant proportion of outpatients referredfor subspecialty PN evaluation may be found to have otherneurologic conditions (30.0% in this series); a significant pro-portion of outpatients referred for PN evaluation may havesomatization disorder (28.3% in this series); no specific diag-nosis may be reached in a small proportion of cases (16.7% inthis series); relatively few individuals referred for PN evalua-tion may be found to have both PN and somatization disorder(1.7% in this series).

INFLAMMATORY CYTOKINES CONDUCT AND REGULATESCHWANN CELL LOCOMOTION

Stettner M, Labus S, Dehmel T, Derksen A, Mausberg

AK, Kieseier BC. Department of Neurology, ResearchGroup for Clinical and Experimental Neuroimmunology,Heinrich-Heine-University, Düsseldorf, Germany.

Migration of Schwann cells (SCs) as glial cells ofthe peripheral nervous system (PNS) is prerequisite forpreceding myelination and remyelination after nerve injury.

Inflammatory neuropathies are characterized by de- andremyelination, orchestrated in part by cytokines. The role ofcytokines in directing SC migration has not been elucidatedso far. The aim of the present study was to investigate howpro- and anti-inflammatory cytokines as well as unspecificmodulators of inflammation, such as lipopolysaccharide(LPS), impact SC locomotion. To record SC migration, assaysfor chemokinetic (undirected) and chemotactic (directed)migration responses were performed by time-lapseanalysis up to 24 h. Undirected migration ability was inves-tigated using a scratch assay, measuring the accumulateddistance and cell velocity. Chemotaxis chambers allowedthe assessment of directed SC migration in a linear gra-dient, analyzing the forward migration index (ratio of thenet distance travelled along the gradient and the accumu-lated distance) and centre of mass displacement. For eachanalysis at least 600 cells were tracked. Experiments wereperformed in a conditioned microscope chamber; SCs wereprepared and purified from sciatic nerves of neonatal ratsor mice. An increase of undirected and directed SC mobilityafter treatment with LPS was observed. Inhibition of matrixmetalloproteinase (MMP) activity diminished this effect. Aspro-inflammatory mediators, both interferon-gamma (IFN-𝛾)and tumor-necrosis-factor-alpha (TNF-𝛼) act as attractants forSCs; IFN-𝛾 exhibited a stronger chemotactical response. Sur-prisingly, interleukin-4 (IL-4) as anti-inflammatory cytokinealso attracted SC, but was the only cytokine to reduceSC velocity. Inhibition of the chemokine receptors CXCR2and CXCR4 resulted in a mitigation of these effects. Weconclude that a specific pattern of cytokines during inflam-mation and regeneration is crucial to conduct and regulateSC locomotion, which was detected to be MMP- andCXCR-dependent. This study provides new insights intorestorative mechanisms of the PNS, which may identifyuseful novel therapeutic pathways.

ELEVATED PAIN THRESHOLD IN PAINFUL NEUROPATHY:A STUDY BY INTRADERMAL ELECTRICAL STIMULATION

Suzuki C, Kon T, Funamizu Y, Ueno T, Haga R, Nishijima

H, Arai A, Tomiyama M, Baba M. Departmentof Neurology, Aomori Prefectural Central Hospital, Aomori,Japan.

Intraepidermal electrical stimulation (IES) is a new tech-nique to assess function of A-delta fibers in the epidermis.Using this technique, we previously reported that epidermalpain threshold was twice higher in asymptomatic diabeticpatients than that of normal subjects, and that the increasein threshold in IES correlated negatively with intraepidermalnerve fiber density in patients with established diabetic neu-ropathy (JPNS 2013;18:S112). The aim of the present studyis to investigate A-delta nerve fiber function in cases withpainful neuropathy. We recruited ten patients with painfulneuropathy (eight diabetic and two toxic); ten healthy sub-jects served as controls. For nociceptive IES, we introduceda newly-designed stainless steel concentric bipolar epider-mal needle electrode manufactured by Nihon Kohden, Tokyo,Japan. This electrode selectively activated cutaneous A-delta

281


fibers (Inui et al: JNNP 2011;83:551-556). We put the IESelectrode on the skin of the dorsum of the foot and deliv-ered weak electrical stimuli: each stimulus consisted of trainof 3 square-wave pulse of duration of 2.2 msec with inter-val 20 ms. Stimulus intensity was increased stepwise by0.01 mA until the subjects reported a prickling sensation.Stimulus intensity was then reduced stepwise by 0.01 mA tothe point where the pain sensation disappeared. We definedpain threshold as minimum electrical intensity by that subjectfelt a pricking sensation. The mean pain threshold values inthe patient group were 0.207± 0.28 mA, while the mean painthreshold values of the control group were 0.028± 0.08 mA(p< 0.05). This finding indicates elevated pain threshold inepidermis in painful neuropathy, that is to say, hypofunction inA-delta nerve fiber terminals in the epidermis even in painfulcondition. It has been morphologically shown that smallnerve fibers such as A-delta and C fibers are predominantlyaffected in typical cases with painful neuropathy. Symptomsof painful neuropathy include burning-/sharp-/shooting-pain,or mixture of them in the feet, and moreover, patients oftendescribe hyperalgesia or allodynia evoked by light touch tothe foot skin. The present study has showed that the properpain sense of epidermis is decreased in diabetic and toxicpainful neuropathies.

THE SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONISTFTY720 PROMOTES PERIPHERAL NERVE REGENERATION

Szepanowski F, Derksen A, Meyer zu Hörste G, Hartung

H-P, Kieseier BC. Heinrich-Heine-University, UniversityHospital, Department of Neurology, Düsseldorf, Germany.

Sphingosine-1-phosphate (S1P) is a bioactive sph-ingolipid that has been implicated in several biologicalprocesses in multiple tissues and cell types and acts as aligand for five G-protein coupled receptors, generally referredto as S1P1 – S1P5. FTY720 is a sphingosine analogue that,after phosphorylation by sphingosine kinases, binds to fourof the five known S1P receptors. As an immunomodula-tory drug, FTY720 is known to prevent lymphocyte egressthrough abrogation of S1P signaling via receptor internal-ization. Its clinical efficacy has been established in multiplesclerosis. In addition, an emerging body of experimentalevidence points to potential direct effects on neurons,astrocytes, and glial cells. The effects of FTY720 on cells ofthe peripheral nerve, however, have not been investigatedin vivo so far. To study the effects of FTY720 on peripheralnerve regeneration, we performed sciatic nerve crush inC57Bl/6 mice. Two weeks post-crush, we assessed sci-atic nerve functionality by electrophysiology and walkingtrack analysis, by histology the degree of myelination andaxonal integrity. To better understand potentially relevantmechanisms, we studied cAMP, a crucial factor for axonalregeneration, as well as oxidative stress. Clinical as well aselectrophysiological measures indicated a significant

improvement of axonal regeneration in FTY720-treatedmice compared to control animals. Histology revealeda significantly increased thickness of myelin sheathsin crushed nerves of FTY720-treated mice. In thesenerves, cAMP levels were found to be increased,whereas dinitrophenyl-labeling of free protein carbonylsand visualization using HRP-DAB pointed to lower oxida-tive stress in FTY720-treated animals. Our data suggestthat FTY720 may exhibit direct effects within the periph-eral nervous system in vivo propagating peripheral nerveregeneration.

CLINICAL FEATURES AND ANTI-GANGLIOSIDEANTIBODIES IN GUILLAIN-BARRÉ SYNDROME WITHDYSAUTONOMIA

Takasaki H1, Kaida K1, Moriguchi K1, Kuwahara M2,

Kusunoki S2, Onoue H1, Ikewaki K1. 1National DefenseMedical College, Tokorozawa, Saitama; 2Kinki UniversitySchool of Medicine, Osakasayama, Osaka, Japan.

Dysautonomia is a considerable complication inGuillain-Barré syndrome (GBS), because it is the mostfrequent cause of death in GBS. To clarify clinical andimmunological features of GBS with dysautonomia, weinvestigated clinical information and antibodies to ganglio-sides or ganglioside complexes in 49 GBS patients (subjects,31 males and 18 females) with dysautonomia. Clinical anal-yses of the 49 patients showed that the mean age of was45.8 years old and the mean score of Hughes functional grad-ing scale at nadir was 4.1. Cranial nerve deficits were foundin 71% of the subjects, bulbar involvement in 43%, andophthalmoplegia in 27%. Regarding autonomic symptoms,fluctuating hypertension appeared in 61% of the subjects,vesicorectal disturbance in 51%, arrhythmia in 29%, anddisturbance of sweating in 13%. ELISA studies of acutephase sera from the 49 patients on IgG antibodies to singleganglioside antigens or ganglioside complexes showed that19 patients (39%) had anti-ganglioside antibodies. The IgGanti-GQ1b antibodies were found in 20% of the subjects,anti-GD1b antibodies in 14%, anti-GT1a antibodies in 14%,anti-GA1/GQ1b complex antibodies in 12%, anti-GA1/GT1ain 12%, anti-GM1/GT1a in 10%, and anti-GM1/GQ1b in10% (in order of frequency). Antibodies to GQ1b or GD1band to ganglioside complexes containing GQ1b are likelyto be associated with development of dysautonomia inGBS, although statistical analysis in a larger population ofGBS with dysautonomia is required. There was no sig-nificant correlation between each autonomic dysfunctionand specific anti-ganglioside antibodies. GBS patients withdysautonomia are characterized by frequent cranial nerveinvolvement and unaided gait at nadir. GQ1b, GD1b, organglioside complexes containing GQ1b may be target anti-gens in autonomic peripheral nerves and dorsal root ganglianeurons.

282


AXONAL EXCITABILITY CHANGES IMMEDIATELY AFTERIVIG IN CIDP

Tsuji Y1, Noto Y1, Shiga K2, Mizuno T1, Nakagawa M3.1Department of Neurology, Graduate School of MedicalScience, Kyoto Prefectural University of Medicine, Kyoto,Japan; 2Department of Medical Education and Primary Care,Kyoto Prefectural University of Medicine, Kyoto, Japan;3North Medical Center, Kyoto Prefectural Universityof Medicine, Kyoto, Japan.

Lin et al. reported that the parameters in axonal excitabil-ity testing alter one week after intravenous immunoglob-ulin (IVIg) infusion in patients with chronic inflammatorydemyelinating polyneuropathy (CIDP). However, it remains toelucidate how fast they change after IVIg treatment. Weconducted nerve excitability testing using TrondNF programin Qtrac® system in five patients with CIDP before treat-ment, within 24 hours after the treatment completion, and10 days after the completion. We compared the follow-ing excitability measures; strength-duration time constant(SDTC), superexcitability, subexcitability, and threshold elec-trotonus (TE). Before treatment, the averaged TE curvesshowed an outward deviation, i.e., “fanning-out”, comparedto those in normal subjects both in depolarized and in hyper-polarized conditions. Within 24 hours after the completion ofIVIg infusion, they tended to show an inward deviation, i.e.,“fanning-in”, in either condition. Of note, in 10 days after theIVIg therapy, they slightly moved back outward compared tothose within 24 hours after the treatment. In contrast, therewas no significant change in other excitability parameters,such as SDTC, superexcitability, and subexcitability duringthe 10-day evaluation in our study. The results of our studyshowed that the axonal excitability might alter just after IVIgtherapy in patients with CIDP, implying the possible directeffect of immunoglobulin on axonal properties of the periph-eral nerves.

IMMUNOGLOBULIN DEPENDENT REGULATION OFSCHWANN CELL DIFFERENTIATION RELATED FACTORS:A ROLE FOR GLIAL IL-18 EXPRESSION?

Tzekova N1, Heinen A1, Bunk S2, Hermann C3, Hartung

H-P1, Küry P1. 1Department of Neurology, Medical Faculty,Heinrich-Heine-University, Düsseldorf, Germany;2Department of Immunology, 3Medical Affairs EMEA,Baxter Innovations, Vienna, Austria.

Schwann cells are the myelinating glial cells of theperipheral nervous system (PNS) and exert important regen-erative functions revealing them as central repair compo-nents of many peripheral nerve pathologies. Intravenousimmunoglobulins (IVIG) are widely used to treat autoimmuneand inflammatory diseases including immune-related neu-ropathies. With this study we wanted to address whetherimmunoglobulins affect glial cell homeostasis and differen-tiation and whether Schwann cell dependent nerve regen-erative processes are influenced. IVIG dependent cellular

reactions were investigated using three different primarySchwann cell culture systems: (a) naïve (immature) Schwanncells, (b) differentiating Schwann cells (by means of p57kip2gene suppression) and (c) myelinating co-cultures made ofdorsal root ganglia cells. We found that primary rat Schwanncells respond to IVIG stimulation with altered cell morpholo-gies accompanied by an accelerated growth of cellular pro-trusions in early stages of the differentiation process. IVIGstimulation was also found to reduce cellular prolifera-tion rates without affecting cell survival. Furthermore, weobserved that IVIG treatment can transiently boost myelingene expression of immature cells, whereas in differentiat-ing Schwann cells P0 and MBP gene and protein expressionis promoted on a long-term scale. Importantly, myelin geneinduction was not detected upon application of IgG1 controlantibodies such as herceptin, synagis, or avastin. Analysis ofIVIG dependent gene/protein expression revealed additionalchanges in the regulation of genes/factors associated withSchwann cell’s repair mediating phenotype. We also demon-strated a specific binding of IVIG to Schwann cells and identi-fied CD64 Fc receptor expression on their surface. Currentlyit is not solved whether the observed cellular responses areFc receptor mediated or some epitope/Fab binding occurs aswell. In order to study IVIG effects on Schwann cell remyeli-nation and axonal regeneration, an in vivo study was per-formed, the results of which will be presented. We concludethat Schwann cells are not only able to respond to but alsospecifically bind immunoglobulins and that IVIG stimulationcan promote their differentiation.

CAN ANTIBIOTICS IMPROVE THE OUTCOME OFDIARRHEA-ASSOCIATED GUILLAIN-BARRÉ SYNDROME?:A DOUBLE-BLIND, PLACEBO CONTROLLEDRANDOMISED STUDY

Umapathi T1, Islam Z2, Islam MB2, Mohammad QD3,

Merkies ISJ4, Huak CY5, Yuki N5, Sejvar J6. 1NationalNeuroscience Institute, Singapore; 2International Centrefor Diarrheal Disease Research, Dhaka, Bangladesh; 3DhakaMedical College and Hospital, Dhaka, Bangladesh;4Maastricht University Medical Centre, Maastricht, TheNetherlands; 5Yong Loo Lin School of Medicine, Singapore;6Centers for Disease Control, Atlanta, GA, USA.

The burden of Guillain-Barré syndrome (GBS) is high inlow-income countries such as Bangladesh, possibly linkedto high incidence of Campylobacter jejuni enteritis. Mostpatients have limited access to intravenous immunoglob-ulins and life-sustaining interventions such as mechanicalventilation. Cost-effective ways of improving GBS outcomesin these regions is needed. The organisms that precipi-tate GBS are most likely eliminated by the time symptomsbegin. The effect of persistent pathogens in exacerbating thedysimmune response and hence worsening outcome hasnot been studied. However, any putative effect of eliminat-ing these pathogens on GBS outcome is likely to be small,especially in patients who have received maximum immunetherapy. In Bangladesh, the large number of GBS patients

283


not given immunotherapy permits a study design that issufficiently powered to detect even a small effect of antimi-crobials in improving GBS outcomes. The aim is to deter-mine if antibacterial treatment of diarrhea-associated GBSimproves its outcome. All GBS patients from 3 medical col-lege hospitals in Dhaka City, Bangladesh, aged 2 years andabove, satisfying Brighton criteria 3 and above, with historyof diarrheal illness within 7 days before symptom-onset andwho provide informed-consent will be given Azithromycin orplacebo for 5 days. Patients will continue to receive standardtreatment. Primary outcome measure is Rasch-built overalldisability score, R-ODS. The proportion of patients reach-ing clinically important improvement, MCID-SE≥ 1.96, in thetreatment and placebo groups will be compared at 95%confidence level. Kaplan Meier curves will estimate thecumulative proportion of patients demonstrating signifi-cant improvement or deterioration at 4, 8 and 24 weeks.Cross-cultural modification and validation of RODS will bedone. Mean change in GBS disability score from presentationto 4 weeks is also measured. Secondary, outcomes mea-sures are: time taken to walk without assistance, return towork; number of patients requiring invasive ventilation, daysventilated and deaths. It is postulated that active treatmentwill raise the improvement by 10% across all epochs. Hence,320 subjects are required for each group for a power of 80%and a 2-sided test of 5%. Duration of the study is estimated at4 years.

PARAPARETIC GUILLAIN-BARRÉ SYNDROME

van den Berg B1, Fokke C1,2,3, Drenthen J1,4, van Doorn

PA1, Jacobs BC1,2. Department of 1Neurology,2Immunology, 4Clinical Neurophysiology, Erasmus MC,University Medical Centre Rotterdam, Rotterdam, TheNetherlands; 3Department of Neurology, Gelre Hospitals,Apeldoorn, The Netherlands.

Guillain-Barré syndrome (GBS) has a variable clinical pre-sentation and diagnosis may be difficult in clinically atypicalcases. Early recognition of this disorder is essential consid-ering the rapidly progressive disease course and need foradequate monitoring and treatment. Also atypical cases mayprogress to a full-blown GBS with respiratory failure and auto-nomic dysfunction. In a previous systematic review of 490well-defined cases of GBS we determined the variation inkey diagnostic features and observed a paraparetic form ofGBS that so far has only been described in smaller caseseries. The aim of the current study was to define the clinicaland diagnostic characteristics of paraparetic GBS, with weak-ness restricted to the legs, compared to the classic quadri-paretic GBS. All data were collected prospectively, accordingto a predefined protocol as part of therapeutic trials or otherclinical studies. Data were acquired with respect to demog-raphy, clinical presentation, severity and clinical course inparaparetic patients during a 6-month follow-up. Forty (8%)patients presented with leg paraparesis without weaknessof arms and hands. In 29 patients (73%) strength of thearms was preserved during the follow-up period. Paraparetic

patients compared to quadriparetic patients had a milderform of GBS, with less frequent cranial nerve involvement,less severe leg weakness, despite the fact that the major-ity of paraparetic patients were unable to walk unaided. Themedian time between onset of weakness and study entrywas 6 days (IQR 4-11 days) for paraparetic patients com-pared to 5 days (IQR 3-8 days) for quadriparetic patients(p= 0.03). Paraparetic patients presented with arm sensorydeficits in 50% and reduced or absent arm reflexes in 73%.Nerve conduction studies demonstrated arm nerve involve-ment in 89% of these patients. After a follow-up of 6 months,98% of paraparetic patients were able to walk unaided com-pared to 81% of quadriparetic patients (p=0.008). Therewas no association between paraparesis and age, gender orpreceding infections. In conclusion, paraparesis is an atyp-ical clinical presentation or subform of GBS, in which thediagnosis is usually supported by the presence of sensorydeficits, reduced reflexes or abnormal nerve conduction ofthe arms.

LONG-TERM IV IMMUNOGLOBULIN TREATMENT INCHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY (CIDP)

van Doorn PA1, Kuitwaard K1,2, Dippel DWJ1, Vermeulen

M3. 1Department of Neurology, Erasmus MC, UniversityMedical Center Rotterdam, The Netherlands; 2Departmentof Neurology, Albert Schweitzer ziekenhuis, Dordrecht, TheNetherlands; 3Department of Neurology, Academic MedicalCenter, Amsterdam, The Netherlands

IV immunoglobulin (IVIg) is beneficial in chronic inflam-matory demyelinating polyneuropathy (CIDP). Most studiesconsidering IVIg treatment in CIDP have had a limited treat-ment and follow-up duration. It is still unknown why somepatients only need one or two IVIg courses whilst othersneed to receive this expensive treatment over many years.We investigated the course of CIDP in a large group ofpatients treated with IVIg, and treated or followed them for aperiod ranging from at least 2 months to almost 30 years.The IVIg dose was regularly decreased or stopped duringthe course of treatment to assess whether the patient stillhad active disease and needed IVIg. Factors related to ini-tial improvement and especially to the total duration thatIVIg treatment was required were analysed. Improvementmeant a beneficial effect on daily life activities, and wasdefined as a reduction of at least one point on the modi-fied Rankin scale. Remission was defined as fully recovered(modified Rankin 0-1) after one or two IVIg courses with-out need for additional treatment (early remission), or afterat least three IVIg courses when IVIg could be stopped foran arbitrary period of at least 6 months while the patientremained in a good and stable neurological condition (modi-fied Rankin 0-1). Additionally, we investigated the long-termsafety of IVIg and whether patients became unresponsiveto IVIg over time. The relationship between IVIg treatmentand subsequent improvement was expressed as an oddsratio, p values were estimated with standard statistical meth-ods (2-sided Chi square and Fisher’s exact test; p< 0.05 was

284


considered statistically significant. Survival analysis methods(Kaplan Meier’s product limit method and Cox proportionalhazards regression) were used to estimate the time to remis-sion, and to analyse the relationship between prognostic fac-tors and duration of long-term treatment in patients whoimproved after IVIg treatment. Data were analyzed with Stata10 (StataCorp, College Station, Texas, USA). We includedand followed over 130 CIDP patients treated with IVIgbetween 1982 and 2014 in the Erasmus MC. Results will bepresented.

DEVELOPMENT OF ELECTROPHYSIOLOGICAL CRITERIAFOR EARLY DIAGNOSIS AND PROGNOSIS INGUILLAIN-BARRÉ SYNDROME IN GENERAL

Verboon C1, Hadden R2, Drenthen J1,3, van Doorn PA1,

Jacobs BC1,4. Department of 1Neurology, 3ClinicalNeurophysiology and 4Immunology, Erasmus MedicalCentre, Rotterdam, The Netherlands; 2Departmentof Neurology, King’s College Hospital, London, UK.

Guillain-Barré syndrome (GBS) is a clinical diagnosis, butnerve conduction studies (NCS) can be important to demon-strate the presence of a poly(radiculo)neuropathy and sup-port the diagnosis, especially in clinically atypical cases. Mostelectrophysiological research in GBS thus far has focused ondeveloping criteria for discriminating subtypes of GBS, espe-cially the acute inflammatory demyelinating polyradiculoneu-ropathy (AIDP), acute motor axonal neuropathy (AMAN) andacute motor-sensory axonal neuropathy (AMSAN). In clini-cal practice these criteria fail to classify almost one-fourthof patients, and in a proportion of patients the classifiedsubtype may change during follow-up. Validated electrophys-iological criteria for the early diagnosis of GBS in general,regardless of subtype, have not yet been developed. In thecurrent study we aim to develop such criteria by using datacollected from large cohorts of well-defined patients withGBS from The Netherlands and from a multinational treat-ment trial. In a study with 135 Dutch severely affected GBSpatients, detailed sensory and motor NCS were performedwithin two weeks after onset of weakness and at two fur-ther visits during the following month. This derivation cohortwill be used to identify the most sensitive set of electrophys-iological characteristics to diagnose GBS, regardless of GBSsubtype. This set of criteria for diagnosing GBS in general willbe validated in independent cohorts of other Dutch patients,including clinically atypical patients, and of 369 patients in themultinational trial. These cohorts will also be used to iden-tify the NCS characteristics best predictive of clinical courseand outcome, irrespective of the electrophysiological sub-type. The data will be presented at the congress. In thisstudy we aim to support neurologists in clinical practice bydeveloping sensitive and validated criteria for the early diag-nosis of GBS, regardless of subtype. In addition, we aimto define which characteristics in NCS are most informativein clinical practice to predict outcome. This information isimportant for early diagnosis, treatment and clinical decisionmaking.

PROGRESS OF INTERNATIONAL GUILLAIN-BARRÉ STUDY(IGOS): A PROSPECTIVE STUDY ON CLINICAL ANDBIOLOGICAL PREDICTORS OF DISEASE COURSE ANDOUTCOME

Verboon C1, van den Berg B1, Chavada G2, Willison HJ2,

Harbo T3, Gorson KC4, Hartung H-P5, Lehmann HC6,

Kusunoki S7, Illa I8, Nobile-Orazio E9, Reisin RC10,

Reddel SW11, Islam Z12, Islam B12, van den Bergh P13,

Feasby TE14, Péréon Y15, Shahrizaila N16, Hsieh S-T17,

van Doorn PA1, Hughes RAC18, Cornblath DR19, Jacobs

BC1,20; for the IGOS Consortium. Departmentof 1Neurology and 20Immunology, Erasmus Medical Centre,Rotterdam, The Netherlands; 2Department of Neurology,University of Glasgow, Glasgow, UK; 3Departmentof Neurology, Aarhus University Hospital, Aarhus, Denmark;4Department of Neurology, Tufts University Schoolof Medicine, Boston, MA, USA; 5Department of Neurology,University of Düsseldorf, Düsseldorf, Germany;6Department of Neurology, University Hospital of Cologne,Cologne, Germany; 7Department of Neurology, KinkiUniversity School of Medicine, Osaka, Japan; 8Departmentof Neurology, Hospital Santa Creu and Santa Pau,Barcelona, Spain; 9Department of Neurology, MilanUniversity, Milan, Italy; 10Department of Neurology, HospitalBritanico, Buenos Aires, Argentina; 11Departmentof Neurology, Concord Repatriation General Hospital,Sydney, Australia; 12Department of Emerging Diseaseand Immunobiology Research Group, CFWD, icddr,b,Dhaka, Bangladesh; 13Department of Neurology, UniversityClinic St. Luc, Brussels, Belgium; 14Departmentof Neurology, University of Calgary, Calgary, Canada;15Department of Neurology, Nantes University Hospital,Nantes, France; 16Department of Neurology, Universityof Malaya, Kuala Lumpur, Malaysia; 17Departmentof Neurology, National Taiwan University Hospital, Tai Pei,Taiwan; 18Department of Neurology, Institute of Neurology,University College, London, UK; 19Department of Neurology,Johns Hopkins University, Baltimore, MD, USA.

Guillain-Barré syndrome (GBS) is a disorder with a highlydiverse clinical presentation, course and outcome. Despitethe progress in understanding the pathogenesis, factors thatdetermine the disease susceptibility, severity and recoveryare poorly understood. GBS is still a life-threatening diseasewith a high morbidity, but development of effective and per-sonalised treatment is delayed by the rarity and variabilityof GBS. International collaboration will provide the opportu-nity to collect clinical data and biomaterials from a sufficientnumber of patients for further understanding the pathogene-sis and for predicting disease course in individual patients.The aim of the International GBS Outcome Study (IGOS)is to identify clinical and biological determinants of diseasecourse and outcome and to provide a platform for the evalua-tion of new treatments. All GBS patients, regardless of age,severity, variant forms, or received treatment, can participateprovided the inclusion is within two weeks after onset ofweakness. Clinical and electrophysiological data and bioma-terials are collected prospectively from at least 1000 patientswith a follow-up period of 1-3 years. IGOS was launched

285


in May 2012 and in March 2014 already 436 patients wereincluded. At present, 129 centres from 16 countries haveIRB approval to participate. Patients were enrolled from theUK (77), USA (72), Bangladesh (49), Denmark (41), Italy (38),Netherlands (37), Spain (32), Germany (25), Argentina (19),Japan (15), Canada (9), Malaysia (8), France (6), Belgium (5),Taiwan (2) and Australia (1). There are 400 adult and 36 paedi-atric patients enrolled, including 297 sensory-motor, 70 puremotor, 46 Miller Fisher (-overlap), and 23 other variants (puresensory, ataxic, pharyngeal-brachial-cervical, and Bickerstaffencephalitis). Data quality from all patients will be checkedusing a standard protocol. We are in the process of raisingExpertise Groups that will each focus on a specific researchtopic including epidemiology, diagnostic criteria, clinimetrics,electrophysiology, preceding infections, antibodies, geneticfactors, proteomics, trial designing, prognostic modelling andlong-term outcome. A further update of IGOS will be pre-sented at the congress.

NEW CLINICAL CLASSIFICATION AND DIAGNOSTICCRITERIA FOR GUILLAIN-BARRÉ SYNDROME, FISHERSYNDROME AND THEIR SUBTYPES

Wakerley BR1, Uncini A2, Yuki N3; for the

GBS-classification group. 1Department of Neurology,Gloucester Royal Hospital, Gloucester, UK; 2Departmentof Neuroscience and Imaging, University “G. d’Annunzio”,Chieti-Pescara, Italy; 3Department of Medicine, Yon Loo LinSchool of Medicine, National University Hospital, Singapore.

Guillain-Barré syndrome (GBS) and its variant, Fishersyndrome (FS), have several clinical subtypes. Ropper et al.proposed diagnostic criteria for pure motor GBS, pure sen-sory GBS, Fisher syndrome (FS), regional subtypes of GBSand pure pandysautonomia. van der Meché et al. subclas-sified GBS into motor-sensory GBS, pure motor GBS, FSand a bulbar form. Although the clinical features of GBSand FS are well recognized, neither of the current classi-fication systems comprehensively describes more or lessextensive forms of both syndromes. Based on the cur-rent understanding of common pathophysiological profileshared by each phenotype, we classify the GBS family intoGBS and FS, and subclassify GBS into localized subtypes(pharyngeal-cervical-brachial weakness, paraparetic GBS andbifacial weakness with paresthesias) and FS into more orless extensive subtypes (the subtype involving also the cen-tral nervous system, Bickerstaff brainstem encephalitis, andthe incomplete forms, acute ophthalmoparesis and acuteataxic neuropathy). We then suggest clinical diagnostic cri-teria for each condition based on the clinical characteristics.We believe this approach to be more inclusive for early clin-ical diagnosis and initiation of appropriate immunotherapy.Other members of the GBS-classification group: B Islam,Bangladesh; P van den Bergh, Belgium; AA Barreira, O Nasci-mento, Brazil; S Baker, Canada; L Yang, China; S Attarian, ACreange and J-P Lefaucheur, France; M Kanikannan, India; NKohara and N Kokubun, Japan; N Shahrizaila, Malaysia; Y-CChan, T Umapathi and E Wilder-Smith, Singapore; S-T Hsieh,Taiwan; R Witoonpanich; Thailand.

TRACHEOTOMY OR NOT: PREDICTION OF PROLONGEDMECHANICAL VENTILATION IN GUILLAIN-BARRÉSYNDROME

Walgaard C1, Lingsma HF2, van Doorn PA1, Steyerberg

EW2, Jacobs BC1,3. Departments of 1Neurology, 2PublicHealth, and 3Immunology, Erasmus Medical Center,Rotterdam, The Netherlands.

Performance and timing of tracheotomy is a clinicaldilemma in ventilated patients with Guillain-Barré syndrome(GBS). Patients may rapidly recover from respiratory insuffi-ciency, but tracheotomy should be considered if the expectedduration of mechanical ventilation (MV) is more than 2 weeksand translaryngeal intubation may cause considerable com-plications. Moreover, prolonged MV is associated with poorrecovery and requires more supportive care. Previous stud-ies showed that the clinical course of individual patients withGBS can be predicted accurately using prognostic modelsbased on simple clinical characteristics. In the current study,we identified risk factors associated with prolonged MV anddeveloped a guideline for clinical decision making about tra-cheotomy. We focused on the group of patients being ven-tilated for one week and aimed to determine the chance ofrequiring prolonged MV (defined as 2 weeks or more) as anindication of tracheotomy. Available were detailed follow-updata from 125 GBS patients requiring MV from previous ther-apeutic trials and prospective clinical studies. The medianduration of MV in this group was 31 days (IQR 16-63 days,full range 8 to >181 days). Prolonged MV was required in101 (81%) of these patients. Three strong predictors for pro-longed MV were identified at 1 week after intubation: (1)inability of flexing both arms in the elbow (sum of MRC scoreof both biceps muscles ≤2) (2) nerve conduction studiesdemonstrating axonal degeneration (AMAN subtype) or inex-citable nerves, and (3) presence of serum antibodies to theganglioside GQ1b. The presence of these characteristics wasrelated to a chance of prolonged MV of, respectively, 96%,100% and 100%. Based on these 3 predictors of prolongedMV we developed a simple algorithm for clinical practice,which can be used at 1 week after intubation to decide ifan individual patient requires tracheotomy or not. Using thisalgorithm, early tracheotomy can be performed in patientswho will need prolonged MV, reducing the risks associatedwith long lasting translaryngeal intubation. In addition, thisalgorithm may prevent unnecessary tracheotomy in venti-lated patients who will recover early, and thereby the risksrelated to this intervention.

SUBCUTANEOUS IMMUNOGLOBULIN THERAPY FORCHRONIC INFLAMMATORY DEMYELINATINGNEUROPATHIES: A TWO-YEAR FOLLOW UP

Wielanek-Bachelet AC, Solé G, Ferrer X, Le Masson G.

Neuromuscular Unit, University Hospital of Bordeauxand Université de Bordeaux, Bordeaux, France.

Intravenous immunoglobulin therapy is a first line treat-ment in chronic inflammatory demyelinating polyneuropathy

286


(CIDP) and is usually given through intravenous infusions. Analternative route is actually under investigation in a multicen-tric double blind prospective study versus placebo consistingof a parallel group, three arm design investigating two differ-ent doses of subcutaneous immunoglobulin (SCIg) in CIDP(PATH). The rationale of this study amongst others is to takeadvantage of more stable serum levels, but also to provide analternative strategy to patients with degraded venous accessor recurrent infectious problems. We report a small openlabel study of 6 patients with CIDP that have been switchedfrom IVIg to SCIg with two-year follow up. We follow theINCAT, MRC and OLNS scores together with quality of lifescales. The efficacy was good (stable scores after two yearsof treatment and stable EMG assessments) and compara-ble to the period of time during which they were under IVIG.However, half of the patients had to be intravenously infusedon average every 8 months when treated at the dose of1 ml/kg twice a week. The tolerance was excellent and theprocedure easy enough to allow self-administration at home.On average, the quality of life has improved for these patientsand none of them stopped SCIg.

COMPLICATIONS OF NERVE ROOT BLOCK INDEGENERATIVE LUMBAR SPINE DISEASES: AN ANALYSISOF 1,000 PROCEDURES PERFORMED BY ONE CLINICIAN

Yabuki S, Kikuchi S, Konno S. Department of OrthopaedicSurgery, Fukushima Medical University, School of Medicine,Fukushima, Japan.

Nerve root block (NRB) has been used for diagnosis andconservative therapy of radiculopathy due to lumbar spinedisease. The purpose of the current study was to clarifythe incidence and type of complications of NRB performedby one clinician. A total of 1,000 NRBs were performed on697 cases of radiculopathy due to lumbar spine diseases byone clinician. There were 409 male and 288 female (meanage: 61 years old). The consecutive cases were including233 cases of lumbar disc herniation (313 NRBs) and 464cases of lumbar spinal canal stenosis (687 NRBs). In thesecases, complications 1) during block procedure and 2) afterblock procedure were retrospectively analyzed. The NRBswere performed with 2 ml of 2% lidocaine and 2 mg ofsteroid (decadron) just after confirmation of the nerve rootwith contrast medium. The block was confirmed with thechanges of spinal sign and neurological findings before andafter NRB. There were no cases of death, anaphylactic shockand infection during and after the NRB procedure. DuringNRB: There were 2 cases (2 NRBs, 0.2%) of tumble justafter NRB. A block was not achieved in 10 cases (11 NRBs,1.1%). All these cases were spinal canal stenosis. After NRB:Prolonged paresis (>2 hours) was recognized in 16 cases (18NRBs, 1.8%). Increased pain after NRB was recognized in9 cases (9 NRBs, 0.9%). All these cases were spinal canalstenosis except for 2 cases of increased pain after NRB. All ofthe complications were improved conservatively. The current

study showed that most of the complications of NRB wererecognized in spinal canal stenosis. These results suggestthat nerve roots in spinal canal stenosis may be fragilecompared to the ones at disc herniation. It has been reportedthat injured nerve roots showed a slow recovery of muscleaction potential after nerve root infiltration of lidocaine. Theseexperimental results may explain the prolonged paresisafter NRB. In conclusion, the incidence of complicationsof NRB in 1,000 procedures was totally 4.0%, and mostcomplications were recognized in the cases of spinal canalstenosis.

THE INFLAMMASOME IS DISPENSABLE FROMRECOVERY AFTER PERIPHERAL NERVE INJURY

Ydens E1, Lornet G2, De Winter V1, Demon D3, Lamkanfi

M3, Timmerman V1, Janssens S2. 1VIB Departmentof Molecular Genetics, University of Antwerp, Antwerp,Belgium; 2VIB Inflammation Research Center, Universityof Ghent, Ghent, Belgium; 3VIB Department of MedicalProtein Research, University of Ghent, Ghent, Belgium.

For a long time interleukin-1𝛽 (IL-1𝛽) has been impli-cated in the neuroinflammatory response after peripheralnerve damage. However, the molecular basis of IL-1𝛽 pro-cessing in the peripheral nerve remains largely unknown.Members of the Nod-like receptor (NLR) family have beenshown to be involved in the production of IL-1𝛽 via the for-mation of the inflammasome. We therefore analyzed theexpression pattern of NLRs in the peripheral nerve bothin basal conditions and after injury. In basal conditions, weobserved a broad expression pattern of NLRs in the PNS,which resembled the pattern seen in Schwann cells. Motorneurons hardly express NLRs, while sensory neurons specif-ically expressed one subfamily of NLRs, the NAIPs. Uponnerve injury, a distinct set of NLRs was induced, which dif-fered completely from the NLR profile induced in the nerveafter intravenous LPS injection. The activation of the inflam-masome, however, could not be shown. Functional recov-ery experiments of inflammasome-deficient mice revealedthat the inflammasome had no significant role in regen-eration after nerve injury. Strikingly, NLRP6-deficient micedisplayed an increased degree of deficit compared to con-trol mice. The underlying mechanism of the neuroprotec-tive effects of NLRP6 is currently addressed. Altogether wehere present the most complete study of NLR expression inthe PNS and show that all inflammasome components areexpressed in the nerve. Despite a potential role of Schwanncells to activate the inflammasome, the inflammasome is notcrucial for the inflammatory response after injury. Further-more, nerve injury induces a shift in NLR expression whichwas distinct from the shift seen upon LPS injection. Theseresults might indicate that NLRs have differential functions inthe presence of exogenous and endogenous ligands. More-over, NLRP6 has a clear neuroprotective role after peripheralnerve injury.

287


SPINAL FLUID PROFILE OF ASIAN PATIENTS WITHGUILLAN-BARRÉ AND FISHER SYNDROME

Yi WAH1, Umapathi T2, Nishimoto Y3, Zhong WY4,

Cheun CY5, Yuki N6. 1Queen Elizabeth Hospital, HongKong SAR; 2National Neuroscience Institute, Singapore;3Wakayama National Hospital, Wakayama, Japan; 4AffiliatedHospital of Jining Medical College, Shandong province,People’s Republic of China; 5National University Hospital,Singapore; 6Yong Loo Lin School of Medicine, NationalUniversity of Singapore, Singapore.

We set out to study the spinal fluid profile ofGuillain-Barré syndrome (GBS) and Fisher syndrome (FS)patients from Singapore, Japan, China and Hong Kong. CSFprotein, cell count and the timing of lumbar puncture werecollated. A total of 507 GBS patients were studied. Overall,half had elevated CSF protein, lower than that reportedin a recent Dutch study (56% vs. 64%). The proportionof patients with mild pleocytosis was also higher (26%vs. 15%). The classic cytoalbuminologic dissociation wastherefore lower. An average of 34% of patients had elevatedCSF protein if lumbar puncture was performed within 3days of symptom onset, which increased to 72% in thesecond week. Cytoalbuminologic dissociation was alsodependent on the timing of spinal tap. In the Singaporecohort it was seen in 50% of the tests at 6-7 days and64% of that between 8-14 days. At 0-1, 2-3 and 4-5 daysthe corresponding numbers were 0%, 38% and 33% only.Of the 164 FS patients studied, just above one-third of thepatients (38%) had elevated CSF protein. The proportion ofpatients with cytoalbuminologic dissociation also increasedif lumbar puncture was performed later; 15% at 0-5 days,50% at 6-7 days and 60% 8-14 days in the Singapore cohort.Less patients with FS compared to GBS had elevated CSFprotein (38% vs. 56%) and pleocytosis (11% vs. 26%), likelyrelated to its the limited nature. However, the proportion ofcytoalbuminologic dissociation among GBS and FS patientswas similar. The results of a second lumbar puncture wereavailable from the Japanese cohort. Among 78 GBS patientswith normal CSF protein in the first spinal fluid (median 4days), 54% of patients had elevation in the second (median14 days). The corresponding percentage was 62% for FSpatients. In conclusion, elevation of CSF protein in GBS andFS depends strongly on the timing of the lumbar puncture;ideal timing is the second week from onset. In the earlystages, electrodiagnosis and anti-ganglioside antibody testscould help corroborate the clinical diagnosis. A delayedsecond spinal tap can be useful.

MORPHOLOGICAL STUDY ON THE COLLATERALSDEVELOPED BY ONE AXON DURING PERIPHERAL NERVEREGENERATION

Yin X, Kou Y, Wang Y, Zhang P, Jiang B. Departmentof Trauma and Orthopedics, Peking University People’sHospital, Beijing, China.

This study aims to investigate the morphological char-acteristics of the collaterals sprouted through 1 axon during

regeneration of rat peripheral nerve. Outgrowth of collateralsprouts from axons is a natural process that arises duringdevelopment of and regeneration in the peripheral nervoussystem. Our previous study showed that if there are enoughdistal endoneurial tubes into which the proximal regenera-tive axons can grow, one axon can support 3-4 collaterals,at most. Here, the tibial nerve was transected, the proximalresidual with axon number of 1/2 of the nerve trunk was fixedto the distal stump and served as the donor nerve. The num-ber of myelinated axons was calculated after 12 weeks. Theratio of distal stump axon numbers to proximal donor nerveaxon number was 1.92, and that yielded ratio of regenera-tive myelinated axon number to proximal donor axon numberof 1.63. The regenerated collaterals were sprouted from thenode of Ranvier with almost the same features of normalfibers. The tibial function index and the nerve conductionvelocities of the regenerated tibial nerve were -57.5± 4.7 and28.6±5.3 m/s. It has been suggested that using collaterals asdonor axons might be an alternative method to reconstruct aperipheral nerve defect.

LOWER MOTOR NEURON SYNDROME ASSOCIATEDWITH IGG ANTI-GM1 ANTIBODIES REVISITED

Yuki N1, Yanaka C2, Sudo M1, Funakoshi M3, Ishida H4,

Hirata K2. 1Department of Medicine, Yong Loo Lin Schoolof Medicine, National University of Singapore, Singapore;2Department of Neurology, Dokkyo Medical University,Tochigi, Japan; 3Institute for Medical Science, DokkyoMedical University, Tochigi, Japan; 4Department of AppliedBioorganic Chemistry, Gifu University, Gifu, Japan.

Some patients who are initially diagnosed as havingamyotrophic lateral sclerosis (ALS) or motor neuron disease(MND) have high titers of IgM antibodies to GM1 or GM2,which are treatable with immunotherapy. A patient, whodeveloped an ALS-like disorder subsequent to gangliosidetreatment, had IgM antibodies to GM2 as well as to minorgangliosides X1 and X2 containing GM2 epitope. X1 and X2have been synthesized. We aim to find an immune-mediatedand treatable condition in patients who were tentativelydiagnosed with ALS or MND. IgG and IgM antibodies togangliosides GM1, GM2, X1 and X2 were tested in seraobtained from patients who were suspected of having ALSor MND (n= 655). Intravenous immunoglobulin was testedin vitro to find out if it inhibited activated complement com-ponent deposition mediated by anti-ganglioside antibodies.Three patients had high titers of IgG anti-GM1 antibodies,but no IgM anti-GM1 antibodies. One of the patients alsohad IgG anti-X2 antibodies. The patients, being diagnosedwith having lower motor neuron syndrome, had neither uppermotor neuron signs nor multifocal conduction block. Onmicrotiter plates, intravenous immunoglobulin inhibited com-plement deposition mediated by IgG anti-GM1 antibodies inthe patients. In conclusion, both IgM and IgG anti-GM1 anti-bodies should be tested in patients who have lower motorneuron syndrome. Further studies are required to elucidatethe clinical features of the patients and response to intra-venous immunoglobulin.

288


ESTIMATING THE ECONOMIC ADVANTAGE OFSUBCUTANEOUS ADMINISTRATION OF IgG FORPATIENTS WITH CHRONIC INFLAMMATORYDEMYELINATING POLYNEUROPATHY (CIDP)

Zbrozek A1, Berger M2, Bullinger A3. 1Global HealthEconomics, 2Research and Development, 3US MedicalAffairs, CSL Behring, King of Prussia, PA, USA.

Immunoglobulin therapy reduces symptoms from CIDPand disability likely from reversal of conduction failure1. Ther-apeutic response in stable patients requires achievement andmaintenance of a minimum serum IgG level, which differs inindividual patients2. The purpose of this analysis is to esti-mate the cost savings from using home, self-infused subcu-taneous IgG (SCIG) instead of intravenous IgG (IVIG) therapyin infusion centers. In two studies of IVIG in CIDP3,4, patientswere dosed with 1 g/kg every 3 weeks. In both studies, themean infusion time was approximately 2.7 hours per dosewith >80% of patients completing infusions in one calendarday. This projected the number of hours per year of ther-apy at 46.8. Applying the estimate of 6 hours of at-homeorientation for SCIG therapy in first year and 6 hours ofyearly maintenance support5, and the hospital-based nurse

compensation range in Canada of C$48.25 to C$65.305,the net savings in nursing costs of C$1679 to C$2272 infirst year and C$1969 and C$2664 per each year there-after were estimated. This estimation assumed that SCIGdosing would be on a 1:1 basis at a comparable rate ofinfusion. These estimates will vary by hourly nursing com-pensation rates. Replacing professional administration ofIVIG with self-administrations by patients who are able todo that at home could provide important savings in nurs-ing time, which can be a limited resource6. Additional sav-ings to provider systems could arise from facility use (over-head) costs avoided by patients receiving therapy at home.From a societal perspective, additional savings would arisefrom the avoided amounts of travel time and energy con-sumed in visits to an infusion facility. 1) JPNS 16:15-23,2011. 2) J Neurol Neurosurg Psychiatry 84:859-61, 2013. 3)Lancet Neurol 7:136-44, 2008. 4) JPNS 18:130-40, 2013. 5)Gerth W et al., Annual Scientific Meeting of the CanadianSociety of Allergy and Clinical Immunology, October 3-6,2013, Toronto; poster. 6) Murphy et al., Canadian NursesAssoc. Ottawa, 2009. Disclosure of potential conflicts ofinterest: A. Zbrozek, M. Berger, and A. Bullinger are employ-ees of CSL Behring and have no other conflicts of interestto declare.

289

Documents

MANNOSE-BINDING LECTIN GENE-2 POLYMORPHISMS ASSOCIATED WITH SUSCEPTIBILITY AND SEVERITY OF GUILLAIN-BARRÉ SYNDROME: NEW EVIDENCE AND META-ANALYSIS