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BackgroundTo assess the ability of the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) clinical criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to include within their classification the whole spectrum of clinical heterogeneity of the disease and to define the clinical characteristics of the unclassifiable clinical forms.MethodsThe 2021 EAN/PNS clinical criteria for CIDP were applied to 329 patients fulfilling the electrodiagnostic (and in some cases also the supportive) criteria for the diagnosis of CIDP. Clinical characteristics were reviewed for each patient not strictly fulfilling the clinical criteria (‘unclassifiable’).ResultsAt study inclusion, 124 (37.5%) patients had an unclassifiable clinical presentation, including 110 (89%) with a typical CIDP-like clinical phenotype in whom some segments of the four limbs were unaffected by weakness (‘incomplete typical CIDP’), 10 (8%) with a mild distal, symmetric, sensory or sensorimotor polyneuropathy confined to the lower limbs with cranial nerve involvement (‘cranial nerve predominant CIDP’) and 4 (1%) with a symmetric sensorimotor polyneuropathy limited to the proximal and distal areas of the lower limbs (‘paraparetic CIDP’). Eighty-one (65%) patients maintained an unclassifiable presentation during the entire disease follow-up while 13 patients progressed to typical CIDP. Patients with the unclassifiable clinical forms compared with patients with typical CIDP had a milder form of CIDP, while there was no difference in the distribution patterns of demyelination.ConclusionsA proportion of patients with CIDP do not strictly fulfil the 2021 EAN/PNS clinical criteria for diagnosis. These unclassifiable clinical phenotypes may pose diagnostic challenges and thus deserve more attention in clinical practice and research.

Introduction Electrophysiological diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be challenging. Thus, with the aim ofproviding some practical advice in electrophysiological approach to a patient with suspected CIDP, we analyzed electrophysiological data from 499 patients enrolled inthe Italian CIDP Database. Methods We calculated the rate of each demyelinating feature, the rate of demyelinating features per nerve, the diagnostic rate for upper andlower limb nerves, and, using a ROC curve analysis, the diagnostic accuracy of each couple of nerves and each demyelinating feature, for every CIDP subtype.Moreover, we compared the electrophysiological data of definite and probable CIDP patients with those of possible and not-fulfilling CIDP patients, and by a logisticregression analysis, we estimated the odds ratio (OR) to make an electrophysiological diagnosis of definite or probable CIDP. Results The ulnar nerve had the highestrate of demyelinating features and, when tested bilaterally, had the highest diagnostic accuracy except for DADS in which peroneal nerves were the most informative.In possible and not-fulfilling CIDP patients, a lower number of nerves and proximal temporal dispersion (TD) measurements had been performed compared to definiteand probable CIDP patients. Importantly, OR for each tested motor nerve and each TD measurement was 1.59 and 1.33, respectively. Conclusion Our findingsdemonstrated that the diagnosis of CIDP may be missed due to inadequate or incomplete electrophysiological examination or interpretation. At the same time, thesedata taken together could be useful to draw a thoughtful electrophysiological approach to patients suspected of CIDP.

ObjectiveTo validate sphingomyelin (SM) dosage in the cerebrospinal fluid (CSF) of patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS) as a reliably assessable biomarker.MethodsWe prospectively enrolled 184 patients from six Italian referral centres, in whom CSF SM levels were quantified by a fluorescence-based assay optimised and patented in our laboratory.ResultsWe confirmed increased levels of SM in the CSF of patients affected by typical CIDP (n=35), atypical CIDP (n=18) and acute inflammatory demyelinating polyradiculoneuropathy, AIDP (n=12) compared with patients affected by non-demyelinating neurological diseases, used as controls (n=85) (p=0.0065 and pConclusionsCSF SM is a diagnostic and staging wet biomarker for acquired demyelinating neuropathies and may effectively improve the management of patients affected by GBS and CIDP.

ObjectiveTo assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.MethodsAntibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.ResultsOf 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.ConclusionsOur findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.Classification of evidenceThis study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).

Background and purpose: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. Results: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1–42days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. Conclusions: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

ObjectivesA few variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been described, but their frequency and evolution to typical CIDP remain unclear. To determine the frequency and characteristics of the CIDP variants, their possible evolution to typical CIDP, and treatment response.MethodsWe applied a set of diagnostic criteria to 460 patients included in a database of Italian patients with CIDP. Clinical characteristics and treatment response were reviewed for each patient. The Kaplan-Meier curve was used to estimate the progression rate from atypical to typical CIDP.ResultsAt the time of inclusion, 376 (82%) patients had a diagnosis of typical CIDP while 84 (18%) had atypical CIDP, including 34 (7%) with distal acquired demyelinating symmetric neuropathy (DADS), 17 (4%) with purely motor, 17 (4%) with Lewis-Sumner syndrome (LSS) and 16 (3.5%) with purely sensory CIDP. Based on retrospective review of the symptoms and signs present at onset and for at least 1 year, 180 (39%) patients had an initial diagnosis compatible with atypical CIDP that in 96 (53%) patients evolved to typical CIDP. Mean disease duration was longer in patients evolving to typical CIDP than in those not evolving (p=0.0016). Patients with DADS and LSS had a less frequent response to immunoglobulin than those with typical CIDP, while patients with purely motor and sensory CIDP had a similar treatment response.ConclusionsThe proportion of patients with atypical CIDP varies during the disease course. DADS and LSS have a less frequent response to intravenous immunoglobulin compared with typical CIDP, raising the possibility of a different underlying pathogenetic mechanism.

Anti-myelin-associated glycoprotein (MAG) antibody is associated with clinically heterogeneous polyneuropathies. Our purpose was to compare neuropathy phenotypes identified by different anti-MAG tests’ results. Cohort study: Sera from 40 neuropathy anti-MAG EIA positive patients were tested for anti-MAG by Western blot (WB), for anti-peripheral nerve myelin (PNM) on monkey nerve by immunofluorescence assay (IFA), and for anti-HNK1 on rat CNS slices by IFA. Anti-sulfatide antibodies, for comparison, were also tested by EIA. Among 40 anti-MAG EIA positive sera, 85% also had anti-PNM IFA reactivity and 67.5% bind HNK1 on rat CNS. Anti-HNK1 positive patients had the classical predominantly distal acquired demyelinating symmetric (DADS) neuropathy with a benign course, while anti-PNM positive but anti-HNK1 negative patients had predominantly axonal neuropathy with a high frequency of anti-sulfatide reactivity and the worst long-term prognosis. Anti-MAG EIA positive patients without anti-PNM or anti-HNK1 IFA reactivity had a CIDP-like polyneuropathy. Different methods to test for anti-MAG antibodies identify different clinical and electrophysiological findings, as well as long-term outcome. HNK1 reactivity is the strongest marker of DADS.

We evaluated serum glial fibrillary acidic protein (GFAP) levels by enzyme-linked immunosorbent assay (ELISA) in controls (n = 30) and in patients with chronic sensory-motor axonal neuropathy (CSMAN) (n = 30), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 30), multifocal motor neuropathy (MMN) (n = 30), and primary muscular spinal atrophy (PMSA) (n = 15). GFAP levels, expressed as optical density, were increased in CSMAN (median = 1.05) compared to controls (median = 0.41; P < 0.05) and CIDP (median = 0.53, P < 0.05). They were also increased in PMSA (median = 0.99) compared to controls (P < 0.05) and MMN (median = 0.66; P < 0.05). To differentiate CSMAN from CIDP and PMSA from MMN, we applied a cutoff of GFAP levels at 0.66, and we obtained good sensitivity and specificity. In neuropathies, serum GFAP correlated with summated sensory nerve action potential amplitudes (r = -0.57; P = 0.0006) and disease severity (r = 0.37; P = 0.0011). Thus, we propose serum GFAP as a marker of axonal damage and severity in chronic neuropathies.

Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene. We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. No dementia or myopathies were revealed in the family history covering two generations. Degenerative changes and rimmed vacuoles together with VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates were observed at the muscle biopsy. Several elements support the pathogenic role of the R159C VCP gene mutation: the occurrence at the same codon of a different, previously identified pathogenic mutation within a VCP gene mutational hot-spot, the histopathological and biochemical evidence of muscle VCP accumulation and the combined clinical presentation of IBM and FTD. These findings suggest VCP gene investigation even in apparently sporadic cases.

We evaluated the efficacy and safety of rituximab in an open-label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti-MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti-MAG antibody at entry and at follow-up. This study suggests that rituximab may be efficacious in patients with anti-MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.

The pathophysiological mechanisms responsible for conduction block in multifocal motor neuropathy (MMN) are still unclear. To clarify the physiological abnormalities at the site of the block, we tested the effects induced by polarizing direct currents on motor conduction along forearm nerves in 25 normal nerves (13 subjects), and at the site of conduction block in six nerves (five patients) with MMN. In healthy controls, whereas nerve depolarization failed to change the conditioned compound muscle action potential (CMAP), hyperpolarization elicited a significant, charge-dependent, decrease in the conditioned CMAP size. Hyperpolarization with 4 mC elicited CMAPs that were 86.76 +/- 5.22% (mean +/- SEM) of the control unconditioned response (P < 0.05). Analysis of individual MMN nerves showed that polarizing currents elicited markedly heterogeneous effects: depending on the nerve tested, depolarization or hyperpolarization in most cases significantly improved conduction along motor fibres across the conduction block. In three MMN nerves, pathophysiological abnormalities were consistent with a hyperpolarizing block, in two with a depolarizing block, and in one with a mixed block. Our observations indicate that the pathophysiological abnormalities at the site of conduction block in MMN may arise from depolarization or hyperpolarization, probably depending on the course of disease.

Progressive brachial and lumbosacral radiculoplexopathies are well known, though infrequent, delayed complications of local irradiation. They present as slowly progressive, generally bilateral but asymmetric, limb weakness mainly affecting distal muscles. The pathogenesis is unknown although some authors supposed an autoimmune process or radio-induced DNA changes. No treatment for this disease is currently available even if some benefits, though transient, have been reported after steroid treatment and more recently, high-dose immunoglobulins (IVIg), suggesting a possible immune-mediated pathogenesis. We previously reported on the beneficial effect of immunotherapies in two patients with postirradiation motor radiculoplexopathy. The first patient had a severe motor lumbosacral radiculoplexopathy starting 20 years after local radiotherapy for seminoma. He became able to walk and run with less waddling and to climb stairs without support after treatment with high-dose intravenous steroids. The other patient had severe left brachial and bilateral lumbosacral plexopathies presenting 12 years after toracoascellar and lumbar irradiation for a Hodgkin lymphoma. She improved her right leg strength after one course of IVIg. After one year of continuous steroid therapy the first patient started to progressively deteriorate notwithstanding the subsequent administration of IVIg, resumed courses of steroids, plasma exchanges and azathioprine. The second patient, after one year of continuous IVIg treatment which led to stabilization without further improvement, was treated with high-dose intravenous steroids and plasma exchange, with a marginal and transient amelioration followed by progressive worsening that was not halted by the resumption of IVIg. Both patients now suspended any therapy. In conclusion, in both our patients, immune therapies only induced a transient and short-term benefit but did not affect the overall progression of the disease. These findings suggest that even if an immune or inflammatory component, possibly triggered by radiation, may be present in this condition, it does not probably represent the bulk of the pathological process.

Antibodies to different neural antigens have been reported in patients with dysimmune neuropathies but their pathogenetic role in these diseases is still debated. In order to identify other possible protein target antigens in these diseases we tested by immunoblot IgG and IgM reactivity with human cauda equina and spinal cord in the sera from 30 patients with Guillain-Barre syndrome (GBS), 14 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and 11 with multifocal motor neuropathy (MMN). As controls we examined sera from 11 patients with amyotrophic lateral sclerosis (ALS), 68 with other neurological and non-neurological diseases (OND) and 28 normal subjects. We found high titers (>1/800) of IgG antibodies to some protein bands of the approximate molecular weight (MW) of 45–50 kDa in spinal cord but not cauda equina, in 20 patients (67%) with GBS, and 1 each with MMN and CIDP (9% and 7%, respectively)(GBS vs. MMN/CIDP p

We tested autoantibodies to neurofascin-186 (NF186) and gliomedin in sera from patients with multifocal motor neuropathy (MMN, n=53) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=95) by ELISA. IgG antibodies to NF186 or gliomedin were found in 62% of MMN and 1% of CIDP sera, and IgM antibodies to the same antigens in 12% of MMN and 1% of CIDP sera. These autoantibodies activated complement. Ten percent of the MMN sera without IgM anti-GM1 reactivity had anti-NF186 antibodies. Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN.

The association of neuropathy with monoclonal gammopathy has been known for several years, even if the nosological position of these neuropathies is still debated. Similarly unsettled is the pathogenetic role and diagnostic relevance in clinical practice of the antineural antibodies frequently associated with monoclonal gammopathies of undetermined significance of IgM isotype, as well as the most effective therapy (if any) to be used in these patients. Over the past 12 months these issues have been addressed in several papers whose results will be critically reviewed here.

Background: Miller Fisher syndrome (MFS), a variant of the Guillain-Barre syndrome, is associated with the presence of neuromuscular blocking antibodies, some of which may be directed at the ganglioside GQ1b. Materials and Methods: The authors investigated the in vitro effects of serum and purified immunoglobulin (Ig) G in a total of 11 patients with typical MFS during active disease, and in three of those patients after recovery. From one patient’s serum, we prepared an IgG fraction enriched in anti-GQ1b antibodies by affinity chromatography. For combined pre- and postsynaptic analysis, endplate currents were recorded by a perfused macro-patch clamp electrode. Postsynaptic nicotinic acetylcholine receptor channels were investigated by an outside-out patch clamp technique in cultured mouse myotubes. Results: AllMFS-sera depressed evoked quantal release and reduced the amplitude of postsynaptic currents. Five of the 11 sera were additionally examined by outside-out patch clamp analysis and caused a concentration-dependent and reversible decrease in acetylcholine-induced currents. The time course of activation and desensitization of nicotinic acetylcholine receptor channels was not altered by MFS-IgG. Nine patients (82 %) were positive for anti-GQ1b antibodies in ELISA and dot–blot. The enriched anti-GQ1b antibody fraction had a similar effect as whole serum. After recovery from MFS, blocking activity was lost and sera originally positive for anti-GQ1b antibodies became negative. Conclusion: Circulating IgG antibodies induce both pre- and postsynaptic blockade and may play a pathogenic role in acute MFS.

We correlated the clinical features of 78 patients with Guillain-Barré syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P

Neuropathy has been frequently reported in patients with IgG monoclonal gammopathy of undetermined significance (MGUS) but it is still unclear whether this association has clinical or pathogenetic relevance. In order to clarify the possible role of IgG MGUS in the neuropathy we correlated the clinical and electrophysiological features of the neuropathy with the duration and anti-neural activity of the M-protein in 17 patients with neuropathy and IgG MGUS. Ten patients (59%) had a chronic demyelinating neuropathy clinically indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) while 7 (41%) had a predominantly sensory axonal or mixed neuropathy. In 80% of patients in the CIDP-like and 28% in the sensory group the IgG M-protein became manifest several months to years after onset of the neuropathy. Antibodies to one or more neural antigens (including tubulin, a 35KD P0-like nerve myelin glycoprotein, GD1a, GM1 and chondrotin sulfate C) were found in 40% of patients with CIDP-like and 43% with sensory neuropathy but also in 37% patients with IgG MGUS without neuropathy. Neuropathy associated with IgG MGUS is probably less heterogeneous than previously considered suggesting that this association may not be merely casual. The evidence for primary pathogenetic role of IgG M-proteins in the neuropathy remains however elusive.

Recent studies showed that rituximab, a chimeric anti-CD20 monoclonal antibody, reduces antibody levels and ameliorates neuropathy in two thirds of patients with neuropathy and anti-myelin-associated glycoprotein (MAG) monoclonal IgM.1–3 Few data are available on the long-term effects of this therapy.4 We report on the long-term follow-up of rituximab responders with anti-MAG polyneuropathy. ### Methods. Ten patients with anti-MAG polyneuropathy responding to rituximab, 375 mg/sq for four consecutive weekly infusions, were prospectively studied for 36 months. The effects of the initial treatment in 13 patients and the type of assessment were previously described.3 The baseline clinical and laboratory data of the 10 responding patients are reported in the table. All but one patient (no. 1) had an IgM monoclonal gammopathy of undetermined significance and a symptom duration of up to 2 years. Three patients had not been previously treated for the neuropathy, whereas seven were unresponsive to immune or cytostatic therapies. We considered as responders patients who improved at month 12 by at least one point in two clinical scales including MRC sumscore (appendix e-1 on the Neurology ® Web site at www.neurology.org), INCAT Disability Scale (appendix e-2), and INCAT sensory sumscore (ISS) …

We studied the frequency, fine specificity and clinical correlate of anti-GQ1b IgG and IgM antibodies in 216 patients with neuropathy including three with Miller Fisher syndrome (MFS), 73 with Guillain-Barre syndrome (GBS), 99 with neuropathy associated with IgM monoclonal gammopathy (PN+IgM) and 41 with other neuropathies, and compared the data with 92 disease or normal controls. We found high (>1/100) anti-GQ1b IgG titers in all three MFS patients and in two GBS patients (2.7%) with ophthalmoplegia and ataxia, while high anti-GQ1b IgM were only found in two patients with a chronic demyelinating sensorimotor neuropathy associated with IgMkappa monoclonal gammopathy (2%). By overlay HPTLC, IgG antibodies in MFS and GBS either selectively reacted with GQ1b or also bound to GD3, and less intensely to GD1b, while IgM antibodies from both patients with PN+IgM also strongly reacted with GD1b and, in one, with GD3 and GT1b. The constant association of anti-GQ1b antibodies with dysimmune neuropathies and the correlation between their isotype, fine specificity and clinical presentation, support a possible pathogenetic link between these antibodies and the neuropathy.

Pain is a subjective condition that cannot be objectively measured; for this reason, self patient-perspective is crucial. Recently, several screening tools to discriminate between nociceptive and neuropathic pain have been developed. We aimed at assessing the consistence and discrepancy of two widely used screening tools, The Douleur Neuropathique 4 (DN4) and the 6-item questionnaire (ID-Pain), by comparing their ability in discriminating neuropathic from nociceptive pain. DN4 and ID-Pain were administered to 392 Italian patients attending 16 outpatient services for peripheral nerve diseases. Based on medical history, clinical findings and diagnostic tools, patients were divided into two groups (neuropathic and nociceptive). Globally, ID-Pain identified neuropathic pain in 60 % of patients (38 % probable, 22 % likely). Interestingly also DN4 diagnosed neuropathic pain in 60 % of cases. A discrepancy was observed in 16 % of cases. DN4 and ID-Pain resulted to be highly interrelated in the identification of neuropathic pain. Sensitivity of DN4 was 82 % and specificity was 81 %, while ID-Pain (considering both probable and likely groups) showed sensitivity 78 % and specificity 74 %. Reliable screening tools for neuropathic pain are well related between them; hence, they are available for researchers and clinicians who may choose the most appropriate for their activity. Since the gold standard for the diagnosis and treatment of neuropathic pain cannot do without a neurological evaluation, perhaps DN4, that includes physician objective measures, may help reducing the percentage of dubious cases. Conversely, when needing a more agile tool (not needing a physician) ID-Pain may be adopted.

Gangliosides are normal constituent of mammalian vertebrate cell membranes and are particularly abundant in the central and peripheral nervous systems. The biological effects of exogenously administered gangliosides have been extensively investigated in vitro and in experimental animal models where they have neuronotrophic and neuritogenic properties. Despite these findings there is still little evidence that treatment with parenteral gangliosides in humans can be effective in peripheral neuropathies or other neuromuscular diseases. The initial preliminary reports on the positive effects of GM1 in cerebrovascular diseases and spinal cord injury need to be confirmed in larger controlled trials. At the same time the occasional development of an acute motor neuropathy clinically presenting as the Guillain-Barré syndrome and associated with high titres of anti-ganglioside antibodies highlights the risks of their widespread use before more consistent data on their efficacy become available.

A 57-year-old woman presented with metastatic renal cell carcinoma (RCC). She was enrolled in a clinical study, in which she received two cycles of neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy. Her primary tumor and rib metastasis showed a good response to neoadjuvant therapy; however, after surgery, the patient developed neurologic symptoms, including flaccid paraparesis with paresthesia and hypoesthesia. MRI of the brain and spine revealed a leptomeningeal lesion at the T12-L1 space, which was presumed to have progressed during the 3-week treatment-free perioperative period. The patient underwent radiation therapy for the intramedullary lesion 1 month later, and sunitinib therapy was subsequently reinstated. After 6 months, her extracranial lesions remained stable and the intramedullary lesion was undetectable on MRI.CT of the chest and abdomen, bone scan, kidney and liver function tests, measurement of serum levels of calcium, electrolytes and lactate dehydrogenase, CBC, MRI of the brain and spine.Progression of a central nervous system metastasis linked to the interruption of neoadjuvant sunitinib therapy.Neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy for the primary RCC; radiation therapy for the intramedullary lesion, followed by reinstatement of sunitinib therapy owing to a good clinical response observed in the extracranial lesions.

We evaluated serum glial fibrillary acidic protein (GFAP) levels by enzyme-linked immunosorbent assay (ELISA) in controls (n = 30) and in patients with chronic sensory-motor axonal neuropathy (CSMAN) (n = 30), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 30), multifocal motor neuropathy (MMN) (n = 30), and primary muscular spinal atrophy (PMSA) (n = 15). GFAP levels, expressed as optical density, were increased in CSMAN (median = 1.05) compared to controls (median = 0.41; P0.05) and CIDP (median = 0.53, P0.05). They were also increased in PMSA (median = 0.99) compared to controls (P0.05) and MMN (median = 0.66; P0.05). To differentiate CSMAN from CIDP and PMSA from MMN, we applied a cutoff of GFAP levels at 0.66, and we obtained good sensitivity and specificity. In neuropathies, serum GFAP correlated with summated sensory nerve action potential amplitudes (r = -0.57; P = 0.0006) and disease severity (r = 0.37; P = 0.0011). Thus, we propose serum GFAP as a marker of axonal damage and severity in chronic neuropathies.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

Antibodies against several neural antigens have been associated with different chronic immune-mediated neuropathies but their practical clinical relevance remains unclear. To determine the possible diagnostic usefulness of these antibodies we reviewed the clinical correlate of IgM antibodies to the myelin-associated glycoprotein (MAG), sulfatide, the gangliosides GM1, GM2, GD1a and GD1b in 539 consecutive patients examined for neuropathy or related diseases in our Neuropathy Clinics and tested for these antibodies in our laboratory since 1985. 302 patients (56%) had an established diagnosis of definite or possible chronic immune-mediated neuropathy while 237 had a neuropathy of non-immune-mediated origin or of unknown aetiology or a closely related disease. Antibodies to one or more antigen were more frequent (chi(2)=63.32; p

An Italian multigenerational family with four members affected by an axonal Charcot-Marie-Tooth type 2D (CMT-2D) or distal spinal muscular atrophy (dSMA) phenotype with upper limb predominance, variable age at onset, degree of disability, and autosomal dominant inheritance is reported. A novel heterozygous missense GARS gene mutation (D500N) was identified.

We studied 14 patients with neurological manifestations of subacute combined degeneration (SCD) and 40 control patients not cobalamin (Cbl)-deficient. The cerebrospinal fluid (CSF) markers of Cbl deficiency (Cbl and total homocysteine [tHCYS] levels) and the CSF levels of tumor necrosis factor (TNF)-alpha and epidermal growth factor (EGF) were measured. Significantly higher levels of tHCYS and TNF-alpha, and significantly lower levels of Cbl and EGF were found in the SCD patients. In human CSF, as in human serum and the rat central nervous system, decreased Cbl concentrations are concomitant with an increase in TNF-alpha and a decrease in EGF-levels. Ann Neurol 2004;56:886-890.

A nti-GM 2 IgM antibodies have been reported in some patients with dysimmune neuropathy or lower motor neuron syndrome. To determine whether these antibodies can induce complement-dependent cytolysis we performed a cytotoxicity assay on neuroblastoma cells with sera from seven patients with demyelinating dysimmune neuropathies and high titers of anti-GM 2 IgM. As controls we used sera from seven patients with other anti-neural reactivities, six with the same neuropathies but no anti-GM 2 or other anti-neural reactivity and from eight normal subjects. Of the seven positive sera tested, six induced complement-mediated cytotoxicity, while none of the controls had any relevant effect on neuroblastoma cells. Preincubation of positive sera with purified GM 2 removed cytotoxic activity. Affinity purified anti-GM 2 IgM had the same cytotoxic effect of whole serum while serum or complement alone did not have any effect. In four anti-GM 2 -positive patients the percentage of cell lysis correlated with anti-GM 2 titers and with IgM staining of neuroblastoma cells while in two the cytotoxic effect was higher than expected from antibody titers. Complement-mediated cell lysis induced by anti-GM 2 IgM antibodies may be a possible mechanism of neural damage in patients with dysimmune neuropathy and high titers of anti-GM 2 IgM antibodies.

Anti-sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti-sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme-linked immunosorbent assay (ELISA), 11 had high anti-sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti-sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicate that high anti-sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.

Anti-GM2 IgM antibodies have been reported in some patients with dysimmune neuropathy or lower motor neuron syndrome, in whom they were often associated with a concomitant reactivity with GM1. To investigate the possible clinical and pathogenetic relevance of these antibodies we measured serum anti-GM2 IgM titers by ELISA in 224 patients with different neuropathies and motor neuron disease and examined their binding to SK-N-SH neuroblastoma cells by indirect immunofluorescence (IIF). High titers of anti-GM2 IgM antibodies were found in eight patients with dysimmune neuropathies including two with multifocal motor neuropathy (MMN), two with purely motor demyelinating neuropathy without conduction block (MN) and four with Guillain-Barre syndrome (GBS). In two MMN patients reactivity with GM2 was associated with anti-GM1 reactivity and in one MN patient with anti-GM1, -GD1a and -GD1b reactivity. All but one patient had a concomitant reactivity with GalNAc-GD1a. Serum IgM from all positive patients intensely stained by IIF the surface of SK-N-SH neuroblastoma cells. This reactivity was blocked by serum pre-incubation with GM2, was not observed with sera from patients without anti-GM2 antibodies including those with high anti-GM1 or other anti-glycolipid antibodies, and correlated with the presence of GM2 in the SK-N-SH neuroblastoma cells. These findings indicate that anti-GM2 antibodies, though infrequent, are strictly associated with dysimmune neuropathies and suggest that SK-N-SH neuroblastoma cells can be a suitable in vitro model to study the functional and biological effects of these antibodies.

Peripheral neuropathy (PN) is a frequent complication during primary macroglobulinemia (PM), whose immunological genesis has been suggested by various authors. This study involved 65 PM patients (44 men and 21 women aged 35-78), diagnostically divided into MGUS (31 cases), and indolent (IWM, 24 cases) or symptomatic (WM, 10 cases) Waldenstrom macroglobulinemia groups. All patients underwent neurological examination, including electrodiagnostic evaluation and the determination of the serum titre of antimyelin-associated glycoprotein (MAG). An evaluation was made of the prevalence of PN and its correlation with a series of hematological variables. The prevalence of PN was 31.6%: of those with PN, 73.1% manifested both clinical and electrophysiological signs of PN, primarily of the demyelinating type. Significant correlations emerged between the presence of PN and sex (M vs. F P = 0.0001), advanced age (P = 0.049), low MC levels (P = 0.025), high anti-MAG titres (P = 0.001) and high Hb levels (P = 0.001). No significant correlation with the diagnostic definition of PM was found, although the majority of cases with (particularly demyelinating) PN were MGUS or IWM. At multivariate analysis, the presence of PN significantly correlated with sex (P = 0.0001), age (P = 0.019), and anti-MAG titre (P = 0.001). Ten of the 26 PN cases showed no MAG reactivity. Significant correlations between PN and low serum MC levels/high MAG reactivity support the hypothesis of the antibody-mediated origin of many PN, and that the presence of PN depends on the characteristics of the proliferating pathological B clone, rather than on the tumor burden of the form of macroglobulinemia. Clinically, our data reconfirm the frequency of PN during PM and indicate simple clinicohematological variables useful for identifying patients at high neuropathic risk.

Article abstract-We treated five consecutive patients with multifocal motor neuropathy (MMN) with high-dose intravenous immunoglobulin (IVIg). Four patients had increased levels of anti-asialo-GM, IgM and two of anti-GM, IgM as well; one patient had no reactivity. We treated them twice with 0.4 g/kg IVIg for 5 consecutive days at a 2month interval, followed by maintenance infusions up to 6 to 12 months. All patients with high anti-asialo-GM, had a consistent clinical improvement starting 3 to 10 days after the first IVIg course; in one patient, recovery was complete and persistent for 12 months without additional treatment, while in three patients, improvement only lasted 20 to 30 days. There was a similar improvement in these patients after the second course of Mg which was maintained by periodic 2-day IVIg infusions. Clinical improvement in these patients was associated with a reduction of conduction block in most, but not all, motor nerves, while antibody titers were not consistently modified by treatment. There was no clinical or electrophysiologic improvement in the patient without antiglycolipid activity after 6 months of Mg. IVIg may be a safe and effective therapy for MMN. NEUROLOGY 1993;43:537-544 Multifocal motor neuropathy (MMN) is characterized by a progressive, predominantly distal, asymmetric limb weakness with conduction block (CB) on motor but not sensory nerves.’-1° High levels of serum antibodies to the ganglioside GM, or to asialo-GM,, or both, may be present in these patient~,’-~,~ and in some, improvement was associated with a decrease of anti-GM, levels,2J1 suggesting that the disease may be immune mediated. Patients with MMN do not usually respond to which may occasionally worsen symptoms (M. Donaghy, unpublished observation), or to plasma e~change,~.~Jl but they often improve with high-dose intravenous cyclophosphamide (3 g/m2 in 8 day~).~.~Jl This treatment, however, has relevant side effects12J3 and may be unsuitable for the less severely affected patients. High-dose intravenous immunoglobulin (IVIg) therapy has been reported to be effective in some dysimmune neuropathies, including Guillain-Barre syndromeI4 and chronic inflammatory demyelinating polyneuropathy (CIDP),15-20 where improvement was associated with reduction of CB.21 We treated five patients with MMN with IVIg therapy for 6 to 12 months. All patients were mildly-to-moderately affected and did not receive additional therapies for the

Chondroitin Sulfate C (ChS-C), is a glycosaminoglycan present in the membranes of neurons and axons. Anti-ChS-C IgM antibodies have been reported in patients with predominantly sensory neuropathy (PN) often associated with IgM monoclonal gammopathy, but also in some neurological controls. In order to evaluate the frequency and clinical correlate of anti-ChS-C IgM antibodies, we tested them by a new Covalink ELISA technique in sera from 206 patients with IgM monoclonal gammopathy including 79 with PN (PN+IgM) with unknown IgM reactivity, 65 with PN with antibodies to the myelin-associated glycoprotein and 62 without PN, and from 33 patients with PN of other causes, 30 with other neurological and non-neurological diseases and 23 normal subjects. We only found high titers of anti-ChS-C IgM in two patients (1/128,000 and 1/256,000 respectively) with IgM monoclonal gammopathy: one had Waldenstrom Macroglobulinemia diagnosed seven years before and a 3 year history of slowly progressive limb weakness, finger paresthesias, unsteady gait and occasional nocturnal cramps. Neurological examination revealed a predominantly large-fiber sensory neuropathy with mild distal atrophy and weakness in upper and lower limbs. Electrophysiological and morphological studies were suggestive of a predominantly demyelinating neuropathy. The other patient had IgM MGUS without PN at the time of antibody testing but developed finger paresthesias seven years later, when he had decreased position sense and abnormal sensory nerve conduction studies. In conclusion high titers of anti-ChS-C IgM, though infrequent, were always associated with the presence or development of sensory PN in patients with IgM M-protein, supporting a possible role for these antibodies in the neuropathy.

Antecedent gastrointestinal or respiratory infections are frequently reported in GBS patients where they have been often attributed to Campylobacter jejuni (CJ), Cytomegalovirus (CMV) or Ebstain-Barr virus (EBV). In order to determine the relative risk (RR) for the development of GBS of anamnestic and/or serological evidence of an antecedent infection we analysed the anamnestic data and sera of 47 GBS patients, 45 neurological controls (NC) and 44 non-neurological controls (NNC) in a prospective case-control study in northern Italy. After receiving an informed consent, we analysed the preceding events reported by GBS patients and controls within 2 months before the onset of the neurological or non-neurological disease leading to admission in the hospital by a questionnaire administered to each subject. Patients' sera were then screened by ELISA for reactivity with CJ, CMV, EBV, Herpes simplex virus (HSV), Mycoplasma Pneumoniae, Hepatitis A, B, C and HIV. The analysis of the questionnaires revealed that 9 GBS patients (19%) have had diarrhea compared to 3 NC and 3 NNC (7% each) (GBS vs. NC/NNC p < 0.05; RR 3.35). By ELISA only 2 of 47 GBS patients (4%), both with diarrhea (22% of GBS patients with diarrhea), and 1 (without diarrhea) of 89 NC and NNC had anti-CJ IgG antibodies (RR: 3.91). An antecedent respiratory tract infection was reported by 32 GBS (68%), 16 NC and 16 NNC (35% and 36%, respectively) (GBS vs. NC/NNC p < 0.05; RR: 3.8). Serological data revealed that 28% and 30% of GBS had anti-CMV and anti-HSV IgM antibodies, respectively, in the acute sera compared to 4% and 11% of controls (p < 0.005 and

In an unselected series of patients with monoclonal gammopathy of undetermined significance (MGUS) we found neuropathy in 2 of 34 patients with IgG (6%), 2 of 14 with IgA (14%), and 8 of 26 with IgM MGUS (31%). The neuropathy was subclinical in 6 patients (1 IgG, 1 IgA, and 4 IgM). Patients with IgG or IgA MGUS had a prominent motor impairment with electrophysiologic and morphologic findings suggestive of predominant axonal degeneration. No deposit of the M-protein in sural nerve and no reactivity of the M-protein with nerve was detected in these patients. Patients with IgM MGUS had a prominent sensory impairment with evidence of predominant demyelination. In 6 of these patients the M-protein reacted with the myelin-associated glycoprotein (MAG). The higher prevalence of neuropathy in patients with IgM MGUS may be related to the frequent reactivity of IgM M-proteins with MAG.

We found anti-GM1 IgM antibodies in 23% of 56 patients with motor neuron disease (MND), in 19% of 69 patients with neuropathy, and in 7% of 107 controls with other neurologic and nonneurologic diseases. Most of these patients had anti-GM1 IgM antibody titers of 1:80 or less; slightly higher antibody titers (up to 1:640) were found in 3 patients, 1 with MND and 2 with neuropathy, and very high titers (1:20,480) in a patient with MND and an IgMμ: M protein that reacted with GM1, GD1b, and asialo GM1 Six other patients with anti-GM1 IgM had serum IgM that also bound to GD1b. Reactivity with GD1b did not correlate with anti-GM1 titers but was only present in patients with MND or neuropathy. Anti-GM1 IgM antibodies may be a normal constituent of the human antibody repertoire but their frequency and, in some cases, their levels are higher in patients with MND and neuropathy. The origin and the pathogenetic role of these antibodies in neural impairment remain to be established.

Despite long-lasting use, several features of thalidomide neurotoxicity have yet to be resolved. A more detailed knowledge of thalidomide-induced sensory neurotoxicity is desirable, particularly in view of the future use of thalidomide derivatives which are currently under investigation. Our study demonstrates that thalidomide sensory neurotoxicity is cumulative dose-dependent, but this effect is evident only when the dose is relatively high (in our study >20 g). In fact, the risk of developing sensory neuropathy is low (around 10%) below this threshold, while it steadily increases with increasing cumulative doses. In our series, a discrepancy between clinical and neurophysiological results was frequent when a low cumulative dose of thalidomide was administered. Regarding the need for thalidomide withdrawal at the onset of any evidence of peripheral neuropathy, we followed up the course of seven patients who were clinically and neurophysiologically normal at baseline, but had treatment-induced neurotoxicity and a very severe change in their SAPs. In all these cases the thalidomide dose was reduced and no clinically-relevant worsening was observed despite a further marked reduction in their SAPs. This finding suggests that thalidomide withdrawal is not mandatory even in the presence of marked abnormalities in sensory neurophysiological parameters, provided that an accurate clinical follow-up is guaranteed and the dose is adjusted.

Painful sensory neuropathies consist of a wide range of neuropathies that can involve large as well as small nerve fibres. Even if most cases remain of unknown cause, some of them may be associated with an underlying disorder such as diabetes, HIV, infections, amyloidosis, and Sjogren's syndrome. Since in some cases an autoimmune mechanism has been postulated, we investigated a panel of circulating autoantibodies including anti-gliadin (AGA), anti-endomysium (EmA), anti-transglutaminase (tTGA) and anti-nuclear (ANA) antibodies in the sera of patients with unexplained painful sensory neuropathies in order to identify other potentially treatable disorders. We tested the sera of 10 patients (4M; 6F) previously investigated for other causes of neuropathies, including anti-nerve, onconeural, anti-extractable nuclear, anti-neutrophil cytoplasmic, anti-thyroglobulin (TgA) and anti-peroxidase (TPOA) antibodies. We found the presence of AGA positivity in 4 patients (40%), ANA in 7 (70%) and AGA + ANA in 4 (40%), two of whom were negative for celiac disease by gastrointestinal biopsy. None of the patients had EmA positivity. Three (30%) had TgA and TPOA and none had anti-nerve or onconeural antibodies. Whether the presence of circulating autoantibodies in patients with unexplained painful neuropathy reflects an autoimmune involvement which may be amenable to immune therapy and not only to symptomatic treatment remains to be established.

POEMS syndrome is a rare disorder characterized by the combination of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. The pathogenesis of this multisystemic disease is not known. Recently, an association with high levels of serum VEGF (vascular endothelial growth factor), a multifunctional cytokine that induces angiogenesis and microvascular hyperpermeability, has been reported. Both VEGF and erythropoietin (EPO), an acidic glycoprotein hormone that also promotes endothelial proliferation, are under the control of a transcription factor called hypoxia-inducible factor (HIF). To determine whether these angiogenic factors may have a pathogenic role in POEMS, we longitudinally evaluated VEGF and EPO serum concentrations by ELISA in ten patients during the clinical course and in relation to the therapy response. All patients had initially high levels of VEGF and low EPO concentration and there was an inverse correlation between VEGF and EPO levels during the disease progression. We have also analyzed sural nerve biopsies of seven POEMS patients. The presence of VEGF/VEGF-R and EPO/EPO-R immunostaining in the endoneurial and perineurial vessels has been shown, as well as in some of the non-myelin forming Schwann cells identified as glial fibrillary acidic protein (GFAP) positive cells.

Anti-sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti-sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme-linked immunosorbent assay (ELISA), 11 had high anti-sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti-sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicates that high anti-sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.

Multifocal motor neuropathy (MMN) is characterized by progressive asymmetric limb weakness usually predominant in the upper limbs associated with conduction block (CB) in motor but not sensory nerves. There are, however, occasional patients with clinically typical MMN in whom no CB can be detected. Whether these patients differ from patients with MMN and CB remains unclear. Since 1991, we have observed 24 patients with the typical clinical features of MMN. In 20 of them (14 men and 6 women), electrophysiological studies disclosed the presence of CB in at least one motor nerve. In four (all women), no evidence of CB could be detected in examined nerves even if three had some features of demyelination, including asymmetric reduction of motor conduction velocities (1 patient) or prolonged or absent F wave latencies (3 patients). Three of them had markedly reduced or absent proximal and distal CMAP amplitudes in some nerves. The mean age of onset of MMN was similar in patients with (41.5 years, range 21–70) and without CB (41.5 years, range 24–57). The mean duration of the disease at the time of our first visit was longer in patients without CB (18.5 years, range 13–25) than in those with CB (6.3 years, 3 months–25 years); only 3 patients with CB had a duration of the disease longer than 10 years. All patients without CB had a predominant or exclusive impairment of upper limbs compared with 18 (90%) of those with CB. The mean Rankin score before therapy was slightly worse in patients without (2.5) than with (2.2) CB. Anti-ganglioside antibodies were found in 1 patient without CB (25%) and in 8 (40%) with CB. All but 2 patients with CB (90%) consistently improved with IVIg. All patients without CB also improved with IVIg, but only one did so consistently. In conclusion, patients with the typical clinical presentation of MMN but no overt CB are clinically and immunologically indistinguishable from those with MMN and CB. The longer duration of the disease and frequent axonal impairment in patients without CB may explain the lower efficacy of IVIg in these patients than in those with CB.

A 58 y.o. man was admitted to our hospital because of severe progressive untreatable radicular pain, limb weakness, and cranial nerve palsies. The patient was well until 2 years before, when he developed progressive perineal sensory loss with impotence. Two months later, he complained of pain in the right foot only partially responding to NSAIDs. A lumbosacral MRI showed a spinal stenosis and multiple lumbar discopathy. During the following year he developed right foot and left arm burning paresthesia only responsive to oral opiates, left facial nerve palsy, right foot drop, arm weakness partially responding to oral steroids, and cyclophosphamide. CSF and electrophysiological studies were consistent with an inflammatory multiple radiculoneuropathy while blood tests, bone scintigraphy, and abdominal echography were normal. Four months before admission, he developed right wrist drop, painful dysesthesia in the left hemithorax, and diplopia. On admission, neurologic examination revealed left oculomotor and facial nerve palsies, distal>proximal weakness in the extensor muscles of the right arm, right foot drop, superficial and deep sensory loss on the right leg, and ubiquitary absent deep tendon reflexes. Four additional spinal taps revealed markedly increased proteins with slightly increased cells (always below 10/mm3) but no tumor cell. Nerve conduction studies were consistent with multiple radiculoneuropathy, while sural nerve biopsy showed an axonal neuropathy. Bone marrow biopsy, chest and abdominal CT, and endoscopy of the gastrointestinal tract were negative for neoplastic lesions. A brain and cervical MRI revealed multiple gadolinium enhancing hyperlucencies in the thalamus, caudate nucleus, and spinal cord. The patient was treated with intravenous steroids and IVIg with no response and with opiates for severe pain. One month later, the patient developed deep vein thrombosis treated with anticoagulants followed four days later by a fatal massive intracranial hemorrhage. Autoptic studies revealed a widespread non-Hodgkin's type B lymphoblastic centrocitic lymphoma involving the stomach, liver, lung, thyroid, spleen, cauda equina, brain, and the spinal cord. This report draws attention to the unusual presentation of a lymphoproliferative disease that escaped an extensive diagnostic evaluation during life.

A delayed progressive impairment of peripheral nervous system including brachial and lumbosacral radiculoplexopathy is a well-known complication of local radiotherapy. No treatment for this infrequent complication is currently available. Recently, improvement after treatment with high dose immunoglobulin (IVIg) has been reported in some patients, suggesting either an immune-mediated inflammatory nerve damage induced by irradiation or a dysimmune neuropathy (CIDP-like) misdiagnosed as a postirradiation disease. We report on two patients who developed motor lumbosacral radiculoplexopathy several years after local radiotherapy. The first patient (ZA) is a 49 y.o. man developing a progressive proximal>distal weakness and hypotrophy of lower limbs, 20 years after radiotherapy of lumbosacral region for seminoma. Electrophysiological studies showed markedly reduced motor conduction velocities (CV) and prolonged F-wave latencies in lower limb nerves. The second patient (BF), is a 52 y.o. woman who developed progressive left brachial plexopathy and distal>proximal weakness and hypotrophy of lower limbs 12 years after a first course of toracoascellar and lumbar irradiation for Hodgkin lymphoma followed by a second course of cervicoclavicular irradiation for tumor recurrence 7 years later. Electrophysiological studies showed markedly reduced CMAP amplitudes and proportionally reduced CV in motor nerves. No sensory impairment was detected in both patients. CSF protein was elevated in both patients while cells were normal. On the assumption of a possible dysimmune origin of the disease, patient ZA underwent high dose intravenous steroid treatment, while patient BF, who had previously deteriorated after steroids, was treated with IVIg. After treatment, patient ZA became able to walk with less waddling, to rise from the floor and climb stairs without support, and to run. Improvement was less consistent in patient BF, whose right leg strength improved even if she still needed bilateral support to walk. The improvement observed in both patients supports the hypothesis that, at least in some patients, an immune-mediated mechanism may underlie postirradiation radiculoplexopathy.

Anti-GQ1b IgG antibodies are detectable in patients with Miller-Fisher syndrome and related to the development of ophthalmoplegia. We report a 56-year-old woman who was admitted in our Hospital because of peripheral facial nerve diplegia, dysphagia, dysphonia, and areflexia two weeks after a mild upper respiratory infection with fever. Gait with superficial and deep sensation appeared normal. Her mental status was intact. CSF, EMG, and MRI of the cervical spinal cord were normal, while GQ1b antibodies (1:1600), were found in the serum. Starting by day 4 after admission, the patient was treated with six plasma-exchanges, over a three-week period. By day 9, facial nerve diplegia, dysphagia, and dysphonia started to improve. By day 35, there were no clinical deficits, and by day 45, deep tendon reflexes were elicitable again. Anti-GQ1b antibodies returned to the normal range (1:800) six months later. Plasma exchange was dramatically effective in the treatment of this patient. This clinical case shows that anti-GQ1b IgG antibodies may be detectable in acute demyelinating polyradiculoneuropathy with bulbar signs and without ataxia and ophthalmoplegia.