Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons.

AIMS: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. METHODS: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. RESULTS: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. CONCLUSION: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

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 1-42 days 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.

Anti-sulfatide/galactocerebroside antibodies in immunoglobulin M paraproteinemic neuropathies.

BACKGROUND AND PURPOSE: Anti-sulfatide antibodies have been observed in heterogeneous neuropathies and their clinical relevance is still controversial. Whether the combination of sulfatide with galactocerebroside would increase sensitivity or specificity of enzyme-linked immunosorbent assay testing compared to sulfatide alone was assessed. METHODS: Immunoglobulin M (IgM) antibodies to sulfatides, galactocerebroside and combined sulfatide and galactocerebroside (Sulf/GalC) were measured in 229 neuropathy patients, including 73 with IgM paraproteinemic neuropathy [62 with anti-myelin-associated glycoprotein (anti-MAG) antibody] and 156 with other neuropathies. Results from 27 patients with IgM monoclonal gammopathy without neuropathy and 28 healthy subjects served as control. RESULTS: Thirty-three patients showed increased titers of anti-sulfatide antibodies, 28 of whom had an IgM paraproteinemic neuropathy (P < 0.0001). When evaluating the reactivity for the combination Sulf/GalC, 57/229 patients were found to be positive, including 36/73 (49%) with IgM paraproteinemic neuropathy (P < 0.0001). Patients with known anti-sulfatide antibodies also showed anti-Sulf/GalC reactivity, with increased titers in 48.5% of the cases. Testing for anti-Sulf/GalC antibodies allowed 24 additional patients to be detected (eight with IgM paraproteinemic neuropathies), who had no reactivity to the individual glycolipids. Amongst the 11 subjects with IgM paraproteinemic neuropathy who were negative for anti-MAG antibodies, only two were reactive to sulfatide, whilst six (55%) were found to be positive when tested against the combination of sulfatide and galactocerebroside. CONCLUSIONS: Testing for both sulfatide and galactocerebroside in IgM paraproteinemic neuropathies seems to increase the sensitivity compared to anti-sulfatide antibodies alone (49% and 39%, respectively, with a slightly reduced specificity, from 97% to 87%), helping the characterization of otherwise undefined neuropathy that could benefit from immunomodulatory therapy.

The autonomic balance predicts cardiac responses after the first dose of fingolimod.

BACKGROUND: Predictive markers of cardiac side effects would be helpful for the stratification and individualized monitoring of multiple sclerosis (MS) patients prescribed with fingolimod. OBJECTIVE: To test whether the autonomic balance predicts a cardiac response after the first dose of fingolimod. METHODS: A total of 55 consecutive relapsing-remitting MS (RRMS) patients underwent 'head-up tilt', Valsalva maneuver, deep breathing and handgrip tests before their first dose of fingolimod. The normalized unit of the high frequency (HF) component (HF normalized units; HFnu), reflecting mostly vagal activity; and the low frequency (LF) component (LF normalized units; LFnu) reflecting mostly sympathetic activity, were considered for the analysis of heart rate (HR) variability. The patients' HR and electrocardiographic parameters ((the interval between P wave and ventricular depolarization (PR); the interval between Q and T waves (QT)) were recorded during 6-hour post-dose monitoring. RESULTS: We found significant correlations between measures of parasympathetic function and fingolimod-induced bradycardia. Subjects with higher Valsalva ratio and HR variation during deep breathing had, in fact, nadir HR ≤ 50 beats/minute (bpm) after the first fingolimod dose. Conversely, significant negative correlations were found between measures of sympathetic function and fingolimod-induced PR interval increase. Subjects with lower LFnu at rest and less increase of blood pressure on the handgrip test showed a PR interval increase > 20 ms after fingolimod. CONCLUSIONS: Assessing autonomic control of cardiovascular functions can be useful to predict cardiac effects after the first fingolimod dose.

Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy.

AIMS: DN4 (Douleur Neuropathique en 4 Questions) is a screening tool for neuropathic pain consisting of interview questions (DN4-interview) and physical tests. It has not formally been validated in diabetes. We evaluated the validity and diagnostic accuracy of DN4 and DN4-interview in identifying neuropathic pain of painful diabetic polyneuropathy. METHODS: In 158 patients with diabetes, the presence of diabetic polyneuropathy and neuropathic pain was assessed using scoring system for symptoms and signs, quantitative sensory testing, nerve conduction studies, pain history, numerical rating scale, and Short-Form McGill Pain Questionnaire. Painful diabetic polyneuropathy was defined as the presence of diabetic polyneuropathy plus chronic neuropathic pain in the same area as neuropathic deficits. A blinded investigator performed DN4. RESULTS: The DN4 score was significantly related to all the neurological and electrophysiological measurements and to Short-Form McGill Pain Questionnaire (ρ = 0.58, P < 0.0001). DN4 and DN4-interview scores showed a high diagnostic accuracy for painful diabetic polyneuropathy with areas under the receiver operating characteristic curve of 0.94 and 0.93, respectively. At the cut-off of 4, DN4 displayed sensitivity of 80%, specificity of 92%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 91%, and likelihood ratio for a positive result (LR(+) ) of 9.6. At the cut-off of 3, DN4-interview showed sensitivity and specificity of 84%, PPV of 71%, NPV of 92%, and LR(+) of 5.3. CONCLUSIONS: This is the first validation study of DN4 for painful diabetic polyneuropathy, which supports its usefulness as both a screening tool for neuropathic pain in diabetes and a reliable component of the diagnostic work up for painful diabetic polyneuropathy.

Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction.

OBJECTIVE: To validate nerve-axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria. METHODS: Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age-matched and sex-matched control group of 10 healthy people was also included. RESULTS: Significant correlations were observed between the neurovascular response at the foot and HDT (r(s) = -0.658; p<0.0001), NDS (r(s) = -0.665; p<0.0001), VPT (r(s) = -0.548; p = 0.0005), tibial nerve conduction velocity (r(s) = 0.631; p = 0.0002), sural nerve amplitude (r(s) = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy. CONCLUSION: Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

Ionic mechanisms underlying differential vulnerability to ischemia in striatal neurons.

Brain cells express extremely different sensitivity to ischemic insults. The reason for this differential vulnerability is still largely unknown. Here we discuss the ionic bases underlying the physiological responses to in vitro ischemia in two neostriatal neuronal subtypes exhibiting respectively high sensitivity and high resistance to energy deprivation. Vulnerable neostriatal neurons respond to ischemia with a membrane depolarization. This membrane depolarization mainly depends on the increased permeability to Na+ ions. In contrast, resistant neostriatal neurons respond to ischemia with a membrane hyperpolarization due to the opening of K+ channels. Interestingly, in both neuronal subtypes the ischemia-dependent membrane potential changes can be significantly enhanced or attenuated by a variety of pharmacological agents interfering with intracellular Ca2+ entry, ATP-dependent K+ channels opening, and Na+/Ca2+ exchanger functioning. The understanding of the ionic mechanisms underlying the differential membrane responses to ischemia represents the basis for the development of rational neuroprotective treatments during acute cerebrovascular insults.

Synaptic transmission in the striatum: from plasticity to neurodegeneration.

Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic-aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.

Glutamate-triggered events inducing corticostriatal long-term depression.

Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons.

Perceptual and conceptual components in implicit and explicit stem completion.

This study was aimed at investigating functional and neuropsychological dissociations between repetition priming and explicit memory tasks. The explicit and implicit versions of the stem completion task were administered to a group of amnesics and a group of control subjects. In Experiment 1 both the explicit and implicit stem completions were significantly higher when the same presentation modality was used for studying and testing than when a change in modality from studying to testing occurred. Amnesics had normal implicit and deficient explicit completion performance. Experiment 2 revealed an advantage of the semantic over the phonological condition only in the explicit task and only in control subjects. Amnesic patients completed the same percentage of words as normal subjects in the phonological and semantic conditions of the implicit task and in the phonological condition of the explicit task but were deficient in intentionally completing semantically processed words. Possible interpretations of these results are discussed according to theoretical models that distinguish memory tasks along an explicit-implicit dichotomy (multiple memory system theory) or along a perceptual-conceptual dichotomy (transfer-appropriate procedures approach), and alternative theoretical positions are evaluated regarding repetition priming and memory deficits in amnesic patients.

Recency effect in anterograde amnesia: evidence for distinct memory stores underlying enhanced retrieval of terminal items in immediate and delayed recall paradigms.

This study was devised to investigate immediate and delayed recency effects in anterograde amnesic patients. For this purpose, a word-list immediate recall paradigm and a modified version of the procedure devised by Baddeley and Hitch [Attention and Performance, Erlbaum, NJ, 1977] for eliciting the recency effect in delayed recall conditions was administered to a sample of amnesic patients and to a group of age-matched healthy subjects. Amnesics disclosed a fully normal recency effect in the immediate recall paradigm and a deficient recency effect in the delayed recall condition. These data, taken together with experimental evidence from a patient affected by a pure form of phonological short-term memory impairment [35], draw a double neuropsychological dissociation suggesting a differential origin for the two kinds of recency effects: a short-term memory output underlying enhanced recall of terminal items in immediate recall paradigms, and an ordinal retrieval strategy applied to long-term memory stored units at the root of the delayed recency effect.

Lexical and conceptual components of stem completion priming in patients with Alzheimer's disease.

This study evaluated the hypothesis of dissociation between normal lexical but deficient conceptual repetition priming in patients with Alzheimer's disease (AD). For this purpose, we administered to patients with AD and age-matched normal controls the Stem Completion task. In Experiment 1, the level of word processing during study was manipulated by requiring subjects to count vowels (graphemic condition) or generate meanings (semantic condition) of target words. In Experiment 2, the presentation modality was varied during the study to obtain an intramodal and crossmodal repetition priming. Probably due to a floor effect of performance in the graphemic condition, in Experiment 1, AD patients exhibited lower priming than normal controls for the semantically processed words but comparable priming for the graphemically processed ones. In contrast, in Experiment 2, AD patients were poorly primed both in the intra- and crossmodal conditions. Results question the hypothesis of a lexical/conceptual dissociation in the repetition priming exhibited by AD patients and call for other explicative hypotheses of the dissociation between normal and deficient forms of repetition priming in degenerative dementia.

Electrophysiology of the neuroprotective agent riluzole on striatal spiny neurons.

Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD). No effective treatment is available to limit neuronal death in this pathological condition. In an experimental model of HD, a beneficial effect has recently been reported by the neuroprotective agent riluzole. We performed intracellular recordings in order to characterize the electrophysiological effects of this compound on striatal spiny neurons. Riluzole (0.1-100 microM) affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. Bath application of this pharmacological agent produced a dose-dependent reduction of the number of spikes evoked by long-lasting depolarizing pulses. The EC50 value for this effect was 0.5 microM. Low doses of riluzole selectively reduced the firing frequency in the last part of the depolarizing pulse suggesting a use-dependent action at low concentrations of this compound. Riluzole produced a dose-dependent reduction of the amplitude of the corticostriatal glutamatergic excitatory post-synaptic potentials (EPSPs) with an extrapolated EC50 value of 6 microM. This effect was reversible and maximal at a concentration of 100 microM. Paired-pulse facilitation (PPF) was not affected by riluzole suggesting that the reduction of excitatory transmission was not only caused by a decrease of presynaptic release. Accordingly, riluzole also reduced the amplitude of membrane depolarization induced by exogenous glutamate. The modulatory action of riluzole on the activity of striatal spiny neurons might support the use of this drug in experimental models of excitotoxicity and in the neurodegenerative disorders involving the striatum.

An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons.

We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, these agents depressed in a dose-dependent and reversible manner the current-evoked repetitive firing discharge. These AEDs also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. However, substantial pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostriatal excitatory transmission. Concentrations of LTG and GBP effective in reducing EPSPs, in fact, produced only a slight inhibition of the firing activity of these cells. LTG, but not PHT and GBP, depressed cortically-evoked EPSPs increasing paired-pulse facilitation (PPF) of synaptic transmission, suggesting that a presynaptic site of action was implicated in the effect of this drug. Accordingly, PHT and GBP, but not LTG reduced the membrane depolarizations induced by exogenously-applied glutamate, suggesting that these drugs preferentially reduce postsynaptic sensitivity to glutamate released from corticostriatal terminals. These data indicate that in the striatum PHT, LTG and GBP decrease neuronal excitability by modulating multiple sites of action. The preferential modulation of excitatory synaptic transmission may represent the cellular substrate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia.

Modulation of gene expression following long-term synaptic depression in the striatum.

A number of behavioural and cellular studies have suggested that activity-dependent synaptic plasticity associated with learning and memory may lead to the expression of various genes whose protein products can play a critical role in memory acquisition and consolidation. Long-term potentiation (LTP) and long-term depression (LTD) represent two forms of synaptic plasticity which have been widely studied by electrophysiological techniques. However, the molecular mechanisms at target gene involved in the generation of long term depression remain to be determined. To elucidate the molecular mechanism underlying activity dependent synaptic remodeling in striatal long term depression, we used the mRNA differential display technology to isolate genes that are induced or modulated by high frequency stimulation of the corticostriatal pathway in a rat brain slice preparation. We have differentially displayed, by means of reverse transcriptase-polymerase chain reaction, mRNA species isolated from striatal slices in which long term depression was induced by tetanic stimuli as well as from slices stimulated at low frequency. We then compared radio-labeled RT-PCR banding patterns to isolate cDNAs that are differentially expressed. Three independent cDNAs were isolated and identified whose mRNA level were enhanced by tetanic stimulation inducing long term depression. We provide evidence that two of these genes encode proteins involved in synaptic vesicle trafficking (dynamin I and amphiphysin II). Moreover, expression of tissue plasminogen activator (t-PA) gene was also increased following striatal long term depression. Our data suggest that a complex pattern of genes acting at presynaptic level and extracellularly may be involved in LTD-associated synaptic remodeling.

Effects of motor cortex rTMS on lower urinary tract dysfunction in multiple sclerosis.

We tested the effects of 5-Hz rTMS over the motor cortex in multiple sclerosis (MS) subjects complaining of lower urinary tract symptoms either in the filling or voiding phase. Our data show that motor cortex stimulation for five consecutive days over two weeks ameliorates the voiding phase of the micturition cycle, suggesting that enhancing corticospinal tract excitability might be useful to ameliorate detrusor contraction and/or urethral sphincter relaxation in MS patients with bladder dysfunction.

Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis.

OBJECTIVE: To investigate whether repetitive transcranial magnetic stimulation (rTMS) can modify spasticity. METHODS: We used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting multiple sclerosis and lower limb spasticity. RESULTS: A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased corticospinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when the patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. CONCLUSIONS: Repetitive transcranial magnetic stimulation may improve spasticity in multiple sclerosis.

Subacute demyelinating polyneuropathy in B-cell lymphoma with IgM antibodies against glycolipid GD1b.

Peripheral neuropathy associated with IgM monoclonal gammopathy of unknown significance is a common disorder, while the association of paraproteinaemic neuropathies with haematological malignancies is far less frequent. We report a 76-year-old patient with a subacute and rapidly progressive sensorimotor demyelinating polyneuropathy causing sensory ataxia, painful paraesthesias and marked motor and sensory deficit in four limbs. Monoclonal gammopathy of IgM type associated with a rectal low-grade B-cell non-Hodgkin lymphoma was detected. Research for anti-MAG and antiganglioside autoantibodies including anti-GM1 and anti-GQ1b evidenced a high titre of IgM antibodies against the disialosyl group of GD1b. This is the first report on a paraproteinaemic polyneuropathy with IgM autoantibodies against glycolipid GD1b associated with B-cell lymphoma. The IgM type of these autoantibodies suggests that they represent all or part of the paraprotein produced by lymphoma cells.

Sodium influx plays a major role in the membrane depolarization induced by oxygen and glucose deprivation in rat striatal spiny neurons.

BACKGROUND AND PURPOSE: Striatal spiny neurons are selectively vulnerable to ischemia, but the ionic mechanisms underlying this selective vulnerability are unclear. Although a possible involvement of sodium and calcium ions has been postulated in the ischemia-induced damage of rat striatal neurons, the ischemia-induced ionic changes have never been analyzed in this neuronal subtype. METHODS: We studied the effects of in vitro ischemia (oxygen and glucose deprivation) at the cellular level using intracellular recordings and microfluorometric measurements in a slice preparation. We also used various channel blockers and pharmacological compounds to characterize the ischemia-induced ionic conductances. RESULTS: Spiny neurons responded to ischemia with a membrane depolarization/inward current that reversed at approximately -40 mV. This event was coupled with an increased membrane conductance. The simultaneous analysis of membrane potential changes and of variations in [Na+]i and [Ca2+]i levels showed that the ischemia-induced membrane depolarization was associated with an increase of [Na+]i and [Ca2+]i. The ischemia-induced membrane depolarization was not affected by tetrodotoxin or by glutamate receptor antagonists. Neither intracellular BAPTA, a Ca2+ chelator, nor incubation of the slices in low-Ca2+-containing solutions affected the ischemia-induced depolarization, whereas it was reduced by lowering the external Na+ concentration. High doses of blockers of ATP-dependent K+ channels increased the membrane depolarization observed in spiny neurons during ischemia. CONCLUSIONS: Our findings show that, although the ischemia-induced membrane depolarization is coupled with a rise of [Na+]i and [Ca2+]i, only the Na+ influx plays a prominent role in this early electrophysiological event, whereas the increase of [Ca2+]i might be relevant for the delayed neuronal death. We also suggest that the activation of ATP-dependent K+ channels might counteract the ischemia-induced membrane depolarization.