Hyperexcitability In Patients Research Articles

Subclinical epileptiform discharges in Alzheimer’s disease are associated with increased hippocampal blood flow

BackgroundIn epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer’s disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer’s disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus.MethodsA total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG.ResultsNo significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC.ConclusionsIncreased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD.Trial registrationThe study is registered at clinicaltrials.gov (NCT04436341).

Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer's Disease: Unanswered Questions and Next Steps.

Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer's disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed "subclinical epileptiform activity" (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

Optimized Electrical Stimulation of C-Nociceptors in Humans Based on the Chronaxie of Porcine C-Fibers

Classically, to electrically excite C-nociceptors, rectangular pulses are used with a duration close to the estimated chronaxie of C-fibres (about 2 ms). Recent results using slow depolarizing stimuli suggest longer chronaxies. We therefore set out to optimize C-fiber stimulation based on recordings of single C-nociceptors in-vivo and C-fiber compound-action-potentials (C-CAP) ex-vivo using half-sine shaped stimuli of durations between 1 and 250ms. Single fiber (n = 45) recording in pigs revealed high chronaxie values for C-touch fibers (15.8 ms), polymodal- (14.2 ms) and silent-nociceptors (16.8 ms). Activation thresholds decreased 2 to 3-fold in all fibre classes when increasing the duration of half-sine pulses from 1 to 25 ms (P < .05). C-CAPs strength-duration curves of the pig saphenous nerve (n = 7) showed the highest sensitivity for half-sine durations between 10 and 25 ms. Half-maximum currents for C-CAPS were reduced 3-fold compared to rectangular pulses (P < .01) whereas the opposite was found for A-fiber compound action potentials. Psychophysics in humans (n = 23) revealed that half-sine stimulus durations >10 ms reduced detection thresholds, pain thresholds, and stimulus current amplitudes required to generate a pain rating of 3 on an 11-point Numeric Rating Scale (NRS) as compared to 1 ms rectangular pulses (P < 0.05). Increasing the duration from 1 to 25 ms led to a 4-fold amplitude reduction for pain-thresholds and stimuli caused an axon-reflex flare. Excitability of single polymodal nociceptors in animals paralleled human psychophysics and we conclude optimized half-sine pulses facilitate C-nociceptor activation. PerspectiveElectrical stimulation with longer lasting half-sine wave pulses preferentially activates C-nociceptors and changes in the strength duration curve may identify nociceptor hyperexcitability in patients with neuropathic pain.

The effectiveness of a one-day workshop based on cognitive behavioral therapy interpretation bias and meta-Emotions of women with postpartum depressive disorder

Aim: The purpose of this research was to investigate the effectiveness of a one-day workshop based on cognitive behavioral therapy of interpretation bias and hyperexcitability in patients with postpartum depression. Methods: It was a quasi-experimental research design of pre-test, post-test and follow-up type with a control group. The statistical population of this study included all women with perinatal depression in Selmas city who were referred to health centers in 2021 to receive psychological services. The sample size includes 50 people (25 people in the experimental group and 25 people in the control group) from the statistical population were selected by available sampling method and divided into two control and experimental groups. For the experimental group, a one-day workshop based on cognitive behavioral therapy based on the Stark model (1996) was implemented, while the control group did not receive any training. The research tools included the Edinburgh Depression Questionnaire by Cox et al. (1996), the Ambiguous Scenarios Test for Depression by Brena et al. The data was analyzed using descriptive statistics and analysis of variance test with repeated measurements. Results: The results showed that the one-day workshop based on cognitive behavioral therapy on interpretation bias (F=258.60, P&lt;0.001) and positive euphoria (F=120.70, P&lt;0.001) and negative excitement (F=56.79, P&lt;0.001) had a significant effect in the post-test and follow-up stages. Conclusion: The findings of this research provide useful information regarding a one-day workshop based on cognitive behavioral therapy, and counselors and psychologists can use this intervention to improve interpretation bias and hyper-excitement in postpartum depression.

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n=65) that were compared with a group of age-matched healthy controls (n=21). We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aβ42 . Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Amplitude of Somatosensory Evoked Potentials (SEPs) Recorded in Short-Latency SEP Condition Is 80% of That in Giant SEP Condition.

Giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex (C-reflex) are useful to detect cortical motor hyperexcitability in patients with myoclonic epilepsy. The recording conditions of giant SEPs are different from those of short-latency SEPs (SSEPs). We investigated the waveform characteristics obtained for each condition. Forty-eight upper limbs of 24 adult normal subjects (12 men, age 35.5 ± 9.7 years [mean ± SD]) were investigated. Somatosensory evoked potentials of each subject were recorded in both conditions on the same day. The main differences in recording conditions were reference electrodes (SSEP: Fz vs. giant SEP: the earlobe electrode ipsilateral to the stimulated limb), stimulus rate (5 vs. 1 Hz), and bandpass filter (20 Hz-3 kHz vs. 1 Hz-1 kHz). Somatosensory evoked potentials were elicited by unilateral percutaneous electrical stimulation of the median nerve at the wrist with intensity of 110% of the movement threshold and recoded at C3'/C4'. The amplitudes of N20 onset-N20 and N20-P25 were significantly larger in giant SEP condition than in SSEP condition ( p < 0.001). The mean + 3SD of N20-P25 amplitude was 10.0 μV in giant SEP condition and 7.8 μV in SSEP condition. The N20-P25 amplitude was significantly correlated between giant SEP condition and SSEP condition ( R = 0.64, p < 0.001). C-reflex was not elicited. The amplitude of SEPs in SSEP condition is equivalent to 80% of that in giant SEP condition. The information is useful for detecting cortical hyperexcitability in various neurological disorders including myoclonic epilepsy.

Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer's disease.

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer's disease patients without subclinical epileptiform activity, 20 Alzheimer's disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer's disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that Alzheimer's disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence than Alzheimer's disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer's disease patients with subclinical epileptiform activity and Alzheimer's disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer's disease.

Noninvasive Brain Stimulation in Epilepsy.

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

Diaphragmatic motor cortex hyperexcitability in patients with chronic obstructive pulmonary disease.

Background and objectivesRespiratory muscles dysfunction has been reported in COPD. Transcranial magnetic stimulation (TMS) has been used for assessing the respiratory corticospinal pathways particularly of diaphragm. We aimed to study the cortico-diaphragmatic motor system changes in COPD using TMS and to correlate the findings with the pulmonary function.MethodsA case control study recruited 30 stable COPD from the out-patient respiratory clinic of Main Alexandria University hospital- Egypt and 17 healthy control subjects who were subjected to spirometry. Cortical conduction of the diaphragm was performed by TMS to all participants followed by cervical magnetic stimulation of the phrenic nerve roots. Diaphragmatic resting motor threshold (DRMT), cortical motor evoked potential latency (CMEPL), CMEP amplitude (CMEPA), peripheral motor evoked potential latency (PMEPL), PMEP amplitude (PMEPA) and central motor conduction time (CMCT) were measured.Results66.7% of COPD patients had severe and very severe COPD with median age of 59 (55–63) years. There was statistically significant bilateral decrease in DRMT, CMEPA and PMEPA in COPD group versus healthy subjects and significant increase in CMEPL and PMEPL (p <0.01). Left CMCT was significantly prolonged in COPD group versus healthy subjects (p <0.0001) but not right CMCT. Further, there was significant increase in CMEPL and CMCT of left versus right diaphragm in COPD group (p = 0.003 and 0.001 respectively) that inversely correlated with FEV1% and FVC% predicted. Right and left DRMT were insignificantly different in COPD group (p >0.05) but positively correlated with FEV1/FVC, FEV1% and FVC% predicted.ConclusionCentral cortico-diaphragmatic motor system is affected in COPD patients with heterogeneity of both sides that is correlated with pulmonary function.SignificanceCoticospinal pathway affection could be a factor for development of diaphragmatic dysfunction in COPD patients accordingly its evaluation could help in personalization of COPD management especially pulmonary rehabilitation programs.

Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome

Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.

Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs)

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = −2.12; T (50) = −2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = −2.12; T (50) = −2.47, p = 0.04) and Fatigue (MD = −3.42; T (50) = −2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.

Вплив ступеня порушення кортикоспінальної іннервації на розвиток сегментарної гіперзбудливості у хворих після півкульного ішемічного інсульту

Вплив ступеня порушення кортикоспінальної іннервації на розвиток сегментарної гіперзбудливості у хворих після півкульного ішемічного інсульту

Afterdischarges following M waves in patients with voltage-gated potassium channels antibodies

ObjectiveTo explore the correlation between afterdischarges in motor nerve conduction studies and clinical motor hyperexcitability in patients with voltage-gated potassium channels (VGKC) antibodies. MethodsSix patients with positive serum antibodies to contactin-associated protein-like 2 (CASPR2) or/and leucine-rich glioma-inactivated protein 1 (LGI1) were recruited, including 5 with autoimmune encephalitis, and 1 with cramp-fasciculation syndrome. Electromyography (EMG), nerve conduction studies (NCS) and F waves were performed, and afterdischarges were assessed. One patient was followed up. ResultsFive patients had clinical evidence of peripheral motor nerve hyperexcitability (myokymia or cramp), and four of them had abnormal spontaneous firing in concentric needle electromyography (EMG). Prolonged afterdischarges following normal M waves were present in all six patients, including the two patients who had no EMG evidence of peripheral nerve hyperexcitability (PNH). Afterdischarges disappeared after treatment with intravenous immunoglobulin (IVIG). ConclusionThe afterdischarges in motor nerve conduction study might be a sensitive indicator of peripheral motor nerve hyperexcitability in patients with VGKC antibodies. SignificanceAfterdischarges in motor nerve conduction study might be more sensitive than needle electromyography for detecting peripheral motor nerve hyperexcitability, and could disappear gradually in accordance with clinical improvement and reduction of antibodies.

Cortical hyperexcitability in patients with C9ORF72 mutations: Relationship to phenotype.

Patients with mutations in C9orf72 can have amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or ALS-FTD. The goals were to establish whether cortical hyperexcitability occurs in C9orf72 patients with different clinical presentations. Cortical thresholds and silent periods were measured in thenar muscles in 19 participants with C9orf72 expansions and 21 healthy controls using transcranial magnetic stimulation (TMS). El Escorial and Rascovsky criteria were used to diagnose ALS and FTD. Fourteen participants with C9orf72 expansions were re-tested 6 months later. Correlations with finger-tapping speed, timed peg test, the ALS functional rating scale, and Dementia Rating Scale were examined. Most participants with C9orf72 expansions had normal or low cortical thresholds. Among them, ALS patients had the lowest thresholds and significantly shorter silent periods. Thresholds correlated with timed peg-test scores. TMS did not correlate with the Dementia Rating Scale. TMS measures of cortical excitability may serve as noninvasive biomarkers of ALS disease activity. Muscle Nerve, 2016 Muscle Nerve 54: 264-269, 2016.

Enhanced endogenous activation of NMDA receptors in pyramidal neurons of hippocampal tissues from patients with mesial temporal lobe epilepsy: A mechanism of hyper excitation

Altered excitatory synaptic transmission is one of the primary causes of seizure generation in patients with mesial temporal lobe epilepsy (MTLE). The present study is designed to delineate the contribution of glutamatergic tone under resting conditions to the hyper excitability in patients with MTLE. Resected hippocampal tissues were obtained from patients with MTLE. In these samples spontaneous excitatory postsynaptic currents (EPSCs), sensitive to NMDA receptor antagonist APV (50μM) and AMPA receptor antagonist CNQX (10μM) were recorded from pyramidal neurons at −70mV. We observed that frequency of EPSCs were 28.2% higher in slices obtained from patients with MTLE compared to that in case of non-epileptic controls. We also examined spontaneous fast current transients (CTs) recorded from these pyramidal neurons under cell-attached configuration. The frequency of CTs increased in the absence of extracellular Mg2+ in brain slice preparations and was completely blocked by APV. We found that the frequency of CTs in pyramidal neurons were higher in case of MTLE samples compared to non-epileptic controls. This study suggests that enhanced endogenous activity of NMDA receptor contributes to excitability in pyramidal neurons of slice preparations obtained from patients with MTLE.

Transcranial Magnetic Stimulation Reveals Cortical Hyperexcitability in Episodic Cluster Headache

Evidence shows involvement of the cerebral cortex in the pathophysiology of cluster headache (CH). Here we investigated cortical excitability in episodic CH patients by using transcranial magnetic stimulation. In 25 patients with episodic CH and 13 healthy subjects we evaluated the motor cortical response to single-pulse (ie, motor threshold, input-output curves, cortical silent period) and paired-pulse (ie, intracortical facilitation, short intracortical inhibition) transcranial magnetic stimulation in both hemispheres. Thirteen patients were evaluated outside bout and the remaining 12 patients inside bout. Our results showed increased slope of the input-output curves after stimulation of both hemispheres in patients outside bout and in the hemisphere contralateral to the headache side in patients inside bout. Increased intracortical facilitation was observed in the hemisphere ipsilateral to the headache side in patients evaluated both outside and inside bout; reduced short intracortical inhibition was observed in patients inside bout ipsilateral to the side of pain. In conclusion, we provide evidence of increased cortical excitability in episodic CH both outside and inside bout, especially in the hemisphere ipsilateral to the side of headache attacks. Our results suggest that an abnormal regulation of cortical excitability could be involved in the pathophysiology of CH. PerspectivesWe investigated cortical excitability in episodic cluster headache by using transcranial magnetic stimulation, providing evidence of cortical hyperexcitability in patients both inside and outside bout. We suggest that an abnormal state of cortical excitability could be involved in the pathophysiology of the disease.

Increased neurokinin-1 receptor availability in temporal lobe epilepsy: A positron emission tomography study using [11C]GR205171

Activation of the neurokinin-1 (NK1) receptor by neuropeptide substance P (SP) induces and maintains epileptic activity in various experimental models of epilepsy. The primary objective of this study was to investigate whether neurobiological changes linked to NK1-SP receptor system are associated with hyperexcitability in patients with temporal lobe epilepsy (TLE). A secondary objective was to investigate the relationship between seizure frequency and NK1 receptor availability. A positron emission tomography study was conducted with the selective NK1 receptor antagonist [(11)C]GR205171 in nine patients with TLE and 18 healthy control participants. Parametric PET images were generated using the Patlak graphical method, with cerebellum as reference region. Data analyses including group comparisons were performed using statistical parametric mapping. Patients with TLE showed increased NK1 receptor availability in both hemispheres with the most pronounced increase in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptor availability and seizure frequency was observed in the medial temporal lobe and in the lentiform nucleus ipsilateral to the seizure onset. Our results suggest that there is an intrinsic network using the NK1-SP receptor system for synaptic transmission and epileptiform activity in TLE.

Brain Maturation-Related Spike Localization in Panayiotopoulos Syndrome: Magnetoencephalographic Study

Focal spike activities in Panayiotopoulos syndrome involve all brain regions in electroencephalography, and commonly reveal multiple foci, often through occipital predominance. To investigate correlations between developmental brain maturation and spike origin in Panayiotopoulos syndrome, we evaluated age-related or duration-related magnetoencephalographic spike localization in 25 patients with Panayiotopoulos syndrome. Regarding age at examination, patients with frontal spikes were significantly older than patients with spikes on rolandic, parieto-occipital, or calcarine sulci. Occipital spikes were classified into two subgroups, located at the calcarine sulcus and parieto-occipital sulcus. Both calcarine and parieto-occipital localizations were seen in patients around the same age. Follow-up magnetoencephalography was performed on three patients, and demonstrated shifting localization or disappearance of magnetoencephalographic spikes. These results suggest that the location of spike discharges is not directly related to seizure symptoms, but instead indicates maturation-related cortical hyperexcitability in patients with Panayiotopoulos syndrome.

SK3 polyglutamine tract polymorphism and acute oxaliplatin neurotoxicity: A translational study

21076 Background: Acute neurotoxicity of l-oxaliplatin (l-OHP), characterized by cold-induced paresthesias, muscle cramps and tightness, seems electrophysiologically related to an abnormal nerve hyperexcitability (NHE) resembling neuromyotonia, an autoimmune disease caused by autoantibodies directed against voltage-gated potassium channels (VGKC). This l-OHP-related channelopathy seems to be reversible, but there is no agreement about the channel involved, most investigators favouring voltage-gated sodium channels. SK3 VGKC are mainly located in the peripheral nervous system and are characterized by an highly polymorphic CAG motif. We hypothesized that SK3 potassium channel dysfunction might be responsible for nerve hyperexcitability in patients treated with l-OHP. Methods: Pts eligible for an l-OHP-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies (NCS) and needle electromyography (EMG) were performed before and after l-OHP administration. Furthermore, a venous blood sample was obtained from each pt in order to perform genetic analysis. Genomic DNA was extracted from pts’ leukocytes and PCR-mediated amplification of the second polyglutamine CAG tract of SK3 gene was carried out; PCR products were analyzed on polyacrylamide gel stained with Ethidium Bromide. Results: We evaluated 20 pts (14M, 6F); mean age was 59 yrs. According to neurophysiologic data it was possible to divide pts into 3 groups: G0 (no symptoms or signs of NHE), 7 pts; G1 (cold induced paresthesias-mild NHE), 8 pts; G2 (muscle cramps-severe NHE), 5 pts. Genetic analysis showed different alleles ranging from 125 to 225 bp. In particular, 75% of pts carrying a 175 bp allele experienced severe acute toxicicy (G2 group), and 15% mild toxicity (G1 group). The 175 bp allele was found only in 1/7 G0 pts (15%); in these pts the alleles distribution was diffusely scattered. Conclusions: Acute and reversible NHE observed in some pts treated with l-OHP might be produced either by an increased sodium conductance or by a decreased activity of VGKC. The high percentage of the 175 bp allele, that we found in the G2 group, induces us to think that the polymorphism at CAG locus of SK3 may be responsible for l-OHP toxicity. Sequence analysis of PCR gene products is ongoing. No significant financial relationships to disclose.

Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome

To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline. The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique. Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects. As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.