Changes in blink reflex after simultaneous supraorbital and mental nerve stimulations in healthy subjects.

Background/aim: In this study, we investigated the blink reflex (BR) after simultaneous and asynchronous stimulation of two trigeminal nerve branches. The objective was to characterize the physiology of trigeminal and facial circuits. Materials and methods: We performed three sets of experiments: recording BR response i. after supraorbital nerve stimulation (SON), after mental nerve stimulation (MN), and after simultaneous SON and MN stimulation (SON+MN) in 18 healthy individuals; ii. after MN (at an intensity eliciting BR response) preceding SON at various interstimulus intervals (ISIs) in seven healthy subjects; iii after MN (at sensory threshold) preceding SON at various ISIs. We compared the magnitudes of early and late responses. Results: The R1 amplitude after simultaneous SON+MN stimulation was greater than responses after single stimulation of the same branches. After simultaneous stimulations, the R2 and R2c areas under the curve (AUC) were smaller than the arithmetic sums of R2 and R2c AUC obtained after single stimulations. The second experiment provided a recovery excitability curve. In the third step, we obtained facilitation of R1 and inhibition of late responses. Conclusion: The SON+MN stimulation caused an increased R1 circuit excitability compared to the arithmetic sum of the single stimulations; however, magnitudes of late responses did not potentiate. Thus, we have provided evidence for R1 circuit enhancement by simultaneous stimulation in humans, whereas modulation of late responses exhibited a recovery curve similar to that shown for paired SON stimulation.

Blink reflex excitability in patients with Hemifacial spasm exhibiting different abnormal discharge patterns: from early isolated discharges to later grouped bursts or tonic spasms.

OBJECTIVE: We studied blink reflex (BR) and BR excitability recovery (BRER) in patients with hemifacial spasm (HFS) exhibiting different abnormal discharge patterns. We hypothesized that patients with groups of clonic or tonic burst activities appear later in the disease course and may have more excitability of the BR circuit at the brainstem compared to patients with isolated twitchings, which occur earlier. METHODS: We included 124 patients with botulinum toxin-naive HFS (mean age 50.6 ± 13.3 years) and 40 healthy subjects. We performed surface polymyography on facial muscles in patients and classified them according to the abnormal discharge pattern: isolated discharges, grouped bursts forming random sequences, tonic spasms, and a combination of these activities. Then, we recorded BR and BRER at 200, 600, and 1000 ms interstimulus intervals. We compared disease duration, R1 and R2 latencies, R2 area-under-the-curve (AUC), and BRER% (i) between healthy subjects and patients and (ii) among groups of patients with different abnormal discharge patterns. RESULTS: There were isolated discharges in 28 patients, grouped bursts forming random sequences in 42, and continuous muscle activity with tonic spasms in one. The remaining patients had combinations. Mean R1 and R2 latencies were significantly longer, and mean R2 AUC was significantly higher on the symptomatic side of patients compared to healthy subjects. The mean BRER was enhanced on both sides in patients than in healthy subjects (p < 0.001). However, it was similar among patient groups with different abnormal discharge patterns (p > 0.05). The mean disease duration in patients with isolated discharges was shorter (3.3 ± 2.0 years) than those with grouped bursts or tonic spasms (p = 0.002; Kruskal-Wallis test). CONCLUSION: Our study observed that excitability at the brainstem was similar in HFS patients with different abnormal discharge patterns, suggesting that the difference in discharge patterns in HFS may be due to a reason other than the difference in BR excitability.

Late Component of the Trigemino-Cervical Reflex: Clinical and Neuroradiological Correlations.

INTRODUCTION: The authors aimed to analyze the possible relationship of the late response of trigemino-cervical reflex (TCR) with various clinical conditions having brainstem lesions and lesion localizations in the brainstem. METHODS: The authors enrolled 30 healthy subjects, 16 patients with stroke, 14 patients with multiple sclerosis (MS), and 9 patients with neuro-Behçet disease. All patients had at least one MRI, and lesion localization was classified into midbrain, pons, medulla oblongata, or their combinations. The TCR was recorded simultaneously from bilateral sternocleidomastoid and splenius capitis muscles. RESULTS: There was no significant difference based on lesion localization within the brainstem. Trigemino-cervical reflex latency was significantly longer in patients with MS compared with all other groups (P < 0.005 for each comparison). The Receiver Operating Characteristic curve analysis of sternocleidomastoid showed a cut-off value of 76.9 ms with 44% sensitivity and 92.7% specificity to predict MS. Similarly, the authors determined a cut-off value of 61.5 ms of splenius capitis latency with 38.5% sensitivity and 91.5% specificity to predict MS. CONCLUSIONS: This study showed that TCR might be abnormal in a given patient with one brainstem lesion, independently from the lesion localization. This may be attributed to a broad network of TCR at the brainstem. Thus, abnormally delayed TCR responses can be used as a tool for the discrimination of MS among other brainstem lesions.

The Thalamic and Intracortical Inhibitory Function of Somatosensory System Is Unchanged in Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis.

PURPOSE: In mesial temporal lobe epilepsy with hippocampal sclerosis, there is parietal atrophy and cognitive involvement in related domains. In this context, we hypothesized that inhibitory input into somatosensory cortex and thalamus may be increased in these patients, which could improve after epilepsy surgery. Thus, we analyzed the inhibitory function of somatosensory system by studying surround inhibition (SI) and recovery function of somatosensory evoked potentials in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. METHODS: Nine patients with unoperated mesial temporal lobe epilepsy with hippocampal sclerosis, 10 patients who underwent epilepsy surgery, and 12 healthy subjects were included. For SI of somatosensory evoked potentials, we recorded somatosensory evoked potentials after stimulating median or ulnar nerve at wrist separately and after median and ulnar nerves simultaneously and calculated SI% in all participants. For recovery function of somatosensory evoked potentials, paired stimulation of median nerve at 40- and 100-millisecond intervals was performed. We compared the findings among groups. As a secondary analysis, we determined the outliers in the patient group and analyzed the relation to the clinical findings. RESULTS: The mean SI% or recovery function was similar among three groups. However, there were five patients with SI loss on normal side in the patient group, which was related to the antiseizure drugs. CONCLUSIONS: In contrast to our hypothesis, both intracortical (SI) and thalamic/striatal (recovery function) inhibitory modulation of the somatosensory cortex was not altered in mesial temporal lobe epilepsy with hippocampal sclerosis and did not differ in surgical and nonsurgical groups.

Cutaneous silent period modulation by tooth clenching, tonic and phasic limb movements in healthy subjects.

OBJECTIVE: We aimed to examine the modulation of the cutaneous silent period (CSP) by tooth clenching and contralateral tonic dorsiflexion of lower limb and phasic voluntary movements of upper limb. METHODS: In 18 healthy subjects, we recorded CSP on right thenar muscle after painful stimulation of index finger during mild contraction at six conditions: baseline, maximum tooth clenching, contralateral tonic dorsiflexion of foot, as well as at the beginning (RT1), in the middle (RT2) and at last part (RT3) of the contralateral phasic wrist extension. We measured latency and duration and calculated suppression indices. RESULTS: During tooth clenching, the suppression index of second inhibitory phase (I2) was significantly higher than that at baseline condition. The suppression index of first inhibitory phase (I1) was reduced in tonic dorsiflexion. The I2 durations in RT2 and RT3 were longer than that at baseline. The I2 suppression indices during RT1, RT2, and RT3 were significantly higher than that at baseline condition (p < 0.05). CONCLUSION: The tooth clenching has an inhibitory effect on CSP. The contralateral phasic hand movements caused higher suppression index. The CSP is modulated by remote influences differently depending on the type of muscle contraction (tonic vs. phasic) and/or where it is realized (tooth, upper or lower limb).

Seizures in patients with respiratory disease - a retrospective single center study.

OBJECTIVE: Seizures are a neurological condition commonly experienced during the follow-up period after systemic or metabolic disorders. The aim of the present study was to determine the etiological factors of seizures in patients at a tertiary care chest clinic. METHODS: We reviewed all neurology consultations that were requested due to seizures in inpatient clinics in a tertiary care hospital specializing in respiratory disorders between January 2011 and January 2018 were retrospectively reviewed. RESULTS: The present study included 705 of 2793 (25.2%) patients who requested consultations for seizures during the study period. The mean age of the sample was 64.05±17.19 years. Of the 705 patients, 307 (43.5%) had a previous history of epilepsy (Group I) and 398 (56.5%) had a first-time seizure and were considered to have symptomatic seizures (Group II). Multiple factors played roles in the development of seizures in 54.8% of the patients. In most patients, metabolic causes, systemic infections, and drug use were identified and an intracranial metastatic mass lesion was the major cause in patients with lung cancer. Rates of hypoxemia and respiratory acidosis were significantly higher in patients with symptomatic seizures (Group II) than in patients with primary epilepsy (Group I). CONCLUSIONS: Blood gas changes such as hypoxemia and respiratory acidosis were among the factors statistically associated with the development of symptomatic seizures in patients with respiratory diseases. Additionally, hypoxemia, hypercapnia, and respiratory acidosis were correlated with mortality in patients hospitalized for respiratory system diseases who requested consultations for seizures.

Seizures in patients with respiratory disease - a retrospective single center study / Convulsões em pacientes com doença respiratória - estudo retrospectivo de centro único

ABSTRACT Objective: Seizures are a neurological condition commonly experienced during the follow-up period after systemic or metabolic disorders. The aim of the present study was to determine the etiological factors of seizures in patients at a tertiary care chest clinic. Methods: We reviewed all neurology consultations that were requested due to seizures in inpatient clinics in a tertiary care hospital specializing in respiratory disorders between January 2011 and January 2018 were retrospectively reviewed. Results: The present study included 705 of 2793 (25.2%) patients who requested consultations for seizures during the study period. The mean age of the sample was 64.05±17.19 years. Of the 705 patients, 307 (43.5%) had a previous history of epilepsy (Group I) and 398 (56.5%) had a first-time seizure and were considered to have symptomatic seizures (Group II). Multiple factors played roles in the development of seizures in 54.8% of the patients. In most patients, metabolic causes, systemic infections, and drug use were identified and an intracranial metastatic mass lesion was the major cause in patients with lung cancer. Rates of hypoxemia and respiratory acidosis were significantly higher in patients with symptomatic seizures (Group II) than in patients with primary epilepsy (Group I). Conclusions: Blood gas changes such as hypoxemia and respiratory acidosis were among the factors statistically associated with the development of symptomatic seizures in patients with respiratory diseases. Additionally, hypoxemia, hypercapnia, and respiratory acidosis were correlated with mortality in patients hospitalized for respiratory system diseases who requested consultations for seizures.

RESUMO Objetivo: Convulsões são uma condição neurológica comumente vivenciada durante o período de acompanhamento após distúrbios sistêmicos ou metabólicos. O objetivo do presente estudo foi determinar os fatores etiológicos das convulsões em pacientes de uma clínica torácica de atendimento terciário. Métodos: Foram revisadas retrospectivamente todas as consultas neurológicas solicitadas devido a convulsões em clínicas de internação em um hospital terciário especializado em distúrbios respiratórios entre janeiro de 2011 e janeiro de 2018. Resultados: O presente estudo incluiu 705 dos 2.793 (25,2%) pacientes que solicitaram consultas para convulsões durante o período do estudo. A idade média da amostra foi de 64,05±17,19 anos. Dos 705 pacientes, 307 (43,5%) tinham história prévia de epilepsia (Grupo I) e 398 (56,5%) tiveram uma convulsão inicial e foram considerados como tendo crises sintomáticas (Grupo II). Vários fatores desempenharam papel no desenvolvimento de convulsões em 54,8% dos pacientes. Na maioria dos pacientes, causas metabólicas, infecções sistêmicas e uso de drogas foram identificadas e uma lesão em massa metastática intracraniana foi a principal causa em pacientes com câncer de pulmão. As taxas de hipoxemia e acidose respiratória foram significativamente maiores em pacientes com crises sintomáticas (Grupo II) do que em pacientes com epilepsia primária (Grupo I). Conclusões: Alterações dos gases sanguíneos, como hipoxemia e acidose respiratória, foram alguns dos fatores estatisticamente associados ao desenvolvimento de convulsões sintomáticas em pacientes com doenças respiratórias. Além disso, hipoxemia, hipercapnia e acidose respiratória foram correlacionadas com a mortalidade em pacientes hospitalizados por doenças do sistema respiratório que solicitaram consultas para convulsões.

Modulation of the Somatosensory Blink Reflex in the Peripersonal Space Is Defective in Episodic Migraine.

OBJECTIVE: In migraine, there is an altered behavior of patients during the attack and an altered connectivity in the cortical structures modulating and encoding the sensation and pain. Thus, we hypothesized that the extent of the peripersonal space (PPS) and the responses in the PPS may change during a migraine attack. For this reason, we analyzed the modulation of somatosensory blink reflex (SBR) in the PPS during episodic migraine. DESIGN: Cross-sectional assessment of modulation of SBR in patients with migraine. SETTING: Headache outpatient clinic of a tertiary referral center. SUBJECTS: We included 22 patients with episodic migraine, of whom 13 individuals were in the interictal period and nine were experiencing a headache episode. We also included 14 healthy individuals. The three groups were similar in age and gender. METHODS: SBR was recorded when the participants were sitting with their forearm in the extrapersonal space and also when their hands were in the PPS surrounding the face. Latency, amplitude, and area under the curve (AUC) were measured and compared. RESULTS: The amplitude and AUC of the SBR were significantly higher in patients during the attack compared with healthy subjects. The magnitude of the SBR was increased in the PPS in healthy subjects, whereas the increase was not significant in patients during the attack or in the interictal period. CONCLUSIONS: We think that the modulation in the PPS is defective in patients with migraine both during the acute attack and in the interictal phase, suggesting diminished top-down modulation of the SBR.

Brainstem reflexes in neuro-Behçet disease.

We hypothesized that brainstem responses may allow detection of functional brainstem changes in patients with neuro-Behçet Disease (NBD). Thus, we recorded electrically-induced blink reflex (eBR), auditory blink reflex (aBR) and electrically-induced masseter inhibitory reflex (eMIR) in 16patients with NBD. However, these neurophysiological tests proved to have a poor overall sensitivity compared to neuroimaging for the diagnosis of brainstem lesions. They also showed low sensitivity for the differential diagnosis of focal pontine lesion versus diffuse brainstem disease in NBD.

Recovery function of somatosensory evoked potentials in juvenile myoclonic epilepsy.

Objective: We analysed the recovery function of somatosensory evoked potentials (SEPs) in juvenile myoclonic epilepsy (JME) patients. We hypothesized that there may be disinhibition in the recovery of SEPs at 20-100 ms intervals in JME patients. Methods: We recorded SEPs and SEP recovery in 19 consecutive patients with JME admitted for a routine follow-up examination, and in a control group composed of 13 healthy subjects who were similar to the patient group regarding age and sex. The recovery function of SEPs was examined using paired stimuli at 30, 40, 60, and 100 ms intervals. Results: The amplitudes of N20-P25 and P25-N33 components were higher in patients with JME. Ten patients had high-amplitude SEPs. By paired stimulation, there was inhibition of SEPs in both groups. The mean recovery percentages of N20-P25 and P25-N33 components at 30, 40, 60, and 100 ms were not different between healthy subjects and patients with JME. Conclusions: The recovery function of SEP is normal in JME even in the presence of high-amplitude SEPs.

Fear leads to a deficit of prepulse inhibition of blink reflex in healthy humans.

OBJECTIVE: We aimed to analyze whether or not fear conditioning exerts an effect on prepulse inhibition (PPI) of blink reflex (BR). To create fear conditioning, we used fearful faces. Since fearful faces lead to a specific set of fear conditioning, we hypothesized PPI of BR would change under the observation of fearful faces. METHOD: We included 17 healthy subjects with a mean age of 30.8 ± 6.9 years and seven healthy subjects with a mean age of 57.7 ± 7.3 years between January 2018 and June 2018 and recorded PPI of BR. The recordings were done before observation of any image, during observation of images, and immediately after observation of images. Observation of images included observation of fearful faces for 30 s and a neutral image of a white screen for 30 s (in a randomized order). RESULTS: There was a R2-PPI deficit during observation of fearful faces in each group whereas R2-PPI fully developed at other time points. R1 amplitude and R2 magnitude were lower during observation of any image compared with baseline and post-observation time points. CONCLUSION: In conclusion, a deficit of R2-PPI develops during observation of fearful faces in humans which is probably related to activation of the amygdala.

Guillain-Barré Syndrome and Its Variants: Clinical Course and Prognostic Factors.

INTRODUCTION: We aimed to analyze the frequency, clinical characteristics, medical treatment options and final functional status of Guillain-Barré syndrome (GBS) and its variants in a population from a tertiary hospital setting. METHODS: All medical records of patients with acute inflammatory polyneuropathy between the years of 1998-2013 were retrospectively screened. Demographic, clinical and laboratory information, treatment options and the rate of recovery of the patients were gathered. RESULTS: A total of 183 patients met the study criteria. Subtypes were typical demyelinating form (n=102, 79.1%), acute motor sensory axonal variant (n=11, 8.5%), acute motor axonal variant (n=10, 7.8%), Miller-Fisher syndrome (n=5, 3.9%), and pure sensory subtype (n=1, 0.8%). Remaining patients had the diagnosis of acute-onset chronic inflammatory demyelinating polynuropathy. The data of treatment option were available for 70 patients. Most of the patients received intravenous immunoglobulin (IVIg) treatment or the combination of IVIg and methylprednisolone. One patient died, there was no improvement in eight patients and rest showed improvement with varying degrees. CONCLUSIONS: We did not observe major change of recovery between different treatment options, however, most of the patients using methylprednisolone required IVIg because of inadequate response.

Effects of vibration on cutaneous silent period.

Suppression of an ongoing muscle contraction following noxious digital stimulation is called cutaneous silent period (CSP) which is under the influence of several physiological factors. In this study, we aimed to evaluate the influence of group Ia afferents on the cutaneous silent period (CSP) by applying 2-min vibration. CSP was obtained from abductor pollicis brevis muscle after stimulating index finger. The recordings were repeated three times-before, during and after vibration-which was applied over the tendon of flexor carpi radialis muscle. Onset latency, duration and magnitude of total CSP, inhibitory phases I1 and I2, and of the long-loop reflex were measured and compared. Suppression indices of CSP, I1 and I2 increased significantly during and after vibration, indicating significantly less exteroceptive EMG suppression outlasting the time of vibration. Vibration also caused mild shortening of I2 end latency (p = 0.048) and I2 duration (p = 0.019). Our findings indicate that vibration exerts a powerful influence on CSPs and causes reduction in the magnitude of exteroceptive EMG suppression during and after vibration. Although vibration is known to activate Ia afferents, we cannot exclude contribution of other afferents, e.g. mechanoreceptors, as well as pre- or postsynaptic inhibitory effects on ensuing interneurons, or enhanced vibration-related excitatory influence.

Role of mesial temporal lobe structures in sensory processing in humans: a prepulse modulation study in temporal lobe epilepsy.

Prepulse modulation (PPM) is an electrophysiological method which enables to assess sensory processing in vivo. Reflex responses may be facilitated or inhibited (prepulse inhibition, PPI) after a weak stimulus. Theoretically, in animal studies, the generator of PPI involves pedunculopontine nucleus which is modulated by various structures, including amygdala. We aimed to investigate whether or not there was a role of limbic structures in the generation of PPM in humans. For this purpose, we studied PPM of the blink reflex (BR) in 10 patients with mesial temporal lobe epilepsy (MTLE group) and in nine patients who had previously undergone amygdala resection for medically resistant MTLE (surgery group). A control group including 19 healthy volunteers was formed. Blink reflex, BR-PPM and BR excitability recovery were recorded in all participants. Two components of BR, first early ipsilateral component (R1) and second late bilateral components (R2 and R2c) were identified. All BR parameters after single stimulation were normal in all groups. Compared to healthy subjects, R2-PPI was more pronounced in the surgery group whereas there was a R2-PPI deficit in the MTLE group. R2-PPI deficit in the MTLE group was more prominent on the lesion side. Ipsilesional R1 facilitation was more evident at ISI of 100 ms in both MTLE and surgery groups compared to healthy subjects. BR excitability recovery was not different between groups. MTLE in humans leads to a PPI deficit. Interestingly, removal of amygdala in humans with MTLE probably provides more efficient functioning of PPI network. Amygdala and hippocampus play roles in the human R2-PPI circuit. Modulation of R1 facilitation is unilateral whereas the modulation of R2-PPI is bilateral, though asymmetric.

Reorganization of sensorimotor gating after peripheral facial palsy starts at brainstem.

Background and objective We aimed to analyze the alterations in sensorimotor gating at brainstem after peripheral facial palsy (PFP). To examine sensorimotor gating, we used prepulse modulation (PPM) of blink reflex (BR). We also recorded BR recovery to identify excitability changes in the facial nucleus. Patients and method We included 33 patients and 39 recordings. Control group was composed of 16 healthy subjects. Simultaneous bilateral baseline BR, BR recovery at ISI of 300-ms and BR-PPM at ISI of 100-ms recordings were performed after stimulation of trigeminal nerve on right sides of healthy subjects and on both sides of patients. Severity of PFP and time lapse from the onset was noted. Results Mean R1 amplitude was increased, whereas mean R2 and R2c magnitude were reduced in all groups after prepulse stimulation. However, multivariate ANOVA showed significance at group level (patients and healthy subjects), at prepulse level (no prepulse and 100-ms prepulse) and group and prepulse level. Suppression of R2 or R2c was lower on both sides of patients compared to healthy subjects and the deficit first started on the symptomatic side. Conclusion Suppression of R2 and R2c after prepulse stimulation is reduced in PFP suggesting decreased filtering of facial sensory input at brainstem level. Trigeminal sensitization at brainstem develops early after PFP.

Myoclonus in the elderly: A retrospective analysis of clinical and electrophysiological characteristics of patients referred to an electrophysiology laboratory.

BACKGROUND AND OBJECTIVE: Late-onset myoclonus in the elderly is mainly related to dementia or systemic disease. In this report, we aimed to investigate the clinical and electrophysiological features of patients with late-onset myoclonus. PATIENTS AND METHOD: We retrospectively assessed the medical records of patients who were referred to our electromyography laboratory. From these records, we included all patients who had myoclonus which started after the age of 60 years and in whom it was confirmed by polymyography. Demographic, clinical and electrophysiological findings were retrieved from the medical records. RESULTS: There were 63 patients with myoclonus. Types of myoclonus were spinal segmental (n = 2), cortical (n = 25) and probable cortico-subcortical involving upper extremities (n = 36). The latter two types displayed reflex sensitivity. Four patients (one with multifocal cortical myoclonus and others with probable cortico-subcortical myoclonus) were diagnosed with probable CJD. Other diagnoses were Parkinsons's disease, Parkinson-plus or dementia syndromes, vascular parkinsonism, polyneuropathy, Celiac disease and post-hypoxic encephalopathy. Eleven patients did not have a specific diagnosis. CONCLUSIONS: Myoclonus in our cohort was mostly associated with parkinsonism. Cortical myoclonus is not rare in the elderly age group. Myoclonus in polyneuropathy is irregular, tremor-like with electrophysiological characteristics similar to the cortical subtype.

Does Valproic Acid/Na Valproate Suppress Auditory Startle Reflex in Patients With Epilepsy?

BACKGROUND AND OBJECTIVE: Auditory startle response (ASR) was normal in juvenile myoclonic epilepsy whereas it was suppressed in progressive myoclonic epilepsy. However, both groups were using valproic acid/Na valproate (VPA) in different doses. Therefore, we aimed to analyze whether VPA has an impact on ASR in a cohort of epilepsy. For this purpose, we included patients with epilepsy and analyzed ASR in patients who were using VPA. PATIENTS AND METHOD: We included 51 consecutive patients who had epilepsy and were using VPA between January 2014 and January 2016. Two control groups of 37 epilepsy patients using other antiepileptic drugs (AEDs) and of 25 healthy subjects were also constituted. All participants underwent investigations of ASR and startle response to somatosensory inputs (SSS) under similar conditions. RESULTS: An analysis of patients using VPA, not using VPA and healthy subjects revealed significantly longer latency and lower probability of orbicularis oculi (O.oc) and sternocleidomastoid responses after auditory stimulation, decreased total ASR probability and longer latency of O.oc response after somatosensory stimulation in patient groups compared with healthy subjects. Multivariate analysis showed type of AED had a role in the generation of abnormalities. VPA, carbamazepine, and multiple AED use caused suppression of ASR. Total ASR probability was decreased or O.oc latency got longer with longer duration of VPA use whereas serum VPA level at the time of investigation did not correlate with total ASR probability. DISCUSSION: Both ASR and SSS are suppressed by the effect of VPA, especially in patients using for a long period and in patients using other AEDs with VPA. Given the fact that VPA leads to long-standing synaptic changes of dopaminergic transmission, abnormalities of this network may be the more likely cause.