4-Phenylbutyrate promoted wild-type γ-aminobutyric acid type A receptor trafficking, reduced endoplasmic reticulum stress, and mitigated seizures in Gabrg2+/Q390X mice associated with Dravet syndrome.

OBJECTIVE: γ-Aminobutyric acid type A (GABAA ) receptor subunit gene mutations are major causes of various epilepsy syndromes, including severe kinds such as Dravet syndrome. Although the GABAA receptor is a major target for antiseizure medications, treating GABAA receptor mutations with receptor channel modulators is ineffective. Here, we determined the effect of a novel treatment with 4-phenylbutyrate (PBA) in Gabrg2+/Q390X knockin mice associated with Dravet syndrome. METHODS: We used biochemistry in conjunction with differential tagging of the wild-type and the mutant alleles, live brain slice surface biotinylation, microsome isolation, patch-clamp whole-cell recordings, and video-monitoring synchronized electroencephalographic (EEG) recordings in Gabrg2+/Q390X mice to determine the effect of PBA in vitro with recombinant GABAA receptors and in vivo with knockin mice. RESULTS: We found that PBA reduced the mutant γ2(Q390X) subunit protein aggregates, enhanced the wild-type GABAA receptor subunits' trafficking, and increased the membrane expression of the wild-type receptors. PBA increased the current amplitude of GABA-evoked current in human embryonic kidney 293T cells and the neurons bearing the γ2(Q390X) subunit protein. PBA also proved to reduce endoplasmic reticulum (ER) stress caused by the mutant γ2(Q390X) subunit protein, as well as mitigating seizures and EEG abnormalities in the Gabrg2+/Q390X mice. SIGNIFICANCE: This research has unveiled a promising and innovative approach for treating epilepsy linked to GABAA receptor mutations through an unconventional antiseizure mechanism. Rather than directly modulating the affected mutant channel, PBA facilitates the folding and transportation of wild-type receptor subunits to the cell membrane and synapse. Combining these findings with our previous study, which demonstrated PBA's efficacy in restoring GABA transporter 1 (encoded by SLC6A1) function, we propose that PBA holds significant potential for a wide range of genetic epilepsies. Its ability to target shared molecular pathways involving mutant protein ER retention and impaired protein membrane trafficking suggests broad application in treating such conditions.

Hereditary hypomagnesemia with secondary hypocalcemia caused by a novel mutation in TRPM6 gene.

OBJECTIVES: Hereditary hypomagnesemia with secondary hypocalcemia (HSH), which results from variations in the transient receptor potential melastatin 6 (TRPM6) genes, is a rare hereditary cause of extremely low serum magnesium levels. We describe an infant with triggered seizures due to hypomagnesemia and a novel mutation in TRPM6 gene was identified. CASE PRESENTATION: A 10-month-old boy presented with multidrug resistant seizures, and axial hypotonia due to severe hypomagnesemia. Electroencephalography and neuroimaging of the patient was normal. He had a favorable outcome with magnesium supplement. In this study, the patient underwent clinical exome sequencing (CES) which detected a novel homozygous variant in the TRPM6 gene: NM_017662.5: c.5571-3C>G. After replacing his magnesium orally, he was free from seizures and had an encouraging outcome at the twelfth-month follow-up. CONCLUSIONS: HSH often presents with developmental issues, treatment-resistant seizures, and increased neuromuscular excitability. Untreated hypomagnesemia can potentially be fatal and severely impair cognitive function. Clinical suspicion is essential for early diagnosis and treatment.

Intestinal hypomagnesemia in an Iranian patient with a novel TRPM6 variant: a case report and review of the literature.

TRPM6 is predominantly expressed in the kidney and colon and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis and plays important roles in epithelial magnesium transport and the active magnesium absorption. In this study, we present a 70-day-old Iranian female patient from consanguineous parents with hypomagnesemia and secondary hypocalcemia. She presented with seizures 19 days after birth and refractory watery non-bloody diarrhea. She consequently had failure to thrive. Other features included hypotonia, wide anterior fontanel, ventriculomegaly, and pseudotumor cerebri following administration of nalidixic acid. She had severe hypomagnesemia and hypocalcemia which were treated with magnesium and calcium supplementation. Despite initial unstable response to supplemental magnesium, she eventually improved and the diarrhea discontinued. The patient was discharged by magnesium and calcium therapy. At the last follow-up at age 2.5 years, the patient remained well without any recurrence or complication. Genetic testing by whole-exome sequencing revealed a novel homozygous frameshift insertion-deletion (indel) variant in exon 26 of the TRPM6 gene, c.3693-3699del GCAAGAG ins CTGCTGTTGACATCTGCT, p.L1231Ffs*36. Segregation analysis revealed the TRPM6 heterozygous variant in both parents. Patients with biallelic TRPM6 pathogenic variants typically exhibit hypomagnesemia with secondary hypocalcemia and present with neurologic manifestations including seizures. In some patients, this is also complicated by chronic diarrhea and failure to thrive. Long-term complications are rare and most of the patients show a good prognosis with supplemental magnesium therapy.

Selective surgical mamillo-thalamic tract disconnection in hypothalamic hamartoma results in complete disappearance of gelastic seizures.

Hypothalamic hamartoma is a less common condition characterized by the several types of epileptic seizures including the gelastic type. It is reported that gelastic seizures are resistant to medical treatment with anticonvulsants, while stereotactic thermocoagulation or Gamma Knife radiosurgery are effective for seizure control. Here, we report an individual case where direct surgical resection disconnecting hypothalamic hamartoma from mammillothalamic tract resulted in complete disappearance of gelastic seizures without deterioration of cognitive function. A 6-year-old boy developed gelastic seizures at the age of 2 and suffered from precocious puberty. Anticonvulsants including carbamazepine and zonisamide failed to control seizures. The patient underwent direct division of the mammillothalmic tract by removal of hypothalamic hamartoma partially via anterior interhemispheric approach. It was observed that gelastic seizures disappeared completely after the surgical treatment without any endocrine and cognitive dysfunction for a follow-up period of 14 years. The mammillothalamic tract which connects anterior nucleus of thalamus and mammillary bodies plays a key role in gelastic seizures related to hypothalamic hamartoma. In this case, we disconnected the hamartoma specifically from the mammillary bodies and not from the rest of hypothalamus. Effectively, it enabled permanent control of seizures. This result shows that fibers connecting other hypothalamic structures and the dorsomedial nucleus of thalamus are not involved in gelastic seizure propagation from the hypothalamic hamartoma. When surgical treatment of hypothalamic hamartomas is performed it has high morbidity associated with hypothalamic disorders. Therefore, disconnection between hypothalamic hamartoma and mammillary bodies presents a possibility of reducing hypothalamic damage. Surgical disconnection between hamartoma and mammillothalamic tract carries minimal hypothalamic injury risk and our results suggest that it has the potential of seizure control for intractable gelastic seizures with less complications.

Neurotoxicity in a child after ingestion of star anise.

In this case report, a four-week-old boy, who since birth had suffered from constipation and infantile colic, presented with seizures, myoclonic jerks and irritability after being fed with a herbal mixture of star anise the day prior to admission. Chinese star anise is a globally used spice and a herbal remedy for infantile colic. The quick recovery of the boy and normal paraclinical findings supported the assumption of star anise intoxication. The frequent use of complementary medicine in children warrants awareness to inform families of the potential dangers of this home remedy.

An Extraordinary EEG Phenomenon Misdiagnosed as Nonconvulsive Status Epilepticus: Frequent Subclinical Periodic Discharges Terminated by Sudden Auditory Stimuli.

Triggering or modulation of seizures and rhythmic EEG patterns by external stimuli are well-known with the most common clinical appearance of stimulus induced periodic discharges (SI- PDs) patterns which are elicited by physical or auditory stimulation. However, stimulus terminated periodic discharges (ST-PDs), in other words, the periodic discharges stopped by external stimuli is an extremely rare electroencephalographic (EEG) finding. We report a 20-year-old woman with a marked psychomotor developmental delay of unknown cause, with frequent EEG patterns of long-lasting (10-60 s) bilateral paroxysmal high-voltage slow waves with occasional spikes, misdiagnosed as non-convulsive status epilepticus. However, no apparent clinical change was noted by the technician, physician, and her mother during these subclinical ictal EEG recordings. Interestingly, however, these epileptic discharges were abruptly interrupted by sudden verbal stimuli on the EEG, repeatedly. Whole exome sequencing and genotyping were performed to investigate possible genetic etiology that revealed two sequence variants, a frameshift variant of CACNA1H NM_021098.3:c.1701del;p.Asp568ThrfsTer15 and a missense variant of GRIN2D NM_000836.4:c.1783A>T;p.Thr595Ser as well as a copy number variant part deletion of ATP6V1A gene arr [hg19]3q13.31(113,499,698_113,543,081)x1 as possible pathogenic candidates. The subclinical periodic discharges terminated by verbal stimuli, is a very rare manifestation and needs particular attention. External modulation of ictal-appearing EEG patterns is important to identify stimulus terminated EEG patterns.

The Interaction Between Sleep and Epilepsy.

PURPOSE OF REVIEW: To review the mutual interactions between sleep and epilepsy, including mechanisms of epileptogenesis, the relationship between sleep apnea and epilepsy, and potential strategies to treat seizures. RECENT FINDINGS: Recent studies have highlighted the role of functional network systems underlying epileptiform activation in sleep in several epilepsy syndromes, including absence epilepsy, benign focal childhood epilepsy, and epileptic encephalopathy with spike-wave activation in sleep. Sleep disorders are common in epilepsy, and early recognition and treatment can improve seizure frequency and potentially reduce SUDEP risk. Additionally, epilepsy is associated with cyclical patterns, which has led to new treatment approaches including chronotherapy, seizure monitoring devices, and seizure forecasting. Adenosine kinase and orexin receptor antagonists are also promising new potential drug targets that could be used to treat seizures. Sleep and epilepsy have a bidirectional relationship that intersects with many aspects of clinical management. In this article, we identify new areas of research involving future therapeutic opportunities in the field of epilepsy.

High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency.

OBJECTIVE: We aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs). METHODS: In this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20-30 mg/kg/day) for 1 year, in addition to previous treatment. RESULTS: All nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient. CONCLUSION: One year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings. (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number: UMIN000024185.).

Relation between coffee consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy.

OBJECTIVE: Caffeine is an antagonist of the adenosine pathway, which is involved in regulation of breathing. Extracellular concentrations of adenosine are increased in the immediate aftermath of a seizure. Seizure-related overstimulation of adenosine receptors might promote peri-ictal apnea. However, the relation between caffeine consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy remains unknown. METHODS: We performed a cross-sectional analysis of data collected in patients included in the SAVE study in Lyon's epilepsy monitoring unit at the Adult Epilepsy Department of the Lyon University Hospital between February 2016 and October 2018. The video-electroencephalographic recordings of 156 patients with drug-resistant focal epilepsy included in the study were reviewed to identify those with ≥1 focal seizure (FS), valid pulse oximetry (SpO2 ) measurement, and information about usual coffee consumption. This latter was collected at inclusion using a standardized self-questionnaire and further classified into four groups: none, rare (≤3 cups/week), moderate (4 cups/week to 3 cups/day), and high (≥4 cups/day). Peri-ictal hypoxemia (PIH) was defined as SpO2 < 90% for at least 5 s occurring during the ictal period, the post-ictal period, or both. RESULTS: Ninety patients fulfilled inclusion criteria, and 323 seizures were analyzed. Both the level of usual coffee consumption (p = .033) and the level of antiepileptic drug withdrawal (p = .004) were independent risk factors for occurrence of PIH. In comparison with FS in patients with no coffee consumption, risk of PIH was four times lower in FS in patients with moderate consumption (odds ratio [OR] = .25, 95% confidence interval [CI] = .07-.91, p = .036) and six times lower in FS in patients with high coffee consumption (OR = .16, 95% CI = .04-.66, p = .011). However, when PIH occurred, its duration was longer in patients with moderate or high consumption than in those with no coffee consumption (p = .042). SIGNIFICANCE: Coffee consumption may be a protective factor for seizure-related respiratory dysfunction, with a dose-dependent effect.

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability.

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

The Effect of Mozart's Music in Severe Epilepsy: Functional and Morphological Features.

Music is a very important factor in everyday life, involving mood, emotions and memories. The effect of music on the brain is very debated. Certainly, music activates a complex network of neurones in auditory areas, mesolimbic areas, cerebellum and multisensory areas. In particular, music exerts its effects on the brain of patients with epilepsy, having a dichotomous influence: it can either be seizure-promoting in musicogenic epilepsy or antiepileptic. Several studies have shown that seizure-prone neural networks may be stimulated by certain periodicities while other frequencies may prevent seizure activity. There are a lot of data in the literature about the so-called "Mozart effect" (Rauscher et al. 1993). In previous studies we observed that in institutionalized subjects with severe/profound intellectual disability and drug-resistant epilepsy, a systematic music listening protocol reduced the frequency of seizures in about 50% of the cases. In this study we are conducting a survey on the observation of what happens to the brain of patients suffering from drug-resistant epilepsy through electroencephalographic investigations, brain MRI and behavioural analysis before and after six months of listening to Mozart music (Sonata K.448). The first step is to present the data of the first patient under investigation.

Bone fractures from generalized convulsive seizures and status epilepticus-A systematic review.

OBJECTIVE: We present a systematic review of the literature regarding types and anatomic distribution of fractures in association with generalized convulsive status epilepticus (GCSE) and convulsive seizures in adult patients accompanied by an illustrative case of a patient with GCSE and diffuse postictal pain from underlying bone fractures. METHODS: The library search engines PubMed and EMBASE were screened systematically using predefined search terms. All identified articles written in English were screened for eligibility by two reviewers. The preferred reporting items for systematic reviews and meta-analyses guidelines were followed. RESULTS: The screening of 3145 articles revealed 39 articles meeting the inclusion criteria. Among all fractures, bilateral posterior fracture-dislocations of the shoulders were reported most frequently (33%), followed by thoracic and lumbar vertebral compression fractures (29%), skull and jaw fractures (8%), and bilateral femoral neck fractures (6%). Risk factors for seizure-related fractures are seizure severity, duration of epilepsy, the use of antiseizure drugs known to decrease bone density, and a family history of fractures. Based on these findings, a three-step screening procedure is proposed to uncover fractures in the postictal state. All studies were retrospective without standardized screening methods for seizure-associated fractures resulting in a very low level of evidence and a high risk of bias. SIGNIFICANCE: Posterior fracture-dislocations of the shoulders, thoracic and lumbar vertebral compression, fractures of the skull and jaw, and bilateral femoral neck fractures are most frequently reported. Preventive measures including bone densitometry, calcium/vitamin D supplementation, and bisphosphonate therapy should be reinforced in epilepsy patients at risk of osteoporosis. As long as the effect of standardized screening of fractures is not investigated, it is too early to integrate such a screening into treatment guidelines. In the meantime, clinicians are urged to heighten awareness regarding seizure-associated fractures, especially in patients with postictal pain, as symptoms can be unspecific and misinterpretation may impede rehabilitation.

Quality of life and correlating factors in children, adolescents with epilepsy, and their caregivers: A cross-sectional multicenter study from Germany.

PURPOSE: To identify factors correlating with poorer quality of life (QoL) in children and adolescents with epilepsy and regarding QoL and depression of their caregivers in Germany. METHOD: A cross-sectional multicenter study on QoL and depression was performed in two representative German states (Hessen and Schleswig-Holstein). Variance analysis, linear regression, and bivariate correlation were used to identify correlating factors for poorer QoL and symptoms of depression. RESULTS: Data from 489 children and adolescents (mean age 10.4 ± 4.2 years, range 0.5-17.8; 54.0% male) and their caregivers were collected. We identified missing seizure freedom (p = 0.046), concomitant diseases (p = 0.007), hospitalization (p = 0.049), recent status epilepticus (p = 0.035), living in a nursing home or with foster parents (p = 0.049), and relevant degree of disability (p = 0.007) to correlate with poorer QoL in children and adolescents with epilepsy. Poorer QoL of caregivers was associated with longer disease duration (p = 0.004), non-idiopathic (mainly structural-metabolic) epilepsy (p = 0.003), ongoing seizures (p = 0.003), concomitant diseases (p = 0.003), relevant disability (p = 0.003), or status epilepticus (p = 0.003) as well as with unemployment of the primary caretaker (p = 0.010). Symptoms of depression of caregivers were associated with non-idiopathic epilepsy (p = 0.003), concomitant diseases (p = 0.003), missing seizure freedom (p = 0.007), status epilepticus (p = 0.004), or a relevant disability (p = 0.004) of their ward. A poorer QoL value of the children and adolescents correlated with a poorer QoL value of the caregivers (p < 0.001). CONCLUSIONS: Epilepsy shows a considerable impact on QoL and symptoms of depression. Early and effective therapy should focus on reduction of seizure frequency and the probability for developing status epilepticus. Furthermore, comprehensive care should pay attention at comorbidities, consequences of disability and dependency on others.

Inhibitory effects of chronic administration of vitamin D3 on pentylenetetrazole-induced seizures in mice.

Vitamin D3 as a neuroactive steroid hormone plays an important role in the nervous system. Recent clinical and experimental studies have shown an association between vitamin D-related disorders and epilepsy. Therefore, this study was designed to examine the effects of chronic administration of vitamin D3 on pentylenetetrazole (PTZ)-induced seizure in mice. This interventional study was conducted on 120 mice in 12 groups. Two control groups acutely and chronically received a mixture of almond oil and paraffin; three groups were acutely given vitamin D3 at doses of 2000, 4000 and 6000 IU/kg; three groups chronically received vitamin D3 with similar doses for two weeks and two groups chronically and acutely received a sub-effective dose of vitamin D3 and diazepam. Slow intravenous infusion of PTZ (5 mg/mL) was performed at a constant rate (0.3 mL/min) via an infusion pump to induce clonic and tonic seizures. Acute injection of different concentrations of vitamin D3 (2000, 4000 and 6000 IU/kg i.p.) did not significantly increase a seizure threshold. However, a seizure threshold in the groups chronically treated with 4000, and 6000 IU/kg of vitamin D3 was significantly higher than that in the control group (P < 0.001). Moreover, a combination of the sub-effective dose of vitamin D3 (2000 IU/kg) and diazepam (0.1 mg/kg) significantly increased seizure threshold. Our findings suggest that administration of vitamin D supplement can be considered as a potential add-on treatment in seizure and due to the vitamin D deficiency results from the long-term use of most anti-seizure drugs, this supplementation becomes more important.

Epilepsy, Physical Activity and Sports: A Narrative Review.

People with epilepsy (PWE) are less physically active compared with the general population. Explanations include prejudice, overprotection, unawareness, stigma, fear of seizure induction and lack of knowledge of health professionals. At present, there is no consensus on the role of exercise in epilepsy. This paper reviews the current evidence surrounding the risks and benefits associated with physical activity (PA) in this group of patients. In the last decade, several publications indicate significant benefits in physiological and psychological health parameters, including mood and cognition, physical conditioning, social interaction, quality of life, as well as potential prevention of seizure presentation. Moreover, experimental studies suggest that PA provides mechanisms of neuronal protection, related to biochemical and structural changes including release of ß-endorphins and steroids, which may exert an inhibitory effect on the occurrence of abnormal electrical activity. Epileptic discharges can decrease or disappear during exercise, which may translate into reduced seizure recurrence. In some patients, exercise may precipitate seizures. Available evidence suggests that PA should be encouraged in PWE in order to promote wellbeing and quality of life. There is a need for prospective randomized controlled studies that provide stronger clinical evidence before definitive recommendations can be made.

[Severe nutritional rickets in young children: Resurgence of an old disease]. / Rachitisme carentiel sévère du nourrisson : de nouveau d'actualité.

Nutritional rickets remains a significant public health issue for children worldwide. Although it has almost disappeared in industrialized countries following routine vitamin D supplementation, recent evidence suggests an increasing incidence, especially in young children. In addition to the classical clinical consequences on bone and the growth plate, rickets may also be associated with life-threatening neurological and cardiac complications in the most severe forms. Consequently, early screening and treatment are required. Here, we report the case of a 2-year-old child who presented with severe nutritional rickets associated with seizure and cardiomyopathy. Family screening revealed rickets in all the siblings. This case report emphasizes the importance of being aware of this disease, notably in population with sociocultural risk factors.

Orienting reaction may help recognition of patients with psychogenic nonepileptic seizures.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are abrupt, paroxysmal changes in behavior or consciousness that may phenomenologically resemble epileptic seizures. Given the known association between anxiety and PNES, we hypothesized that in these subjects there may be evidence that the nervous system is hypersensitive to external stimuli. We aimed to test our hypothesis by means of the auditory startle reaction (ASR). By investigating ASR, we also had the opportunity to test presence of orienting reaction, which is generally defined as the second phase of response after the auditory stimulus, with longer latency. METHODS: We included 22 patients diagnosed as PNES and 25 age- and gender-matched healthy subjects. Clinical assessments and ASR recordings were performed. Electrophysiological findings were compared between patients with PNES and healthy subjects, including the presence of an orienting reaction. Orienting reaction was defined as a late response with latency between 100-1000ms. RESULTS: The mean ages of patients with PNES and healthy subjects were 34.9±12.3 years and 33.3±10.9 years, respectively (P=0.709). All patients were diagnosed as having conversion disorder. Additionally, 19 patients had depressive disorder and four had anxiety. The recruitment pattern of muscles and probability were similar between patients with PNES and healthy subjects. Orienting reaction was solely observed in patients with PNES (n=13, 59.1% of the patients vs. no healthy subject). The sequence and contribution of muscles in the orienting reaction changed almost in all patients. The duration of these responses was long, sometimes more than 200ms. CONCLUSION: PNES is associated with orienting reaction. This provides a possible electrophysiological marker of altered nervous system function in patients with PNES and may also reflect the distorted emotional processing in these patients.

Preclinical evaluation of intravenous NAX 810-2, a novel GalR2-preferring analog, for anticonvulsant efficacy and pharmacokinetics.

OBJECTIVE: Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice. METHODS: NAX 810-2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF-1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810-2 levels were determined from trunk blood samples. NAX 810-2 was also added to human plasma at various concentrations for determination of plasma protein binding. RESULTS: In the mouse corneal kindling model, NAX 810-2 dose-dependently blocked seizures following intravenous administration (median effective dose [ED50 ], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810-2 dose-dependently blocked seizures following bolus administration (0.375-1.5 mg/kg, i.v.; ED50 , 0.7 mg/kg), with a time-to-peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one-half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810-2 show linear pharmacokinetics following intravenous administration and a half-life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810-2 effectively activates GalR2 at therapeutic concentrations. SIGNIFICANCE: These studies further suggest the potential utility of NAX 810-2 as a novel therapy for epilepsy.

Ictal bradyarrhythmias and asystole requiring pacemaker implantation: Combined EEG-ECG analysis of 5 cases.

BACKGROUND: Seizures can lead to cardiac arrhythmias by a number of mechanisms including activation/inhibition of cortical autonomic centers, increase in vagal tone through activation of brainstem reflex centers, and respiratory failure. Ictal asystole (IA) is a potential mechanism underlying sudden unexpected death in epilepsy (SUDEP). We analyzed the clinical features of 5 patients who developed IA requiring pacemaker implantation. METHODS: Patients with ictal arrhythmias were identified from the video-telemetry and ambulatory EEG database at Greater Manchester Neurosciences Centre, as well as an independent epilepsy residential care facility. Only those who had IA requiring pacemaker implantation were included in the analysis. A total of 5 patients were identified. RESULTS: Of the 5 patients with IA, 4 were female. All 5 patients had focal epilepsy, and four had temporal lobe epilepsy. Ictal asystole occurred with focal seizures with impairment of awareness. Seizure onset was left-sided in 2 patients, right-sided in one, left-sided onset with switch of lateralization in one, and nonlateralized in one patient. Three patients had hippocampal sclerosis, one of whom had undergone epilepsy surgery, one had traumatic encephalomalacia of the temporal lobe, and one patient had no lesions detected on MRI. Interictal epileptiform activity was more pronounced during sleep in all patients. Asystole occurred in association with sleep-related seizures in 4 of 5 patients. CONCLUSIONS: Ictal asystole (IA) occurred in association with sleep-related seizures in 4 out of 5 cases, predominantly in patients with temporal lobe epilepsy. These findings may be of relevance to SUDEP.

Evidence in support of using a neurochemistry approach to identify therapy for both epilepsy and associated depression.

The present study aimed to develop a neurochemistry-based single or adjuvant therapy approach for comprehensive management of epilepsy and associated depression employing pentylenetetrazole-kindled animals. Kindling was induced in two-month-old male Swiss albino mice by administering a subconvulsant pentylenetetrazole dose (35mg/kg, i.p.) at an interval of 48±2h. These kindled animals were treated with saline and sodium valproate (300mg/kg/day, i.p.) for 15days. Except for the naïve group, all other groups were challenged with pentylenetetrazole (35mg/kg, i.p.) on days 5, 10, and 15 to evaluate the seizure severity. Depression was evaluated in all experimental groups after normalization of locomotor activity, using tail suspension and forced swim test on days 1, 5, 10, and 15. Four hours after behavioral evaluations on day 15, all animals were euthanized to collect their serum and discrete brain parts. Corticosterone levels were estimated in all the experimental groups as a marker of a dysregulated hypothalamus pituitary adrenal axis. Neurochemical alterations (norepinephrine, dopamine, tryptophan, kynurenine, serotonin, glutamate, GABA, and total nitrate levels) were also estimated in the cortical and hippocampal areas of the mouse brain. Results revealed that saline-treated kindled animals were associated with significant depression and altered neurochemical milieu in comparison with naïve animals. Chronic valproate treatment in kindled animals significantly reduced seizure severity score bud did not ameliorate associated depression or completely restore altered biochemical and neurochemical milieu. Based on the observation of neurochemical changes in all the groups, we propose that restoration of altered neurochemical milieu, elevated indoleamine 2,3-dioxygenase enzyme activity, and corticosterone levels using pharmacological tools with/out valproic acid may be explored for management of both epilepsy and comorbid depression.