Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats.

OBJECTIVE: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death. METHODS: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. RESULTS: Seizures caused hypertension, tachycardia, and tachypnea punctuated by recurrent transient apneas. Salivation increased considerably: in 11 of 12 rats, liquid with alkaline pH consistent with saliva was expelled from the mouth. Most transient apneas were obstructive: nasal airflow ceased, while, in 83%, efforts to breathe persisted as continued rhythmic activity of respiratory pre-Bötzinger neurons, inspiratory electromyography (EMG), and excursions of the chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases (16%) of incomplete apnea, but not in rare cases (1%) of transient central apneas. During transient obstructive apneas, the frequency of all inspiratory efforts decreased abruptly by ~30%, suggesting a resetting of the central respiratory rhythm generator. Twenty-two of thirty-one rats died, due either to obstructive apnea (12) or central apnea following progressive slowing of respiration (10). Most rats dying of central apnea had experienced several transient obstructive apneas. Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous reports on spreading depolarization in mouse models. Timing suggests that the DC shift is a consequence rather than cause of respiratory collapse. Cardiac activity continued for tens of seconds. SIGNIFICANCE: Seizure activity in forebrain induces pronounced autonomic activation and disrupts activity in medullary respiratory centers, resulting in death from either obstructive or central apnea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of sudden unexpected death in epilepsy (SUDEP).

Postictal electroencephalographic (EEG) suppression: A stereo-EEG study of 100 focal to bilateral tonic-clonic seizures.

OBJECTIVES: We aimed to describe intracerebral aspects of postictal generalized electroencephalography suppression (PGES) following focal to bilateral tonic-clonic ("secondarily generalized tonic-clonic") seizures (GTCS) recorded using stereoelectroencephalographic (SEEG), and to correlate these with electroclinical features. METHODS: Three independent observers scored semiologic and SEEG features. Patient and epilepsy characteristics were collected. Descriptive statistics and multivariate analysis were performed. The operational definition of PGES on SEEG used strict criteria (absence of visible signal at 20 µV/mm amplitude, in all readable channels). Postictal regional suppression (RS) was identified if only a subset of implanted electrodes showed absence of signal. RESULTS: We evaluated 100 seizures in 52 patients. Interobserver agreement was good (κ 0.72 for clinical features and 0.73 for EEG features). PGES was present in 27 of 100 and RS without PGES present in 42 of 100 seizures. Region of RS included epileptogenic zone in 43 of 51 (86%). No effect of sampling (multilobar or bilateral exploration) was seen. Oral tonicity (mouth opening and/or tonic vocalization during the tonic phase of GTCS) was associated with the presence of PGES (P = 0.029; negative predictive value [NPV] 0.91). Bilateral upper limb extension during the tonic phase correlated with PGES (P = 0.041; NPV 0.85). Association of both oral tonicity and bilateral upper limb extension had a high NPV of 0.96. SIGNIFICANCE: SEEG recordings confirm true absence of signal during postictal EEG suppression. PGES is unlikely when both upper limb extension and oral tonicity are absent. We hypothesize that bilateral tonic seizure discharge at bulbar level brainstem regions is associated with the production of oral signs and may relate to mechanisms of PGES.

Neural network underlying ictal pouting ("chapeau de gendarme") in frontal lobe epilepsy.

In order to determine the anatomical neural network underlying ictal pouting (IP), with the mouth turned down like a "chapeau de gendarme", in frontal lobe epilepsy (FLE), we reviewed the video-EEG recordings of 36 patients with FLE who became seizure-free after surgery. We selected the cases presenting IP, defined as a symmetrical and sustained (>5s) lowering of labial commissures with contraction of chin, mimicking an expression of fear, disgust, or menace. Ictal pouting was identified in 11 patients (8 males; 16-48 years old). We analyzed the clinical semiology, imaging, and electrophysiological data associated with IP, including FDG-PET in 10 and SEEG in 9 cases. In 37 analyzed seizures (2-7/patient), IP was an early symptom, occurring during the first 10s in 9 cases. The main associated features consisted of fear, anguish, vegetative disturbances, behavioral disorders (sudden agitation, insults, and fighting), tonic posturing, and complex motor activities. The epileptogenic zone assessed by SEEG involved the mesial frontal areas, especially the anterior cingulate cortex (ACC) in 8 patients, whereas lateral frontal onset with an early spread to the ACC was seen in the other patient. Ictal pouting associated with emotional changes and hypermotor behavior had high localizing value for rostroventral "affective" ACC, whereas less intense facial expressions were related to the dorsal "cognitive" ACC. Fluorodeoxyglucose positron emission tomography demonstrated the involvement of both the ACC and lateral cortex including the anterior insula in all cases. We propose that IP is sustained by reciprocal mesial and lateral frontal interactions involved in emotional and cognitive processes, in which the ACC plays a pivotal role.

A reliable method for intracranial electrode implantation and chronic electrical stimulation in the mouse brain.

BACKGROUND: Electrical stimulation of brain structures has been widely used in rodent models for kindling or modeling deep brain stimulation used clinically. This requires surgical implantation of intracranial electrodes and subsequent chronic stimulation in individual animals for several weeks. Anchoring screws and dental acrylic have long been used to secure implanted intracranial electrodes in rats. However, such an approach is limited when carried out in mouse models as the thin mouse skull may not be strong enough to accommodate the anchoring screws. We describe here a screw-free, glue-based method for implanting bipolar stimulating electrodes in the mouse brain and validate this method in a mouse model of hippocampal electrical kindling. METHODS: Male C57 black mice (initial ages of 6-8 months) were used in the present experiments. Bipolar electrodes were implanted bilaterally in the hippocampal CA3 area for electrical stimulation and electroencephalographic recordings. The electrodes were secured onto the skull via glue and dental acrylic but without anchoring screws. A daily stimulation protocol was used to induce electrographic discharges and motor seizures. The locations of implanted electrodes were verified by hippocampal electrographic activities and later histological assessments. RESULTS: Using the glue-based implantation method, we implanted bilateral bipolar electrodes in 25 mice. Electrographic discharges and motor seizures were successfully induced via hippocampal electrical kindling. Importantly, no animal encountered infection in the implanted area or a loss of implanted electrodes after 4-6 months of repetitive stimulation/recording. CONCLUSION: We suggest that the glue-based, screw-free method is reliable for chronic brain stimulation and high-quality electroencephalographic recordings in mice. The technical aspects described this study may help future studies in mouse models.

[Anticonvulsant and neuroprotective effects of cyclopentyladenosine on the model of convulsive status in rats].

The neuroprotective and anticonvulsant effects of cyclopentyladenosine (CPA) have been studied on a new experimental model of the convulsive status in rats aged 3-4 months and 10 days. The convulsive status was modeled by intracerebroventricular injection of ferakril (water-soluble polymer of polyacrylic acid) solution. It is established that prophylactic administration of CPA results in a relatively lower degree of neurological deficit, both in the acute phase and on the next day, compared to the untreated control. Considering that adenosine receptor agonists are analogs of the natural metabolites that have minimal side effects and expressed neuroprotective properties, the use of agents of this group is perspective for both prevention and treatment of seizure conditions in neurology and neurosurgery.

Provoked and reflex seizures: surprising or common?

Most patients with epilepsy report that seizures are sometimes, or exclusively, provoked by general internal precipitants (such as stress, fatigue, fever, sleep, and menstrual cycle) and by external precipitants (such as excess alcohol, heat, bathing, eating, reading, and flashing lights). Some patients describe very exotic and precise triggers, like tooth brushing or listening to a particular melody. Nevertheless, the most commonly noticed seizure increasers by far are stress, lack of sleep, and fatigue. Recognized reflex seizure triggers are usually sensory and visual, such as television, discotheques, and video games. Visually evoked seizures comprise 5% of the total of 6% reflex seizures. The distinction between provocative and reflex factors and seizures seems artificial, and in many patients, maybe all, there is a combination of these. It seems plausible that all of the above-mentioned factors can misbalance the actual brain network; at times, accumulation of factors leads then to primary generalized, partial, or secondarily generalized seizures. If the provoking factors are too exotic, patients may be sent to the psychiatrist. Conversely, if the seizure-provoking fluctuating mechanisms include common habits and environmental factors, these may hardly be considered as provocative factors. Awareness of precipitating factors and its possible interactions might help us to unravel the pathophysiology of epilepsy and to change the notion that seizure occurrence is unpredictable. This article provides an overview of the epidemiology, classification, diagnosis, treatment, and especially similarities in the variety of provocative and reflex factors with resulting general hypotheses.

Dynamics of large-scale cortical interactions at high gamma frequencies during word production: event related causality (ERC) analysis of human electrocorticography (ECoG).

Intracranial EEG studies in humans have shown that functional brain activation in a variety of functional-anatomic domains of human cortex is associated with an increase in power at a broad range of high gamma (>60Hz) frequencies. Although these electrophysiological responses are highly specific for the location and timing of cortical processing and in animal recordings are highly correlated with increased population firing rates, there has been little direct empirical evidence for causal interactions between different recording sites at high gamma frequencies. Such causal interactions are hypothesized to occur during cognitive tasks that activate multiple brain regions. To determine whether such causal interactions occur at high gamma frequencies and to investigate their functional significance, we used event-related causality (ERC) analysis to estimate the dynamics, directionality, and magnitude of event-related causal interactions using subdural electrocorticography (ECoG) recorded during two word production tasks: picture naming and auditory word repetition. A clinical subject who had normal hearing but was skilled in American Signed Language (ASL) provided a unique opportunity to test our hypothesis with reference to a predictable pattern of causal interactions, i.e. that language cortex interacts with different areas of sensorimotor cortex during spoken vs. signed responses. Our ERC analyses confirmed this prediction. During word production with spoken responses, perisylvian language sites had prominent causal interactions with mouth/tongue areas of motor cortex, and when responses were gestured in sign language, the most prominent interactions involved hand and arm areas of motor cortex. Furthermore, we found that the sites from which the most numerous and prominent causal interactions originated, i.e. sites with a pattern of ERC "divergence", were also sites where high gamma power increases were most prominent and where electrocortical stimulation mapping interfered with word production. These findings suggest that the number, strength and directionality of event-related causal interactions may help identify network nodes that are not only activated by a task but are critical to its performance.

Seizures during pegylated interferon and ribavirin therapy for chronic Hepatitis C: observations from the WIN-R trial.

BACKGROUND: Seizures are reported as an uncommon side effect of interferon therapy. AIM: To determine the frequency and presentation of seizures occurring during pegylated interferon-α (PEG-IFNα) and ribavirin therapy for chronic hepatitis C. METHODS: Patients were identified using data from the WIN-R trial database, a US multicenter study comparing fixed (800 mg) versus weight-based (800 to 1400 mg) daily dosing of ribavirin in combination with PEG-IFNα-2b (1.5 µg/kg/wk). RESULTS: Of the 4913 enrolled patients, 8 (0.16%) had a seizure. Three patients had a grand mal seizure and the seizure type was unknown in 5 patients. At the time of seizure, 6 patients were taking antidepressants (including 3 on bupropion), 1 was hyponatremic, and 1 had consumed a significant amount of alcohol. One patient had a history of seizures. Neuroimaging and electroencephalographic studies were negative. Antiepileptic medications were continued in the patient with a history of seizures and initiated in 1 patient. PEG-IFNα-2b plus ribavirin therapy was continued in 2 patients following seizure and neither experienced a recurrent seizure. CONCLUSIONS: Seizures occur infrequently in patients receiving PEG-IFNα-2b plus ribavirin, and appear to be associated with other risk factors including antidepressant use.

Depiction of seizure first aid management in medical television dramas.

OBJECTIVES: The objective of this study was to investigate whether medical television dramas portray proper seizure first aid. METHODS: Episodes of the four highest-rated US medical dramas ("Grey's Anatomy," "House M.D.", "Private Practice," and "ER") were screened for the presence of seizures. "Patient" age, sex, semiology, and etiology were recorded. The appropriateness of seizure first aid management was determined by comparison to the Epilepsy Foundation of America (EFA) guidelines. RESULTS: Among 364 television programs, 65 seizures (in 59 individuals) were identified (30 males; 29 females). Seizures were primary or secondarily generalized tonic-clonic in 53 (81.5%) cases. Other seizure types included complex partial (5, 7.7%), simple partial (1, 1.5%), myoclonic (1, 1.5%), absence (1, 1.5%), and psychogenic (1, 1.5%). On 63 occasions (96.9%), first aid was performed by a health care professional. First aid management was judged appropriate in 21 (32.3%) seizures, inappropriate in 28 (43.1%), and indeterminate in 16 (24.6%). Inappropriate practices included holding the person down (17, 26.2%), trying to stop the involuntary movements (10, 15.4%) and putting something in the person's mouth (11, 16.9%). CONCLUSIONS: The first aid management of seizures performed by actors portraying health care professionals was inappropriate in nearly half of all cases. Inaccurate depiction of seizure first aid management may contribute to misinformation of the general public. The television industry could easily incorporate the simple first aid EFA seizure guidelines as a public service without sacrificing dramatic impact.

Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures.

PURPOSE: Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus-pituitary-adrenal (HPA) axis and its end-product cortisol. We tested several relevant HPA-axis functions in patients with PNES and related them to trauma history. METHODS: Cortisol awakening curve, basal diurnal cortisol, and negative cortisol feedback (using a 1 mg dexamethasone suppression test) were examined in 18 patients with PNES and 19 matched healthy controls (HCs) using saliva cortisol sampling on two consecutive days at 19 time points. Concomitant sympathetic nervous system (SNS) activity was assessed by analyzing saliva alpha-amylase (sAA). RESULTS: Patients with PNES showed significantly increased basal diurnal cortisol levels compared to HCs. This effect was driven mainly by patients reporting sexual trauma who showed a trend toward higher cortisol levels as compared to patients without a sexual trauma report. Importantly, the increased basal diurnal cortisol levels in patients were not explained by depression, medication, or smoking, or by current seizures or group differences in SNS activity. DISCUSSION: This is the first study showing that basal hypercortisolism in patients with PNES is independent of the acute occurrence of seizures. In addition, basal hypercortisolism was more pronounced in traumatized patients with PNES as compared to nontraumatized patients with PNES. These findings suggest that HPA-axis activity provides a significant neurobiologic marker for PNES.

Recognizing and refuting the myth of tongue swallowing during a seizure.

OBJECTIVE: There is a harmful myth that persists in modern culture that one should place objects into a seizing person's mouth to prevent "swallowing the tongue." Despite expert guidelines against this, the idea remains alive in popular media and public belief. We aimed to investigate the myth's origins and discredit it. METHODS: A medical and popular literature review was conducted for the allusions to "swallowing one's tongue" and practice recommendations for and against placing objects into a seizing person's mouth. Current prevalence of these beliefs and relevant anatomy and physiology were summarised. RESULTS: The first English language allusions to placing objects in a patient's mouth occurred in the mid-19th century, and the first allusions to swallowing one's tongue during a seizure occurred in the late 19th century. By the mid-20th century, it was clear that some were recommending against the practice of placing objects in a patient's mouth to prevent harm. Relatively recent popular literature and film continue to portray incorrect seizure first aid through at least 2013. There is ample modern literature confirming the anatomical impossibility of swallowing one's tongue and confirming the potential harm of putting objects in a patient's mouth. CONCLUSION: One cannot swallow their tongue during a seizure. Foreign objects should not be placed into a seizing person's mouth. We must continue to disseminate these ideas to our patients and colleagues. As neurologists, we have an obligation to champion safe practices for our patients, especially when popular media and culture continue to propagate dangerous ones.

Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures.

PURPOSE: Psychogenic nonepileptic seizures (PNES) have long been considered as paroxysmal dissociative symptoms characterized by an alteration of attentional functions caused by severe stress or trauma. Although interpersonal trauma is common in PNES, the proposed relation between trauma and attentional functions remains under explored. We examined the attentional processing of social threat in PNES in relation to interpersonal trauma and acute psychological stress. METHODS: A masked emotional Stroop test, comparing color-naming latencies for backwardly masked angry, neutral, and happy faces, was administered to 19 unmedicated patients with PNES and 20 matched healthy controls, at baseline and in a stress condition. Stress was induced by means of the Trier Social Stress Test and physiologic stress parameters, such as heart rate variability (HRV) and cortisol, were measured throughout the experiment. RESULTS: No group differences related to the acute stress induction were found. Compared to controls, however, patients displayed a positive attentional bias for masked angry faces at baseline, which was correlated to self-reported sexual trauma. Moreover, patients showed lower HRV at baseline and during recovery. DISCUSSION: These findings are suggestive of a state of hypervigilance in patients with PNES. The relation with self-reported trauma, moreover, offers the first evidence linking psychological risk factors to altered information processing in PNES.

Mouth breathing increases the pentylenetetrazole-induced seizure threshold in mice: a role for ATP-sensitive potassium channels.

Nasal obstruction and consequent mouth breathing have been shown to change the acid-base balance, producing respiratory acidosis. Additionally, there exists a large body of evidence maintaining that acidosis affects the activity of ATP-sensitive potassium (K(ATP)) channels, which play a crucial role in the function of the central nervous system (CNS), for example, in modulating seizure threshold. Thus, in the study described here, we examined whether mouth breathing, induced by surgical ligation of nostrils, could affect the seizure threshold induced by pentylenetetrazole in male NMRI mice. Using the selective K(ATP) channel opener (diazoxide) and blocker (glibenclamide), we also evaluated the possible role of K(ATP) channels in this process. Our data revealed that seizure threshold was increased 6 to 72 hours after nasal obstruction, reaching a peak 48 hours afterward, compared with either control or sham-operated mice (P<0.01). There was a significant decrease in pH of arterial blood samples and increase in CO(2) partial pressure (PCO(2)) during this time. Systemic injection of glibenclamide (1 and 2mg/kg, ip, daily) significantly prevented the increase in seizure threshold in 48-hour bilaterally nasally obstructed mice, whereas it had no effect on seizure threshold in sham-operated mice. Systemic injection of diazoxide (25mg/kg, ip, daily) had no effect on seizure threshold in all groups, whereas higher doses (50 and 100mg/kg, ip, daily) significantly increased seizure threshold in both 48-hour-obstructed and sham-operated mice. The decrease in seizure threshold induced by glibenclamide (2mg/kg, ip, daily) was prevented by diazoxide (25mg/kg, ip, daily). These results demonstrate for the first time that mouth breathing, which could result in respiratory acidosis, increases seizure threshold in mice and K(ATP) channels may play a role in this effect.

Identifying seizure-onset zone and visualizing seizure spread by fMRI: a case report.

AIM: To visualize by ictal, functional MRI, the initial haemodynamic change (i.e. putative seizure-onset zone) and subsequent seizure spread during an epileptic seizure. METHODS: A 20-year-old woman was investigated during a simple partial seizure consisting of right-sided mouth clonus. An internal reference curve, correlated with signal change pixelwise, was applied to obtain correlation coefficient maps. The reference curve was shifted scan by scan to examine the correlation at each time point. To demonstrate seizure onset and propagation, a lag time map was produced showing the temporal sequence of activation in various brain regions. RESULTS: fMRI analysis showed that the lower part of the insular cortex was activated first, and its signal alteration preceded the clinical beginning of the seizure (i.e. mouth clonus) by more than one minute. Most of the activations started before clinical seizure onset. The activation corresponding to the motor area of the right face showed only a 7.5 second-long, pre-ictal phase. BOLD signal alterations were also observed in the left caudate nucleus, left thalamus, along with various areas of the left cerebral and cerebellum hemispheres. CONCLUSIONS: The present study demonstrates a whole-brain activity simultaneously in time and space, during an epileptic seizure. Our results also support the existence of the pre-ictal state in epilepsy. Replication of our results would be of major interest for presurgical evaluation of patients with drug-resistant epilepsy.

Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy.

OBJECTIVE: Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve. APPROACH: We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long-Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter. MAIN RESULTS: In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls. SIGNIFICANCE: The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans.

Cleft-type cyclophanes confer neuroprotection against excitatory neurotoxicity in vitro and in vivo through inhibition of NMDA receptors.

The cleft-type cyclophanes (ACCn, DNCn and TsDCn) were found to strongly inhibit macroscopic currents at heteromeric NMDA receptors (NR1/NR2) but not AMPA receptors expressed in Xenopus oocytes at voltage-clamp recording. The inhibition by cleft-type cyclophanes was voltage-dependent, because the inhibition was larger at -100 mV than at -20 mV. Mutations at NR1 N650, located in the vestibule of the channel pore, reduced the inhibition by DNCn and TsDCn, suggesting that the residue (N650) interacts with these cleft-type cyclophanes. Cell toxicity of TsDCn on SH-SY5Y cells was slightly weaker than that of memantine. The neuroprotective effects of cleft-type cyclophanes against cell damage caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 10 microM DNCn or TsDCn into the medium ablated the neurotoxicity induced by NMDA, and a similar effect was also observed with memantine. The neuroprotective effects of cleft-type cyclophanes were then assayed on NMDA-induced seizures in mice. Intracerebroventricular injection of TsDCn (5 mg/mouse) decreased the seizure induced by intraperitoneal injection of NMDA (115 mg/kg) in mice. The results demonstrate that these cleft-type cyclophanes interact directly with the extracellular mouth of the NMDA channel pore and exhibit neuroprotective effects on NMDA-induced excitatory toxicity in primary cultured neurons and mice.

Physiological reactivity to spontaneously occurring seizure activity in dogs with epilepsy and their carers.

There is a complex bidirectional relationship between stress and epilepsy. Stressful stimuli and subsequent cortisol release act as a trigger for seizure activity in some individuals with epilepsy, and seizure activity itself may act as a stressor to the affected individual. Epilepsy is the most common chronic neurological condition in domestic dogs and requires chronic management by their human carers, impacting upon the quality of life of both dog and carer. Seizures occur unpredictably and may be stressful for carers to witness and manage. In the present study we investigated the role of seizure activity as a stressor, measuring the effect of spontaneously occurring seizure activity in dogs with epilepsy upon their own cortisol levels and that of their carers. Furthermore, we tested whether individual differences in HPA reactivity were associated with owner personality characteristics and the quality of the dog-carer relationship. Saliva samples were obtained from sixteen dog-carer dyads in the home setting 20 and 40minute post-seizure, and at time-matched points on the following (non-seizure) day. Significant differences in cortisol levels were found in dogs at 40minute post-seizure (265.1% increase), and at 20minute post-seizure in their carers (40.5% increase). No associations were found between cortisol reactivity and the strength of the dog-carer bond. Carers with higher neuroticism scores exhibited higher cortisol levels at both post-seizure sampling points. As there was a gender bias in the carer sample (15/16 were female), and there are known sex differences in cortisol reactivity in response to psychological stress, the conclusions of this study may be limited to female carers. These findings are the first to objectively demonstrate the acutely stressful effects of seizures in dogs with epilepsy and their carers.

Mandibulofacial dysostosis with microcephaly: A case presenting with seizures.

We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.

Forced mouth opening reaction: a primitive reflex released from cortical inhibition.

We report the case of a 6-year-old girl with congenital adrenal hyperplasia, who showed 'forced mouth opening reaction' during the course of acute encephalopathy due to adrenal crisis. When an object was moved towards her mouth, or when the corner of her mouth was stroked with a tongue depressor, she would immediately open her mouth fully and hold it open. This reaction appeared transiently during the course of her illness in association with other frontal release signs including the rooting, groping and palmomental reflexes. Magnetic resonance imaging showed bilateral widespread lesions involving the gray and white matters in the frontal lobes, and less severe lesions in the temporal and parietal areas. We propose that this unique reaction is a sign of a release phenomenon, and represents the emergence of primitive reflexes in the absence of cortical inhibition in some types of encephalopathies.