Visually sensitive seizures: An updated review by the Epilepsy Foundation.

Light flashes, patterns, or color changes can provoke seizures in up to 1 in 4000 persons. Prevalence may be higher because of selection bias. The Epilepsy Foundation reviewed light-induced seizures in 2005. Since then, images on social media, virtual reality, three-dimensional (3D) movies, and the Internet have proliferated. Hundreds of studies have explored the mechanisms and presentations of photosensitive seizures, justifying an updated review. This literature summary derives from a nonsystematic literature review via PubMed using the terms "photosensitive" and "epilepsy." The photoparoxysmal response (PPR) is an electroencephalography (EEG) phenomenon, and photosensitive seizures (PS) are seizures provoked by visual stimulation. Photosensitivity is more common in the young and in specific forms of generalized epilepsy. PS can coexist with spontaneous seizures. PS are hereditable and linked to recently identified genes. Brain imaging usually is normal, but special studies imaging white matter tracts demonstrate abnormal connectivity. Occipital cortex and connected regions are hyperexcitable in subjects with light-provoked seizures. Mechanisms remain unclear. Video games, social media clips, occasional movies, and natural stimuli can provoke PS. Virtual reality and 3D images so far appear benign unless they contain specific provocative content, for example, flashes. Images with flashes brighter than 20 candelas/m2 at 3-60 (particularly 15-20) Hz occupying at least 10 to 25% of the visual field are a risk, as are red color flashes or oscillating stripes. Equipment to assay for these characteristics is probably underutilized. Prevention of seizures includes avoiding provocative stimuli, covering one eye, wearing dark glasses, sitting at least two meters from screens, reducing contrast, and taking certain antiseizure drugs. Measurement of PPR suppression in a photosensitivity model can screen putative antiseizure drugs. Some countries regulate media to reduce risk. Visually-induced seizures remain significant public health hazards so they warrant ongoing scientific and regulatory efforts and public education.

Long-term clinical course and prognosis of hot water epilepsy: 15-Year follow-up.

OBJECTIVE: Hot water epilepsy (HWE) is a type of reflex epilepsy triggered by bathing with hot water. Hot water epilepsy is generally considered as a self-limiting benign disease although its long-term course and prognosis remains unknown. In this study, we aimed to determine the long-term clinical course and prognosis of hot water epilepsy and possible factors affecting them. METHODS: The diagnosis of HWE was made based on the clinical history obtained from patients and their first degree relatives witnessing to the seizures and video recordings of seizures if available; then, the type of seizure was identified. Good prognosis was defined as patients whose seizures were controlled with or without preventive measures and who did not require antiepileptic treatment. The poor prognosis was defined as patients whose seizures continued despite preventive measures and required antiepileptic treatment. RESULTS: The study included 50 (31 male and 19 female) patients with a mean follow-up of 17.63 ±â€¯10.46 (median, 15.0) years. The age at onset of seizure was 14.52 ±â€¯12.71 (median: 10.0) years. There were 38 (76%) patients in the good prognosis group. 18 (36%) of them achieved complete remission, who did not require preventive measures. In the remaining 20 (40%) patients, seizures could be controlled with only preventive measures. Seizures could be controlled with antiepileptic treatment in only 1 (2%) of 12 (24%) patients in the poor prognosis group. A significant relationship was found between the frequency of hot water seizures (HWSs) and poor prognosis (p = 0.019), as well as the presence of spontaneous seizures outside of bathing and poor prognosis (p = 0.000). SIGNIFICANCE: Hot water epilepsy, as previously known, is not a self-limiting benign disease. Approximately ¾ of the cases have a good prognosis, but the rest are in the case of chronic epilepsy. The low response rate to antiepileptics' treatment suggests that the pathogenesis of the HWE may differ from other epilepsies.

Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome.

Sensory processing abnormalities are frequently associated with autism spectrum disorders, but the underlying mechanisms are unclear. Here we studied auditory processing in a mouse model of Fragile X Syndrome (FXS), a leading known genetic cause of autism and intellectual disability. Both humans with FXS and the Fragile X mental retardation gene (Fmr1) knockout (KO) mouse model show auditory hypersensitivity, with the latter showing a strong propensity for audiogenic seizures (AGS) early in development. Because midbrain abnormalities cause AGS, we investigated whether the inferior colliculus (IC) of the Fmr1 KO mice shows abnormal auditory processing compared with wild-type (WT) controls at specific developmental time points. Using antibodies against neural activity marker c-Fos, we found increased density of c-Fos+ neurons in the IC, but not auditory cortex, of Fmr1 KO mice at P21 and P34 following sound presentation. In vivo single-unit recordings showed that IC neurons of Fmr1 KO mice are hyperresponsive to tone bursts and amplitude-modulated tones during development and show broader frequency tuning curves. There were no differences in rate-level responses or phase locking to amplitude-modulated tones in IC neurons between genotypes. Taken together, these data provide evidence for the development of auditory hyperresponsiveness in the IC of Fmr1 KO mice. Although most human and mouse work in autism and sensory processing has centered on the forebrain, our new findings, along with recent work on the lower brainstem, suggest that abnormal subcortical responses may underlie auditory hypersensitivity in autism spectrum disorders.NEW & NOTEWORTHY Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

Reflex Epilepsy with Hot Water: Clinical and EEG Findings, Treatment, and Prognosis in Childhood.

Hot water epilepsy (HWE) is a subtype of reflex epilepsy in which seizures are triggered by the head being immersed in hot water. Hot water or bathing epilepsy is the type of reflex epilepsy most frequently encountered in our clinic. We describe our patients with HWE and also discuss the clinical features, therapeutic approaches, and prognosis. Eleven patients (10 boys, 1 girl), aged 12 months to 13 years, admitted to the pediatric neurology clinic between January 2018 and August 2019, and diagnosed with HWE or bathing epilepsy based on International League Against Epilepsy (ILAE)-2017, were followed up prospectively for ∼18 months. Patients' clinical and electroencephalography (EEG) findings and treatment details were noted. All 11 patients' seizures were triggered by hot water. Age at first seizure was between 2 months and 12 years. Seizure types were generalized motor seizures, absence, and atonic. EEG was normal in two patients, but nine patients had epileptiform discharges. Magnetic resonance imaging of the brain was performed and reported as normal (except in one case). Histories of prematurity were present in two patients, unprovoked seizures in one, and low birth weight and depressed birth in the other. Patients with HWE have normal neuromuscular development and neurological examination results, together with prophylaxis or seizure control with a single antiepileptic drug, suggesting that it is a self-limited reflex epilepsy.

Age-Dependent and Sleep/Seizure-Induced Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy.

The loss-of-function S284L-mutant α4 subunit of the nicotinic acetylcholine receptor (nAChR) is considered to contribute to the pathomechanism of autosomal dominant sleep-related hypermotor epilepsy (ADSHE); however, the age-dependent and sleep-related pathomechanisms of ADSHE remain to be clarified. To explore the age-dependent and sleep-induced pathomechanism of ADSHE, the present study determined the glutamatergic transmission abnormalities associated with α4ß2-nAChR and the astroglial hemichannel in the hyperdirect and corticostriatal pathways of ADSHE model transgenic rats (S286L-TG) bearing the rat S286L-mutant Chrna4 gene corresponding to the human S284L-mutant CHRNA4 gene of ADSHE, using multiprobe microdialysis and capillary immunoblotting analyses. This study could not detect glutamatergic transmission in the corticostriatal pathway from the orbitofrontal cortex (OFC) to the striatum. Before ADSHE onset (four weeks of age), functional abnormalities of glutamatergic transmission compared to the wild-type in the cortical hyperdirect pathway, from OFC to the subthalamic nucleus (STN) in S286L-TG, could not be detected. Conversely, after ADSHE onset (eight weeks of age), glutamatergic transmission in the hyperdirect pathway of S286L-TG was enhanced compared to the wild-type. Notably, enhanced glutamatergic transmission of S286L-TG was revealed by hemichannel activation in the OFC. Expression of connexin43 (Cx43) in the OFC of S286L-TG was upregulated after ADSHE onset but was almost equal to the wild-type prior to ADSHE onset. Differences in the expression of phosphorylated protein kinase B (pAkt) before ADSHE onset between the wild-type and S286L-TG were not observed; however, after ADSHE onset, pAkt was upregulated in S286L-TG. Conversely, the expression of phosphorylated extracellular signal-regulated kinase (pErk) was already upregulated before ADSHE onset compared to the wild-type. Both before and after ADSHE onset, subchronic nicotine administration decreased and did not affect the both expression of Cx43 and pErk of respective wild-type and S286L-TG, whereas the pAkt expression of both the wild-type and S286L-TG was increased by nicotine. Cx43 expression in the plasma membrane of the primary cultured astrocytes of the wild-type was increased by elevation of the extracellular K+ level (higher than 10 mM), and the increase in Cx43 expression in the plasma membrane required pErk functions. These observations indicate that a combination of functional abnormalities, GABAergic disinhibition, and upregulated pErk induced by the loss-of-function S286L-mutant α4ß2-nAChR contribute to the age-dependent and sleep-induced pathomechanism of ADSHE via the upregulation/hyperactivation of the Cx43 hemichannels.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.

NEOCORTICAL IMPACT ON THE AUDIOGENIC SEIZURE ACTIVITY DEVELOPMENT.

Out of genetically determined epilepsy models a special interest draws the model of audiogenic seizures, which does not require whatever additional intervention (e.g. pharmacological or/and electric stimulation), because epileptic responses are elicited by specific sensory stimulation only. Notwithstanding the fact that different formations of the central nervous system are recruited in audiogenic seizure reactions, critical importance for the manifestation of this type epilepsy is attributed to the inferior colliculus and brainstem reticular nuclei. Significance of the diencephalic structures and the thalamic reticular nucleus, in particular for development and/or modulation of audiogenic seizures is ambiguous. Total of eight Krushinsky- Molodkina (KM) strain rats, weighting 250-300 g, served as the subjects of chronic experiments. The neocortex was bilaterally activated by way of administration of 1 µl strychnine (0.1% solutipon) with a microsyringe through a metal capillary prefixed on the cortical surface. Metal electrodes for recording electrical activity were implanted into the neocortex and brainstem reticular formation. Experiments have shown that against strychnine discharges in the neocortex there occurred an increase in the latency of wild runs and the pause between the first and second wild runs in response to a sound stimulus. Proceeding from the above-said, it can be assumed that activation of the neocortex must stipulate intensification of the thalamic reticular nucleus neuronal activity that, in turn, should have a modulating effect on the audiogenically induced seizure reactions.

Reflex Seizures Triggered by Diaper Change in Dravet Syndrome.

Dravet syndrome (DS) is a severe epilepsy syndrome characterized by early onset of multiple types of seizures. We report the first case of reflex seizures triggered by diaper change in a girl at 9 months old and 2 years old with a mutation in the SCN1A gene causing DS. Reflex seizures have been reported in patients with DS provoked by increased body temperature or visual stimulation. The case we report widens the spectrum of triggers causing reflex seizures in children with DS. Cortical hyperexcitability resulting from the genetic defect explains the tendency to experience such reflex seizures.

Musicogenic Epilepsy and Treatment of Affective Disorders: Case Report and Review of Pathogenesis.

Musicogenic epilepsy is a rare syndrome in which music triggers seizures. Affective network processing appears to play a key role in epileptogenesis. Many people with epilepsy suffer from comorbid affective disorders, the shared basis of which involves similar pathophysiologies, including deficiencies of serotonergic and noradrenergic function. Seizures and mood disorders may thus have reciprocal effects on one another, particularly in emotionally precipitated syndromes such as musicogenic epilepsy. I report a man with long-standing depression and anxiety who developed focal epilepsy that evolved into musicogenic seizures. His case suggests a pathophysiologic basis for this shared phenomenon.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition--including hyperactivity, repetitive behaviors, and seizures--as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor--which we call FRAX486--also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Antagonists of Metabotropic Glutamate Receptors Prevent the Development of Audiogenic Seizures.

Pretreatment with mGluR1 antagonist AIDA (1 mg/kg) nearly completely prevented the onset of tonic-clonic seizures and increased generation of NO in the cerebral cortex of rats with genetically determined audiogenic reaction to acoustic stimulation. Administration of mGluR5 antagonist MPEP (10 mg/kg) before audiogenic exposure was followed by a significant decrease in the degree of seizure and partially prevented increased generation of NO due to acoustic stimulation. These data indicate that mGlu receptors and NO play an important role in the pathogenetic mechanisms of audiogenic seizures.

Cortical network dysfunction in musicogenic epilepsy reflecting the role of snowballing emotional processes in seizure generation: an fMRI-EEG study.

AIM: Patients suffering from musicogenic epilepsy have focal seizures triggered by auditory stimuli. In some of these patients, the emotions associated with the music appear to play a role in the process triggering the seizure, however, the significance of these emotions and the brain regions involved are unclear. In order to shed some light on this, we conducted fMRI and EEG in a case of musicogenic epilepsy. METHODS: In a 32-year-old male patient with seizures induced by a specific piece of Russian music, we performed video-EEG monitoring as well as simultaneous fMRI and EEG registration. RESULTS: Video-EEG monitoring revealed a left temporo-frontal epileptogenic focus. During fMRI-EEG co-registration, BOLD signal alterations were not only found in the epileptogenic focus but also in areas known for their role in the processing of emotions. Prior to a seizure in some of these areas, BOLD contrasts exponentially increased or decreased. CONCLUSION: These results suggest that in our case, dysfunction of the regulation processes of the musically-induced emotions, and not the musical stimulus itself, led to the seizures.

[Rare cases of reflex epilepsy in patients with gliomas of the left hemisphere].

We present the cases of symptomatic reflex epilepsy in patients with left hemisphere tumors. The first case: a 23-year-old man has had tonic-clonic seizures of the tongue with rare secondary localization over the past several months. The seizures were caused by intense tongue movements, in particular rightward and leftward (when having chewing gum or a candy in his mouth), but not during speech production or eating. MRI scanning detected a small tumor in the lower segments of the central gyrus. It was found during the surgery under electrophysiological control that the tumor (Gr II astrocytoma) resided in the zone corresponding to the right half of the tongue and included this zone. The tumor was partially resected. The second patient, a 52-year-old man, has been suffering from generalized seizures since 1998. The seizures were caused by intense verbal load, in the beginning of spontaneous speech and subsequently when the patient was listening to others' speech or was writing. Spontaneous seizures emerged when the patient stopped taking his anti-seizure medications unilaterally. MRI showed glioma in the posterior segments of the left temporal lobe. The patient underwent radiation and chemotherapy. In 2013, the patient's condition worsened (right-sided hemiparesis and severe speech impairment emerged); the tumor was partially resected and an extensive cyst was opened. The third patient, a 38-year-old man with Gr III astrocytoma in the left insula with past medical history of spontaneous vegetative seizures, had only a seizure anticipation caused by strong smells. All the patients were prescribed chemo-, radiation, and anti-seizure therapy.

Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.

A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug. We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naïve) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60 mg) showed the strongest effect with an effect lasting up to 28 h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted.

Effects of age, sex, and sertraline administration on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP).

DBA/1 mice are susceptible to audiogenic seizure-induced respiratory arrest (S-IRA), leading to death, which is a model of human sudden unexpected death in epilepsy (SUDEP). Female DBA/1 mice exhibited 71% susceptibility to S-IRA on the third daily test when seizure testing began at postnatal day (PND) 24-30, which was slightly (>10%) but not significantly lower than males. When initial seizure testing was delayed (to >7 weeks of age), DBA/1 mice of both sexes exhibited significantly reduced S-IRA susceptibility, as compared to mice tested initially at PND 24-30. These sex and age issues had not been previously evaluated and may be important for the future use of this SUDEP model. We also observed that 30 min after administering a selective serotonin reuptake inhibitor (SSRI), sertraline (40, 50, or 75 mg/kg i.p.), a significantly reduced S-IRA incidence in DBA/1 mice occurred without blocking seizures, which may be relevant to SUDEP prevention.

Music and epilepsy: a critical review.

The effect of music on patients with epileptic seizures is complex and at present poorly understood. Clinical studies suggest that the processing of music within the human brain involves numerous cortical areas, extending beyond Heschl's gyrus and working within connected networks. These networks could be recruited during a seizure manifesting as musical phenomena. Similarly, if certain areas within the network are hyperexcitable, then there is a potential that particular sounds or certain music could act as epileptogenic triggers. This occurs in the case of musicogenic epilepsy, whereby seizures are triggered by music. Although it appears that this condition is rare, the exact prevalence is unknown, as often patients do not implicate music as an epileptogenic trigger and routine electroencephalography does not use sound in seizure provocation. Music therapy for refractory epilepsy remains controversial, and further research is needed to explore the potential anticonvulsant role of music. Dopaminergic system modulation and the ambivalent action of cognitive and sensory input in ictogenesis may provide possible theories for the dichotomous proconvulsant and anticonvulsant role of music in epilepsy. The effect of antiepileptic drugs and surgery on musicality should not be underestimated. Altered pitch perception in relation to carbamazepine is rare, but health care professionals should discuss this risk or consider alternative medication particularly if the patient is a professional musician or native-born Japanese. Studies observing the effect of epilepsy surgery on musicality suggest a risk with right temporal lobectomy, although the extent of this risk and correlation to size and area of resection need further delineation. This potential risk may bring into question whether tests on musical perception and memory should form part of the preoperative neuropsychological workup for patients embarking on surgery, particularly that of the right temporal lobe.

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.

Hot water epilepsy with pachygyria.

Hot water epilepsy (HWE) refers to a specific type of reflex epilepsy precipitated by the stimulus of bathing in hot water. Pathogenesis is still unknown and temporal lobe has been thought to take part in the epileptogenesis. HWE can be symptomatic of focal cortical malformation, and few cases were reported. This is the third report of HEW in which a parietal malformation has been observed. Our hypothesis that sensory cortex might be implicated in the epileptogenic process is corroborated by two previous reports on patients with HWE and malformation of the parietal cortical development.