Robyn Whitney

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

The Utility of Surveillance Electroencephalography to Guide Early Antiepileptic Drug Therapy in Infants With Tuberous Sclerosis Complex

BACKGROUNDnSeizures are a common early presentation in infants with tuberous sclerosis complex (TSC) and can be preceded by electrographic changes on electroencephalography (EEG) before clinical seizure onset. A limited number of studies have addressed the initial EEG findings in TSC and the outcome of early treatment with antiepileptic medication prior to clinical seizure onset.nnnMETHODSnWe describe two infants with tuberous sclerosis complex whose surveillance EEG showed focal seizures that were not previously recognized by caregivers. We review previously reported patients with TSC with early EEG findings. Our patients were started on vigabatrin after the onset of focal seizures with the aim of preventing seizure recurrence, halting the possible progression to infantile spasms or focal seizures, and preventing neurodevelopmental decline.nnnRESULTSnBoth patients remain seizure free and have reached appropriate developmental milestones.nnnCONCLUSIONSnWe recommend early serial EEG monitoring once a diagnosis of TSC is suspected or confirmed in infants. Additional prospective studies are needed to assess the long-term outcome of early antiepileptic drug initiation as soon as electrographic seizure activity is detected.

Micturition-induced seizures: a rare form of reflex epilepsy.

BACKGROUNDnReflex seizures are referred to as epileptic seizures that are consistently precipitated by a specific sensory stimulus. Reflex seizures induced by micturition are very rare, and few cases have been described.nnnMETHODSnThis study reports a case of an 11-year-old girl with seizures provoked by micturition with reference made to previously reported cases in the literature. Seizures were characterized by head and eye deviation to the right, flexed dystonic posturing of the left upper limb, extension of the right upper limb, and eventual generalized tonic-clonic seizure. Ictal electroencephalogram revealed clear electrographic evolution from the midcentral region with secondary generalization. Magnetic resonance imaging of the head was normal. Seizures were treated with a combination of lacosamide and clobazam.nnnCONCLUSIONSnA midcentral ictal focus is in keeping with previous reports of this area as a potential epileptogenic center for micturition-induced seizures.

Incidence of sudden unexpected death in epilepsy in children is similar to adults

Objective To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada. Methods Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012). Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence. Results Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval 0.68–1.88) per 1,000 pediatric epilepsy person-years. The definite/probable incidence, including definite (n = 11), definite plus (n = 2), or probable (n = 3) SUDEP cases, was 1.11 (0.63–1.79). Capture-recapture analysis indicated an estimated 21 (16–39) definite/probable SUDEP cases occurred during the study period, giving an adjusted incidence of definite/probable SUDEP of 1.45 (0.90–2.22) per 1,000 pediatric epilepsy person-years. Conclusion SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

Spiders, ladybugs and bees: A case of unusual sensations in a child with cingulate epilepsy

Cingulate epilepsy is a rare form of epilepsy. Seizures from the anterior cingulate may present with mood change, fear, hypermotor activity, and autonomic signs, while posterior cingulate seizures resemble temporal lobe seizures. We describe a child with cingulate epilepsy who experienced unpleasant/painful sensory phenomenon. The sensations were described as spiders crawling on his forehead/right leg, ladybugs causing right ear pain and bees stinging his head/right extremities. Unpleasant sensory phenomenon/pain are rarely reported in cingulate epilepsy. Recognizing the role of the cingulate in producing pain/unusual sensory phenomenon is important, and may have localizing value when evaluating children for epilepsy surgery.

Paroxysmal Alpha Activity in Rett Syndrome: A Case Report

BACKGROUNDnRett syndrome is a severe neurodevelopmental disorder that primarily affects females. Classically the disorder is characterized by early normal development, followed by a period of regression and later recovery or stagnation. Typical features include a loss of purposeful hand skills, development of hand stereotypies, loss of spoken language, gait abnormalities, and acquired microcephaly. Epilepsy affects between 70% and 90% of individuals with Rett syndrome. A number of stereotypical electroencephalography findings have been reported in Rett syndrome.nnnPATIENT DESCRIPTIONnWe report a 9-year-old girl with Rett syndrome and epilepsy with a unique electroencephalography finding consisting of intermittent paroxysms of alpha activity in both wakefulness and sleep without clinical signs.nnnRESULTSnThis unique electroencephalography signature has not previously been reported in the English literature.nnnCONCLUSIONSnKnowledge of this unique electroencephalography pattern of diffuse paroxysmal alpha activity represents an additional distinct feature of the electroencephalogram in Rett syndrome and expands the spectrum of electroencephalography abnormalities in Rett syndrome.

Feasibility of Pedometer Use to Assess Physical Activity and Its Relationship With Quality of Life in Children With Epilepsy: A Pilot Study

BACKGROUNDnChildren and youth with epilepsy have lower rates of self-reported and parent-reported physical activity as well as quality of life when compared with their peers. Increased physical activity may be associated with improved health and quality of life in children and youth with epilepsy through biopsychosocial mechanisms; however, supportive evidence is lacking.nnnMETHODSnThis pilot study aims to determine the feasibility of pedometer use-an objective method-to assess daily steps and ability to complete quality of life-related questionnaires in children and youth with epilepsy. Feasibility was determined by percentage of study completion and participant enjoyment of physical activity in the form of walking as determined by the Childhood Self Adequacy and Predilection in Physical Activity. Secondary measures included the KidScreen 27 Quality of Life questionnaire, Childhood Depression Index, Body Mass Index, Harters Self Perception Scale, and Parental Stress Index.nnnCONCLUSIONSnEight of 12 eligible participants completed the study. Step counts ranged from 266 to 17,220 steps per day. Seven participants found physical activity enjoyable regardless of step count, suggesting they would be amenable to participate in a future physical activity program.

Perineal stimulation triggering seizures in a child with Dravet syndrome

The reported case demonstrates the clinical and EEG features of an interesting seizure precipitant in a child with Dravet Syndrome. It also showed exacerbation of preexisting epilepsy by mild head injury.

Hypsarrhythmia in epileptic spasms: Synchrony in chaos

PURPOSEnHypsarrhythmia is an electroencephalographic pattern associated with epileptic spasms and West syndrome. West syndrome is a devastating epileptic encephalopathy, originating in infancy. Hypsarrhythmia has been deemed to be the interictal brain activity, while the electrodecremental event associated with the spasms is denoted as the ictal event. Though characterized as chaotic, asynchronous and disorganized based on visual inspection of the EEG, little is known of the dynamics of hypsarrhythmia and how it impacts the developmental arrest of these infants.nnnMETHODSnAs an exploratory and feasibility study, we explored the dynamics of both hypsarrhythmia and electrodecremental events with EEG phase synchronization methods, and in a convenience sample of three outpatients with epileptic spasms. As ictal events are associated with prolonged phase synchronization, we hypothesized that if hypsarrhythmia was indeed the interictal brain activity that it would have lower phase synchronization than the electrodecremental event (ictal phase).nnnRESULTSnWe calculated both the phase synchronization index and the temporal variability of the index in three patients with infantile spasms. Two patients had hypsarrhythmia and electrodecremental events and one had hemi-hypsarrhythmia. We found that the hypsarrhythmia pattern was a more synchronized state than the electrodecremental event.nnnCONCLUSIONSnWe have observed that the hypsarrhythmia pattern may represent a more synchronized state than the electrodecremental event in infants with epileptic spasms. However, larger studies are needed to replicate and validate these findings. Additionally, further inquiry is required to determine the impact that increased synchronization may have on developmental outcomes in infants with epileptic spasms.

Peri-oral myoclonia with absences with multiple facial and upper body myoclonia: Overlap epilepsy syndrome

A 17-years old girl presented with an 8-year history of absences with peri-oral twitching, eyelid twitching and head nodding, with poor response to anti-epileptic drugs. Video EEG revealed ictal and inter-ictal generalized spike wave discharges, and absences with peri-oral (predominant), eyelid, neck and shoulder myoclonia. There was also prominent eye closure sensitivity. Conundrums regarding epilepsy syndrome classification and pathophysiology are discussed.