Tuesday, February 28, 2017

Ultra-rare genetic variation in common epilepsies

Epi4K consortium.; Epilepsy Phenome/Genome Project.. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017 Feb;16(2):135-143.

Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies.
We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies.
We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes.

We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future.

Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.

In recent years, researchers have identified dozens of genes that, alone or in combination with other factors, cause rare pediatric epilepsies. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease treatment, have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy…

The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.

For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center…

The findings have important implications for clinical practice and for research. “At present, all common epilepsies are treated the same way, with the same group of medications,” said Dr. Goldstein. “But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype.”

“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”


Monday, February 27, 2017

Selfie epilepsy

P.M. Brna and K.G. Gordon.  “Selfie-Epilepsy”: A Novel Photosensitivity.   Seizure.  In press.



Photosensitivity is a well-described phenomenon; affecting a relatively small proportion of individuals with epilepsy. Typically people with photosensitive epilepsies are at risk of seizures induced by shimmering natural light, strobe lights and with particular patterns or flicker frequencies on television and video games.

Methods & Results

We present a novel case of photosensitivity captured during video EEG monitoring showing reproducible photosensitivity with the ever-popular social phenomenon; the “selfie.” The patient had previously demonstrated photosensitive myoclonus with intermittent photic stimulation on routine EEG.


This case suggests that taking “selfies” may represent a new area of caution for those with photosensitive epilepsies.

From the article

The popularity of the self-photograph coined “selfie” has risen dramatically over the last several years. In recent years, the risks of taking selfies in precarious situations such as driving or posing with weapons have become increasingly apparent. However, there may be additional unique risks for those with photosensitive epilepsy as many camera phones use a pulsed LED flash to enable red eye reduction prior to taking a photo in a dark environment. We are not aware of any previous reports of a photoparoxysmal response demonstrated while taking a “selfie”. Herein, we describe a patient with previously documented photosensitivity, clinical myoclonus and photoparoxysmal response to taking a “selfie” with a smartphone…

In addition, we noted time-locked bursts of generalized spike wave with the patient’s use of an iPhone-5 camera to take “selfies” with flash and red-eye reduction in a dimly-lit room. This was
only seen with the camera held close to the patient’s face at arm’s length. The adolescent was not aware of any unusual jerks with these paroxysmal EEG discharges and no accompanying myoclonus was seen on video monitoring…

The popularity of the “selfie” photo continues to grow being used by celebrities, politicians and the general public alike. Though photosensitivity is fairly uncommon among those with epilepsy, people with photosensitive epilepsies must be aware of potential triggers. The finding of a photosensitivity response to a “selfie” raises concern over this seemingly harmless everyday activity for those with a prominent photosensitive response. Injuries while taking “selfies” have already been frequently documented in the media but those with photosensitive epilepsies may need extra caution. There are reports of deaths and serious injury incurred while taking “selfies” and of frequent “selfies” taken while driving motor vehicles. If a person with epilepsy were to have myoclonus induced by the flash of a “selfie” they could certainly sustain significant injury; particularly if they were already in a dangerous situation.

There are frequent warning labels for people with epilepsy pertaining to the use of video games. Many of these are not substantiated by evidence of a real elevated risk of seizure while playing the particular video game. Nevertheless, these warning labels are pervasive. However, mobile phones capable of producing “selfies” with provoking flash frequencies do not come with any such
warning. We feel that this is an area for further consideration. Our finding was isolated to one patient discovered incidentally during continuous video EEG monitoring and should be corroborated in other individuals with known photosensitivity on EEG before any official warning labels would be recommended.

NORSEmen and women

Christian M. Cabrera Kang, Nicolas Gaspard, Suzette M. LaRoche and Brandon Foreman.  Survey of the diagnostic and therapeutic approach to new-onset refractory status epilepticus.  Seizure.  In press.

New-onset refractory status epilepticus (NORSE) is a syndrome of prolonged seizures that typically develops in otherwise healthy, young individuals without a history of epilepsy or obvious initial cause. The term was first coined in a case series of 7 young women with prior good health who developed refractory status epilepticus (RSE) with an extensive, negative diagnostic work-up and poor outcome. While the incidence of RSE is estimated between 9–43% of all episodes of SE, no such data exists for NORSE. Patients with NORSE experience prolonged lengths of stay in the hospital/intensive care unit (ICU) and myriad complications with poor short and long-term outcomes. In one study, the average duration of NORSE was 36 days, and the average length of stay in the ICU was 33.5 days. The costs of NORSE are substantial both in terms of functional outcome and healthcare dollars.

The etiology of NORSE is often presumed to be due to viral encephalitis, but more than half of cases remain cryptogenic despite extensive investigations.   In retrospective case series, autoimmune or paraneoplastic causes of encephalitis with RSE make up the majority of cases with an established etiology, and a proportion of cryptogenic cases may be caused by antibodies yet to be described. Immunotherapy has been proposed as empiric treatment for RSE and emerging evidence suggests that this may benefit patients with NORSE specifically. Currently, there are no published protocols to guide the diagnostic work-up of NORSE, and while there are general recommendations for the management of RSE, no specific guidelines address which treatment options should be given and when, particularly when it comes to immunotherapy. We sought to identify practice patterns in the diagnosis and management of NORSE in order to identify commonalities that could be used to standardize the approach to these patients and to identify areas of uncertainty that require further study…

Within 24 h, most practitioners obtain a non-contrast head CT (100%), continuous EEG (89%) and lumbar puncture (LP; 76%). Microbe serologies, particularly viral studies, are sent during this period by 42%. Between 24–72 h, 55% obtain a brain MRI. More than one-third also begin an autoimmune work-up (42%), anti-neuronal antibodies (40%), and cytology/flow cytometry (35%) during this period. After 72 h, no clear consensus emerged regarding further work-up. The majority of practitioners reported that they would never obtain a SPECT, brain/body PET, genetic testing or angiogram without an additional indication. Similarly, heavy metals, porphyrins, ovarian/testicular ultrasound, 14-3-3 protein, and neoplastic screening CT of the chest, abdomen, and pelvis were not regularly considered as part of the work-up…

For a patient with NORSE refractory to an initial anesthetic agent, respondents indicated they would first administer: additional AEDs (77%), additional anesthetics (52%), and antimicrobials (37%). Steroids (24%) were considered next followed by plasma exchange (PLEX; 28%). A five-day course of pulse-dose methylprednisolone was the most commonly used steroid regimen and typically started immediately in patients with a suspected autoimmune or paraneoplastic etiology, or when clinical symptoms, including RSE, do not improve within 1 week. Following immunotherapy, respondents reported using the ketogenic diet (41%) or hypothermia (25%).

Nearly one-third (29%) of respondents reported they would never use IVIG in the setting of NORSE; 24% would not use PLEX. Further, 29% eventually transition to steroid-sparing immunosuppressants. Most respondents do not consider transcranial magnetic stimulation, electroconvulsive therapy, or epilepsy surgery unless indicated for another reason.

Respondents were asked to select non-continuous, bolus-dose or oral anticonvulsants that they would use as adjunct treatment for ongoing RSE and rank the order in which they would initiate them. Most selected benzodiazepines first: lorazepam (93%; 39/42), midazolam (32%; 12/38) and diazepam (67%; 4/6) followed by fosphenytoin (55%; 30/55), phenytoin (38%; 10/26) and carbamazepine (33%; 2/6). Levetiracetam (34%; 24/71) was most commonly added third, and lacosamide (29%; 17/58) was fourth.

Efficacy was ranked the most influential determinant when choosing AEDs (64%) followed second by drug interactions (43%) and third by hemodynamic instability (36%). Respondents selected anesthetics in the following order: midazolam, propofol, pentobarbital/thiopental, and ketamine…

The most consistently tested causative agent was HSV, for which 99% tested CSF via PCR in the first 24 h. HSV is the most commonly diagnosed viral encephalitis and there is an established role for early treatment as delays beyond 48 h after hospital admission can be associated with a worse prognosis. Thus, it is often standard practice for anti-viral therapies to be started empirically and continued if diagnosis is confirmed. Ninety-two percent tested VZV within this same time period. We found that Enterovirus is less often tested at 61% compared to HSV and VZV, despite the combination of the three making up the vast majority of diagnosed viral encephalitides. Infectious etiologies with important public health implications, such as WNV and mycobacterium tuberculosis, as well as treatable disease like mycoplasma pneumoniae, were less frequently tested for and not included as part of the initial work-up.

We found that one-quarter of respondents would never perform an autoimmune or paraneoplastic work-up in the setting of NORSE unless indicated for another reason. This could result in a significant number of missed diagnoses as a recent multi-institutional retrospective review of 130 NORSE cases found that autoimmune and paraneoplastic were the most common identifiable etiologies at 19% and 18%, respectively, with 52% remaining cryptogenic. Further, the favored initial autoimmune work-up primarily encompassed rheumatologic antibodies, e.g., ANA, dsDNA, rheumatoid factor, ANCA, etc., while an expanded work-up included anti-neuronal antibodies. Ideally, autoimmune and paraneoplastic evaluations would coincide, as there is no evidence that one is more prevalent in NORSE than the other. This may be due to the higher expense of the anti-neuronal/paraneoplastic antibody panels or long wait times for results after sending the specimens to the few labs that are equipped to perform the analysis.

There was a preference of sending a serum and CSF specimen for the anti-neuronal/paraneoplastic work-up, which the majority of providers (72%) agreed was more appropriate than sending any one specimen alone. This is consistent with increased sensitivity for NMDA receptor antibodies when both CSF and serum are tested (sensitivity 100% and 85.6%, respectively). Some providers may desire to avoid subjecting a patient to a repeat LP, after an initial one that was performed within 24 h to rule out infectious etiologies. However, repeat LP may ultimately be necessary in some situations even to fully rule out infectious causes as the HSV CSF PCR sensitivity increases 4 or more days after symptom onset.

A majority of respondents would not perform a malignancy work-up, e.g., CT, PET, or ultrasound, in the setting of NORSE despite paraneoplastic disorders (PND) being a commonly diagnosed etiology.  A neoplastic work-up would be particularly important in the setting of a positive anti-neuronal antibody, especially one with a known association with tumor (e.g., NMDA receptor antibodies and ovarian teratoma), as treatment of the tumor may be therapeutic/curative for the PND . There may exist some system barriers to obtaining inpatient PET scans, as RSE likely would not be a recognized indication. However, in situations where the etiology of NORSE is cryptogenic or the clinical scenario points to PND, then this work-up would be warranted.

Based on our survey of, expert opinion on the diagnostic approach to NORSE, studies performed within the initial 24 h of presentation include CT head, continuous EEG, LP and microbe serologies that include HSV, VZV, and bacterial evaluation. Thereafter, MRI brain followed by repeat LP to evaluate for an autoimmune or neoplastic cause should be obtained. Additional work-up should be individualized to the patient and based on clinical context.

Saturday, February 25, 2017

Relative efficacy, safety and tolerability of prophylactic medications for migraine

He A, Song D, Zhang L, Li C. Unveiling the relative efficacy, safety and tolerability of prophylactic medications for migraine: pairwise and network-metaanalysis. J Headache Pain. 2017;18(1):26.

A large number patients struggle with migraine which is classified as a chronic disorder. The relative efficacy, safety and tolerability of prophylactic medications for migraine play a key role in managing this disease.
We conducted an extensive literature search for popular prophylactic medications that are used for migraine patients. Pairwise meta-analysis and network meta-analysis (NMA) were carried out sequentially for determining the relative efficacy, safety and tolerability of prophylactic medications. Summary effect for migraine headache days, headache frequency, at least 50% reduction in headache attacks, all-adverse events, nausea, somnolence, dizziness, withdrawal and withdrawal due to adverse events were produced by synthesizing both direct and indirect evidence.
Patients with three interventions exhibited significantly less average migraine headache days compared with those treated by placebo (topiramate, propranolol, divalproex). Moreover, topiramate and valproate exhibited a significantly increased likelihood of at least 50% reduction in migraine headache attacks compared to placebo. Patients with topiramate and propranolol also exhibited significantly reduced headache frequency compared to those with placebo. On the other hand, patients with divalproex exhibited significantly higher risk of nausea compared to those with placebo, topiramate, propranolol, gabapentin and amitriptyline. Finally, divalproex was associated with an increased risk of withdrawal compared to placebo and propranolol.
Topiramate, propranolol and divalproex may be more efficacious than other prophylactic medications. Besides, the safety and tolerability of divalproex should be further verified by future studies.

From the article:

A total of ten direct comparisons with respect to each endpoint were produced by using pairwise meta-analysis. Patients with topiramate exhibited significantly less average headache days, less headache frequency, a higher likelihood of at least 50% reduction compared to those with placebo (migraine headache days: −0.28, 95% CI = −0.53 to −0.03; headache frequency: −0.31, 95% CI = −0.45 to −0.17; ≥ 50% reduction: OR = 2.33, 95% CI = 1.58–3.42). However, patients with topiramate appeared to have significantly higher risk of all-adverse events and withdrawal due to adverse events compared to those with placebo (all-adverse events: OR = 1.35, 95% CI = 1.06–1.73, withdrawal due to adverse events: OR = 2.08, 95% CI = 1.56–2.78). Patients with propranolol exhibited a significantly less average headache days but higher risk of all-adverse events, somnolence and withdrawal due to adverse events compared to those with placebo (migraine headache days: −0.29, 95% CI = −0.49 to −0.09; all-adverse events: OR = 2.02, 95% CI = 1.05–4.08, somnolence: OR = 4.33, 95% CI = 1.21 to 15.53, withdrawal due to adverse events: OR = 1.87, 95% CI = 1.09 to 3.09). Although there is no significant differences in the average migraine days, headache frequency or the likelihood of at least 50% reduction in headache attacks between patients with gabapentin and those with placebo, gabapentin appeared to be associated with an increased risk of somnolence and dizziness (somnolence: OR = 2.23, 95% CI = 1.11 to 4.46; dizziness: OR = 3.13, 95% CI = 1.73 to 5.56). Patients treated with amitriptyline or divalproex exhibited a reduced headache days or headache frequency as well as a better performance in at least 50% reduction in headache attacks compared to those with placebo (amitriptyline: headache frequency: −0.36, 95% CI = −0.62 to −0.10; ≥ 50% reduction: OR = 1.81, 95% CI = 1.03–3.20; divalproex: migraine headache days: −0.40, 95% CI = −0.61 to −0.18; ≥ 50% reduction: OR = 4.27, 95% CI = 1.30–13.99), however, this was offset by an increased risk of all-adverse events or nausea (amitriptyline: all-adverse events: OR = 2.20, 95% CI = 1.04–4.66; divalproex: nausea: OR = 2.23, 95% CI = 1.21–4.10). Besides that, we were not able to identify any significant results between direct comparisons produced by conventional meta-analysis. Besides, propranolol was safer comparing to topiramate (all-adverse events: OR = 0.57, 95% CI = 0.36–0.90; withdrawal: OR = 0.66, 95% CI = 0.44–0.99; withdrawal due to adverse events: OR = 0.58, 95% CI = 0.37–0.91)…

Results of our NMA indicated that three interventions may be particularly efficacious for reducing the corresponding symptoms of migraine: divalproex, propranolol and valproate. In our study, divalproex ranked the highest with respect to the reduction of monthly headache days whereas propranolol appeared to be the most preferable intervention for reducing headache frequency. Moreover, our study also suggested that valproate exhibited superior performance with respect to at least 50% reduction in headache attacks. Accordingly to the American Academy of Neurology (AAN) and the American Society of Headache (AHS), divalproex is classified as level-A medication and it is offered to patients for migraine prophylaxis. Another study conducted by Kaniecki et al. revealed that both divalproex and propranolol significantly reduced headache frequency and the number of headache days compared to placebo, however, there was no significant difference in the efficacy between the two interventions. The above conclusions were verified by our NMA which did not suggest any significant difference in the efficacy between divalproex and propranolol. As suggested by AAN and AHS, valproate is also classified as level-A medication that should be offered to migraine patients. The efficacy of valproate in reducing migraine attacks has been verified by several studies, for instance, Sørensen et al. was the first one who suggested that valproate exhibited a noteworthy effect on patients with severe migraine with respect to migraine prophylaxis. Although our study suggested that patients with valproate were more likely to experience at least 50% reduction in migraine attacks than those with placebo, the wide confidence interval resulted from potential inconsistency or inadequate evidence should be addressed by conducting large-scale studies in order to verify the above conclusions.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/02/22/migraineefficacysafetytolerabilitynetwork-meta-analysis/7065588/?category=latest&page_id=6

Adolescent daytime sleepiness as a risk factor for adult crime

Raine A, Venables PH. Adolescent daytime sleepiness as a risk factor for adult crime. J Child Psychol Psychiatry. 2017 Feb 23. doi: 10.1111/jcpp.12693. [Epub ahead of print]

While recent cross-sectional research has documented a relationship between sleep problems and antisocial behavior, the longitudinal nature of this relationship is unknown. This study tests both the hypothesis that adolescent daytime sleepiness is associated with later adult criminal offending, and also tests a biopsychosocial mediation model in which social adversity predisposes to sleepiness, which in turn predisposes to attentional impairment, and to adult crime.
Schoolboys aged 15 years rated themselves on self-report sleepiness. Age 15 antisocial behavior was assessed by teacher ratings and self-reports, while convictions for crime were assessed at age 29. Attentional capacity at age 15 was assessed by autonomic orienting, with arousal assessed by the electroencephalogram (EEG).
Sleepy adolescents were more likely to be antisocial during adolescence, and were 4.5 times more likely to commit crime by age 29. The sleepiness-adult crime relationship withstood control for adolescent antisocial behavior. Self-report sleepiness predicted to adult crime over and above objective measures of daytime sleepiness (EEG theta activity) and age 15 antisocial behavior. Poor daytime attention partly mediated the sleep-crime relationship. Mediation analyses also showed that social adversity predisposed to daytime sleepiness which was associated with reduced attention which in turn predisposed to adult crime.
Findings are the first to document a longitudinal association between sleepiness in adolescence and crime in adulthood. The longitudinal nature of this relationship, controlling for age 15 antisocial behavior, is consistent with the hypothesis that adolescent sleepiness predisposes to later antisociality. Findings are also consistent with the notion that the well-established link between social adversity and adult crime is partly explained by sleepiness. Results suggest that a very brief and simple assessment of subjective daytime sleepiness may have prognostic clinical value, and that interventions to reduced sleepiness could be a useful avenue for future crime prevention.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/02/24/adolescent-daytime-sleepiness-crime/7069496/?category=latest&page_id=2

Friday, February 24, 2017

Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children

B. Chen, K. Detyniecki, H. Choi, L. Hirsch, A. Katz, A. Legge, R. Wong, A. Jiang, R. Buchsbaum, P. Farooque.  Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy.  European Journal of Paediatric Neurology.  In press.

•Psychiatric/behavioral side effects of AEDs are compared in pediatric patients.
•Psychiatric history and intractable epilepsy are associated with higher PBSE rates.
•Absence seizures and frontal lobe epilepsy are associated with higher PBSE rates.
•Levetiracetam use is associated with higher PBSE incidence in pediatric patients.
•Zonisamide use is associated with higher cessation rate secondary to PBSE.

The objective of the study was to compare the psychiatric and behavioral side effect (PBSE) profiles of both older and newer antiepileptic drugs (AEDs) in children and adolescent patients with epilepsy.

We used logistic regression analysis to test the correlation between 83 non-AED/patient related potential predictor variables and the rate of PBSE. We then compared for each AED the rate of PBSEs and the rate of PBSEs that led to intolerability (IPBSE) while controlling for non-AED predictors of PBSEs.

922 patients (≤18 years old) were included in our study. PBSEs and IPBSEs occurred in 13.8% and 11.2% of patients, respectively. Overall, a history of psychiatric condition, absence seizures, intractable epilepsy, and frontal lobe epilepsy were significantly associated with increased PBSE rates. Levetiracetam (LEV) had the greatest PBSE rate (16.2%). This was significantly higher compared to other AEDs. LEV was also significantly associated with a high rate of IPBSEs (13.4%) and dose-decrease rates due to IPBSE (6.7%). Zonisamide (ZNS) was associated with significantly higher cessation rate due to IPBSE (9.1%) compared to other AEDs.


Patients with a history of psychiatric condition, absence seizures, intractable epilepsy, or frontal lobe epilepsy are more likely to develop PBSE. PBSEs appear to occur more frequently in adolescent and children patients taking LEV compared to other AEDs. LEV-attributed PBSEs are more likely to be associated with intolerability and subsequent decrease in dose. The rate of ZNS-attributed IPBSEs is more likely to be associated with complete cessation of AED.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/02/21/epilepsy-seizure-psychiatric-side-effect-behavioral/7058998/?category=latest&page_id=9

Thursday, February 23, 2017

Early motor skills development predicting language development in autism

Hayley C. Leonard, Rachael Bedford, Andrew Pickles, Elisabeth L. Hill, the BASIS Team.   Predicting the rate of language development from early motor skills in at-risk infants who develop autism spectrum disorder.   Research in Autism Spectrum Disorders. Volumes 13–14, May 2015, Pages 15–24.

• Motor and social skills are closely related in typical and atypical development.
• The link between motor and language skills was examined in infants at-risk of ASD.
• Motor skills predicted rate of language development in infants who developed ASD.
• This relationship was evident for expressive but not receptive language.
• Research in ASD should focus on interactions between these systems over development.

The aim of the current paper was to use data from a prospective study to assess the impact of early motor skills on the rate of language development in infants with an older sibling with autism spectrum disorder (ASD), who are at increased risk of developing ASD themselves. Infants were tested prospectively at four points (7, 14, 24 and 36 months), and were assessed for ASD at the last visit. Latent growth curve analysis was used to model rate of language development using the Vineland Adaptive Behavior Scales between 7–36 months in infants at high and low familial risk for ASD. Motor scores from the Mullen Scales of Early Learning at 7 months were used as predictors of language growth. Gross Motor scores predicted the subsequent rate of expressive, but not receptive, language development in at-risk siblings who were later diagnosed with ASD. Although the pattern was similar for fine motor skills, the relationship did not reach significance. It seems that early motor delay impacts the rate of development of expressive language, and this may be of particular importance to infants at increased risk of developing ASD.

Leonard HC, Bedford R, Charman T, Elsabbagh M, Johnson MH, Hill EL; BASIS
team.. Motor development in children at risk of autism: a follow-up study of
infant siblings. Autism. 2014 Apr;18(3):281-91.


Recently, evidence of poor or atypical motor skills in autism spectrum disorder has led some to argue that motor impairment is a core feature of the condition. The current study uses a longitudinal prospective design to assess the development of motor skills of 20 children at increased risk of developing autism spectrum disorder, who were recruited and tested at 9 and 40 months of age, on the basis of having an older sibling diagnosed with the condition. All children completed a range of motor, face processing, IQ and diagnostic assessments at a follow-up visit (aged 5-7 years), providing a detailed profile of development in this group from a number of standardised, parental report and experimental measures. A higher proportion of children than expected demonstrated motor difficulties at the follow-up visit and those highlighted by parental report as having poor motor skills as infants and toddlers were also more likely to have lower face processing scores and elevated autism-related social symptoms at 5-7 years, despite having similar IQ levels. These data lend support to the argument that early motor difficulties may be a risk factor for later motor impairment as well as differences in social communication and cognition, traits that are related to autism spectrum disorder.

Should doctors wear beards?

In 1895, a physician by the name of F.A. Colby published a correspondence in the Boston Medical and Surgical Journal; his letter was titled, "Should Doctors Wear Beards?"

"I wear a beard," Dr. Colby wrote, "and grant you that probably, like many of my professional brothers, it is a comfort to stroke it and look wise while making a doubtful diagnosis. It is a comfort in the cold, bleak days of winter...I cultivated mine sedulously after graduation, so that I might lose the title of 'the young doctor.'"…

Still, Dr. Colby's 1895 letter brings up a longstanding controversy over whether physicians should be growing beards at all—hygiene.

"We note with what care the surgeon disinfects his hands, arms, instruments, all that comes in contact with the patient in a surgical case," Dr. Colby wrote,"but the beard of the doctor attending diseases and so easily communicable as some are, how many thoroughly disinfect that before visiting the next patient? Surely we should take every precaution, or not wear beards."

Colby's concerns found their way into the next century, as researchers began to study the question of beard hygiene. In 1967, a study titled, "Microbiological Laboratory Hazard of Bearded Men" appeared in the journal Applied Microbiology. The authors tested "the hypothesis that a bearded man subjects his family and friends to risk of infection if his beard is contaminated by infectious microorganisms while he is working in a microbiological laboratory."…

Nonetheless, later studies raised similar concerns about the possible infectious risks of beards. For example, a 2000 study in the journal Anaesthesia examined the effectiveness of surgical masks for preventing bacterial contamination, finding bearded subjects shed considerably more bacteria—even when wearing masks—compared to non-bearded subjects. The authors recommended that surgical personnel “avoid wiggling the face mask” and that “bearded males may also consider removing their beards.”…


But in the last few years, new studies have cast doubt on the dangers of beards in the healthcare settings. In 2014, one of the largest studies on this topic upended the prevailing wisdom. The study examined over 400 medical staff and found bacterial colonization was “similar in male healthcare workers with and without facial hair." Of note, staff without facial hair had higher rates of colonization with pathogenic bacteria like methicillin-resistant coagulase-negative staphylococci.

Published in 2016, another study–titled “To Beard or Not to Beard? Bacterial Shedding Among Surgeons”—re-examined the question of beard hygiene in surgical settings. The authors compared bearded and clean-shaven subjects who performed facial motions behind surgical masks. This time, however, "bearded surgeons did not appear to have an increased likelihood of bacterial shedding compared with their nonbearded counterparts while wearing surgical masks."…

Debates over hair hygiene are inciting controversy among leading medical organizations. For instance, the Association of periOperative Registered Nurses, an organization representing over 40,000 nurses, issued guidelines calling for stricter hair covering in operating rooms. These regulations, which led some hospitals to change surgical attire, have stirred outrage among surgeons. The American College of Surgeons released competing guidelines last year, directly challenging the nursing group's proposals…

Healthcare-associated infections remain a pressing issue, but the jury is still out on whether beards truly pose a risk to patients and colleagues in clinical care. After 122 years, we’ve yet to answer Dr. Colby’s question:

"In these days of microbes, bacilli, and crawling, creeping and flying things that find a resting-place for development of diseases in the human system, coming from the air we breathe, liable to assault the weak and strong...should doctors wear beards?"

Courtesy of Doximity

                                                                  me again

Tuesday, February 21, 2017


An Oklahoma mom has decided to give birth to her terminally ill daughter so that she can donate the newborn’s organs.

Keri Young, from Oklahoma City, was devastated to discover that her baby, who she named Eva, would be born without a portion of her brain and skull due to a condition known as anencephaly.

Keri – who learned of the child’s fate during her 20-week ultrasound – is scheduled to give birth to her child on May 7 and will likely only spend a few days with the newborn before she dies.

Her husband, Royce, was in awe of his wife’s heartbreaking choice to carry their baby — all to potentially save another child’s life, though he says he’s not surprised.

“Donating was on Keri’s mind from darn near the second we found out and while the experience of holding and kissing our daughter will be something we cherish forever, the gift(s) she’s got inside that little body of hers is what really matters. Keri saw that almost instantly,” Royce wrote in a Facebook post last week that has since been shared thousands of times.

Royce, a writer, said that his wife has proven her strength numerous times during their eight-year marriage, but that this time he was most impressed.

“It hit me that not only am I married to my very best friend, but to a truly remarkable, special human being,” he said.

His wife was also very public about the difficult decision to go through with the birth, something she’s grappled with even though she is pro-life.

She wrote of dreading the thought of attending a funeral for her own child, but after making an appointment with a doctor and her pastor to talk about organ donation, she decided it would be the best decision for her and her family.

“We learned her whole heart would not be eligible for transplant and that was disappointing. But then we learned her heart valves would be eligible along with her kidneys and liver and maybe pancreas. We could also donate her lungs to research. We’d get the opportunity to meet her recipients if they wanted to meet us,” Keri wrote in a Facebook post two months ago.

The couple, who already have a son named Harrison, learned that donating Eva’s organs can save up to 50 lives in as little as 24 hours.

“There’s another family out there hurting and hoping for a miracle for their baby, knowing full well someone else’s baby will need to die first. Eva can be that miracle,” Royce wrote.

“We’re getting closer to the finish line, and while it’s going to be amazing to run through that tape and meet Eva, it comes at a cost. We’ll go to the hospital for a birth, and go home without a baby,” he continued.

Scores of people have expressed their gratitude for the couple’s bravery — something that they said still causes them grief.

“Finally, this is not over for us. We’ll almost assuredly have doubts on if we’re actually doing the right thing. Or if we can even handle this. May 7th is far away. Please continue to think and pray for us,” Keri wrote.

Plasma tau and return to play after concussion

Gill J, Merchant-Borna K, Jeromin A, Livingston W, Bazarian J. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017 Feb 7;88(6):595-602.

To determine whether tau changes after sport-related concussion (SRC) relate to return to play (RTP).
Collegiate athletes underwent preseason plasma sampling and cognitive testing and were followed. After a SRC (n = 46), athletes and controls (n = 37) had sampling at 6 hours, and at 24 hours, 72 hours, and 7 days after SRC. A sample of 21 nonathlete controls were compared at baseline. SRC athletes were grouped by long (>10 days, n = 23) and short (≤10 days, n = 18) RTP. Total tau was measured using an ultrasensitive immunoassay.
Both SRC and athlete controls had significantly higher mean tau at baseline compared to nonathlete healthy controls (F101,3 = 19.644, p < 0.01). Compared to SRC athletes with short RTP, those with long RTP had higher tau concentrations overall, after controlling for sex (F39,1 = 3.59, p = 0.022), compared to long RTP athletes, at 6 (p < 0.01), 24 (p < 0.01), and 72 hours (p = 0.02). Receiver operator characteristic analyses showed that higher plasma tau 6 hours post-SRC was a significant predictor of RTP >10 days (area under the curve 0.81; 95% confidence interval 0.62-0.97, p = 0.01).
Elevated plasma tau concentration within 6 hours following a SRC was related to having a prolonged RTP, suggesting that tau levels may help inform RTP.

“Right now, return-to-play [RTP] is based mostly on subjective measures,” the study leader Jessica Gill, PhD, RN, chief of the brain unit at the National Institute of Nursing Research, told Neurology Today. “If players resume playing too quickly, they may be vulnerable to ongoing symptoms such as headache, dizziness and cognitive deficits, and risk getting a repeat hit to the head before the brain is fully recovered.”

Dr. Gill said it would be helpful to have an objective blood test for tau to add to the clinical exam information and, in some cases, neurocognitive testing currently used to gauge whether a concussed athlete is ready to go back on the field.

“We really have no way to tell patients what is going to happen and prepare them so we can maximize care during recovery,” Dr. Gill said.

She noted, however, that more research is needed as is a refinement of the tau test before it would be ready for clinical use.

“Right now, [the tau test] has about an 81 percent prediction rate, but that's not good enough,” said Dr. Gill, who conducted the study along with researchers at the University of Rochester in New York.

The researchers noted that tau has been linked to axonal damage following traumatic brain injury (TBI), and that a Swedish study of professional hockey players found that higher levels of tau were predictive of a longer return-to-play period….

Dr. Hainline said data from the ongoing study suggests that more attention is being paid to clearing athletes for RTP compared to a few years ago. He said a study from 2001 found that “92 percent of repeat concussions happened with 10 days of a player returning to play.”

Data from the current study of college athletes show that the typical RTP is about 13 days and that the average time for the small percentage of athletes who suffer a repeat concussion is 75 days after return to play, he said.

“That means we are no longer sending people back right away and setting them up for a repeat brain injury,” Dr. Hainline said. “This represents a positive change in the culture of sport.”…

Dr. Diaz-Arrastia said the study, known as TRACK/TBI, plans to enroll 3,000 people; among objectives, the researchers hope to determine whether tau or other biomarkers might be useful to predict which patients may have an extended or incomplete recovery from mild TBI.

While the majority of patients with mild TBI recover quickly, about 10 to 15 percent have lingering symptoms and the mechanisms of why that is the case are not known. Being able to predict whether some are at higher risk for a long recovery might help steer the most vulnerable people toward rehabilitative services.


The flawed designs of drug trials for autism

Taylor Stevenson’s family never left him out of conversations, but they never expected him to participate, either. His contributions, if he made any, were a few random words—gibberish or a Big Bird quote.

So when Taylor started speaking his mind in his squeaky, sing-songy voice, his mother, Debbie Stevenson, was stunned. “It was such a huge shock,” Stevenson says. She cried tears of joy. This was in late 2012, when Taylor was 16. Over the next year, his once-cursory answers spun into three- to five-word sentences. Phrases such as “I’m okay, thank you” became part of his repertoire.

Taylor has fragile X syndrome, a genetic condition that causes lifelong intellectual disability. One in three people with the syndrome also have autism. Taylor is not one of them, but he does have some autism-like features, such as difficulties with language. At first, Stevenson wasn’t sure what was triggering her son’s changing behavior. Perhaps Taylor’s new high school had sparked the improvement, or perhaps the countless hours of intensive therapy he had endured were finally paying off.

Stevenson began to suspect that a new drug Taylor was taking was responsible. A few months earlier, Taylor had enrolled in a clinical trial exploring the effects of an experimental drug called mavoglurant, manufactured by the pharmaceutical giant Novartis, for people with fragile X syndrome. Stevenson had heard about the trial through her volunteer fundraising work with the nonprofit FRAXA Research Foundation, a fragile X research and advocacy organization. Because there are no approved drugs to treat fragile X, she eagerly signed Taylor up.

Taylor enrolled in the 12-week trial in September 2012 and began taking either mavoglurant or an inactive placebo twice a day. (Neither the Stevensons nor the researchers knew which drug Taylor was taking.) The family flew from their New York City home down to Atlanta, Georgia, once a month for questionnaires and behavioral testing at Emory University, one of the trial’s 38 sites.

Within a few months, Stevenson noticed a slight shift in Taylor’s behavior. He started asking her for help when he needed it, and his anxiety diminished. These improvements persisted even after he switched to the second, long-term phase, during which he and the other participants took mavoglurant for more than a year. Stevenson became convinced that Taylor’s improvement really was due to the drug.

To Stevenson’s surprise, however, rumors that the trial wasn’t going well began to spread through FRAXA circles in February 2014. When the family showed up at Emory for another testing session a few months later, the researchers told them Novartis was suspending the trial. “I was beyond shocked,” Stevenson says. “I thought that even if only 25 percent of the population has seen what I’ve seen, of course they’ll approve it—because we have nothing else.”

When Taylor’s supply of the drug ran out, his strides forward reversed. Within a few months, his sentences diminished to single words, and now he mostly ignores questions, as he did before the trial.

Stevenson, who took Taylor’s regression the hardest, wished the study had been able to capture Taylor’s progress. But it would become clear to her that the trial had been poised to fail even before it got off the ground. Deeper issues—the wrong design and inadequate tests—crippled the study from the start…

“I was pretty horrified,” Stevenson says. “Do we have a drug that is getting slammed because we didn’t measure this properly?”

As it turns out, this trial’s misfire wasn’t an isolated incident. The same problems have dogged major trials exploring three of the most promising drugs for fragile X, including ventures launched within the past decade by Roche and the now-defunct Seaside Therapeutics. Stunted by flawed designs, each of the trials flopped, and by late 2014 all three drugs had been yanked from the research pipeline. To date, no drugs are approved to treat fragile X syndrome.

In the case of autism, too, few drugs have proven effective in trials, and several have failed due to poor design. Just two drugs, risperidone and aripiprazole, are approved by the U.S. Food and Drug Administration (FDA) for autism and are intended to relieve irritability. A few others treat attention deficit hyperactivity disorder and epilepsy, which often accompany autism. But none have passed muster for treating the condition’s core social impairments or repetitive behaviors…

The researchers thought that blocking a protein called mGluR5, which counters the normal role of FMRP, might restore the balance of synaptic proteins in people with fragile X syndrome. To their delight, the idea worked—in mice. A string of studies showed that in mouse models of fragile X, mGluR5 blockers normalize synapse function and improve learning. More than 30 papers thus far have shown the benefits of mGluR5 blockers in animal models, says Elizabeth Berry-Kravis, professor of pediatrics, neurological sciences, and biochemistry at Rush University in Chicago. “That’s one of the biggest bodies of basic-science evidence for a mechanism ever amassed.”

Emboldened by this bulk of evidence, several drug companies launched clinical trials in people with fragile X syndrome. In 2009, a 12-person trial sponsored by Neuropharm Ltd., a U.K.-based company now owned by Autism Therapeutics, found that an mGluR5 blocker called fenobam eases oversensitivity to sounds, a common feature in people with fragile X. That same year, Novartis’ mavoglurant showed early promise for treating hyperactivity, social difficulties and repetitive behavior in seven people with fragile X who lack FMRP. And an early Roche-sponsored trial, which also began in 2009, found that the drug basimglurant, another mGluR5 blocker, seemed to alleviate anxiety.

However, as Novartis and Roche prepared to launch much larger trials to test these drugs further, Berry-Kravis, who ran studies at Rush for both companies, grew concerned. The drugs target connections between neurons, which have the most capacity for change during early brain development, so they should work best in children. But both proposed trials were focused on adults and adolescents, which is the typical first step for large clinical trials. If these trials failed to show a benefit, the chances that the companies would launch studies in children were slim, Berry-Kravis says. (The companies ran early studies to test the drugs’ safety in children but didn’t include children in larger trials.)…

The researchers voiced their concerns about the trials’ design to Novartis and Roche, but the companies wouldn’t budge. Beginning in 2010, hundreds of adults and teens, including Taylor, enrolled in the trials. During each study session, the participants’ parents completed the ABC and several other questionnaires, gauging traits such as social impairment and anxiety. But none of the measures seemed to capture Taylor’s extraordinary progress. Stevenson was concerned. “All those amazing things I had just seen in the last month and then I’d told the clinicians about at Emory, none of it translated to what I was putting down on this piece of paper,” Stevenson says.

The failure of these trials, with their repetition of earlier mistakes, is a source of enormous frustration for scientists. “It’s very possible that we could have drugs that work really well on development, and we’ve missed them because of the way we develop drugs,” Berry-Kravis says…

Learning from the long string of failures, autism researchers are collaborating with drug companies and federal agencies to revamp the way clinical trials are conducted.

One team of researchers spanning multiple centers has embarked on a $28 million initiative to put autism measures and biomarkers through rigorous testing…

Taylor still uses words sparingly and fixates on unusual things, such as the compact discs that go into his beloved portable DVD player. But he likes being around other people and making them laugh with a funny look or a non sequitur. He lives at a residential school for people with disabilities on farmland a couple of hours away from his family’s home in New York City. In November, he moved into the adult house at the school, and Stevenson drove up to help him get settled. “It’s huge, because this is where he could really stay for the rest of his life,” she says.

Given all of his difficulties, Taylor may need a whole cocktail of drugs, Stevenson says, and so may many others like him. The trick will be getting enough drugs on the market to try out different combinations. In the meantime, she is open to anything that might help her son navigate his world, like his new adult program. Everyday skills, such as brushing his teeth and cooking himself dinner, are still challenging for Taylor. Learning little things like this, she says, would dramatically change his life.

Courtesy of Doximity

Monday, February 20, 2017

Psychogenic paroxysmal nonepileptic events in children

Morgan LA, Buchhalter J. Psychogenic Paroxysmal Nonepileptic Events in Children: A Review. Pediatr Neurol. 2015 Jul;53(1):13-22.

Paroxysmal nonepileptic events are common in children. Events with a psychological basis, historically referred to as pseudoseizures, are a large subset of paroxysmal nonepileptic events.
A review of the relevant pediatric and adult literature was performed.
It was found that these events have many semioloigc features similar to epileptic events and can be challenging to correctly identify. The use of a detailed history in combination with video encephalography and knowledge of psychogenic paroxysmal nonepileptic events will facilitate making the correct diagnosis. Paroxysmal nonepileptic events are important to identify as comorbid disorders such as depression, anxiety disorder, family discord, and school issues are frequent. In addition, prior sexual, emotional, and/or physical abuse may be present.
Pediatric patients with paroxysmal nonepileptic events need to be recognized in order to avoid unnecessary antiepileptic drugs and emergency department or hospital visits and to facilitate appropriate psychological intervention to address the underlying etiologies. This review will focus on evaluation and identification of paroxysmal nonepileptic events, in addition to reviewing the various comorbidities, effective treatments, and outcomes for pediatric patients. The key differences between pediatric and adult patients with paroxysmal nonepileptic events are addressed.

From the article

In the pediatric population, 76.8%-80% of PNEs have an abrupt start, and 68% end abruptly.  Eye closure during the entire attack occurs in 22%-45% and tremor in 25% in upper instead of lower extremities.  Furthermore, the episodes can be classified as only unresponsiveness, unresponsiveness with subtle motor activity, or unresponsive episodes of motor activity not typical of known types of epileptic seizures such as generalized limb jerking, thrashing of bodies and extremities, swooning, and generalized arrhythmic flailing of extremities.  In one pediatric series in which “nonresponsive” was specifically mentioned, the event was associated with generalized violent, thrashing, and uncoordinated movements in 44%, generalized trembling in 26%, and only nonresponsiveness in 9%.  Swoon type can be misdiagnosed as a vasovagal event, but swoon type events prolonged over a minute should raise suspicion for PNEs. 

Several studies note that older children and adolescents have more motor manifestations, whereas younger school-age children more frequently exhibit staring.  When motor manifestations are present, they most commonly mimic generalized tonic-clonic movements (60%), followed by focal clonic like movements (10%), and akinetic (10%).  There are conflicting data as to whether children more typically demonstrate a single PNE semiology or multiple semiologies.  To best group the various semiologies, a proposal of five major categories was created, allowing the entire study cohort to be classified. These include: (I) abnormal motor comprising (IA) hypermotor, (IB) partial motor, (II) affective/emotional behavior phenomena, (III) dialeptic, (IV) “aura,” and (V) mixed pattern. 

Correctly distinguishing PNEs from epileptic seizures remains a diagnostic challenge, more so because up to 78% of PNEs in pediatric patients are stereotypic and repetitive in nature.  One study demonstrated a sedentary, dialeptic form of events more frequently in younger children (less than 14 years) than adults (29% versus 11%).  Adults typically retain awareness, even during generalized convulsions  and have no discrete gaps of missing memory.  Both pediatric and adult patients are usually at their baseline level of responsiveness immediately following the event without displaying postictal confusion or sleepiness.

Emotional manifestations are more common in adults than in children and may include combativeness, crying, yelling, and vulgar language.  In adult patients, weeping is relatively common and strongly suggestive of PNEs.  Pelvic thrusting is uncommon in children, unlike in adults, although it has been documented at a frequency of 8.9% in children.   Ictal eye closure, convulsions longer than 2 minutes, postictal speech change, and vocalizations during the tonic-clonic phase all occur significantly more in adults than children.   Ictal eye closure can still be noted at any age and is more common in PNEs compared with epileptic seizures.  Pupillary dilation is thought to be more specific to epileptic seizures, yet dilation of pupils may occur from increased sympathetic discharge from a stress response and thus may be seen with PNEs.  Some historically classic signs for PNEs, such as opisthotonos, postictal whispering, and biting the tip of the tongue, appear to be rare in both children and adults. 

PNEs vary in length, lasting from 30 seconds to upwards of 10 minutes, with events typically longer than 3 minutes,  whereas epileptic seizures have a duration of less than 3 minutes.  One pediatric study documented the mean duration of PNEs to be 269 ± 549 seconds (4 minutes, 29 seconds ± 9 minutes, 9 seconds) compared with epileptic seizure duration of 83.2 ± 222.4 seconds (1 minute, 32.2 seconds ± 3 minutes, 42.4 seconds).    In a separate study of 10 children presenting to the emergency department, PNEs were documented with a broad range including 1 minute in three patients and 20-180 minutes in seven patients.  Another pediatric study reported PNE durations of 10-35 minutes; and those events characterized by unresponsiveness have been reported to last as long as 40 minutes. 

When PNEs were first described, it was thought that patients would not suffer injurious behavior or have incontinence. Many adult and pediatric studies to date have refuted this early belief, reporting injuries such as tongue biting, patients injuring themselves against the bed guard rails, bruises, fractures, clawing at the face, intubation, not responding to painful stimuli, and urinary incontinence and defecation.  In adult patients, caregiver reporting and self-reporting of injuries is as high as 30.8% and includes tongue biting, lacerations, limb fractures, and dental injury.   In patients with injury, the frequency of violent shaking movements, nocturnal PNEs, and urinary incontinence is higher.  46  In addition, injury is more common during PNEs in patients who have attempted suicide previously (61% versus 30%)  8  and those with a history of physical abuse.  In adults, urinary or fecal incontinence, or both, may occur up to 20% of the time.  Overall, injury is not a common feature in children.  34 36  In a study of 10 children seen in the emergency department with PNE, none had incontinence and none were injured, but nine had invasive procedures performed or laboratory tests obtained by the emergency department or paramedics.  

Epilepsy in MELAS

Lee HN, Eom S, Kim SH, Kang HC, Lee JS, Kim HD, Lee YM. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatr Neurol. 2016 Nov;64:59-65.

Epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are heterogeneous with no pathognomonic features. We reviewed epilepsy characteristics and clinical outcome exclusively in a pediatric population.
Twenty-two children and adolescents (13 males) with confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to mitochondrial DNA A3243G mutation and epilepsy were recruited. Clinical data including seizure semiology, treatment response, neuroimaging findings, and electroencephalography were analyzed. We also examined the effect of the age at seizure onset and initial symptoms on the clinical variables.
Seizure semiology and electroencephalography abnormalities showed no syndrome-specific findings. Focal seizures occurred in 21 of 22 subjects (95.5%), whereas generalized seizures developed in seven of 22 subjects (31.8%). Twenty of 22 subjects (90.9%) achieved partial to complete reduction of clinical seizures for more than one year with a combination of more than two antiepileptic drugs. The subgroup with earlier seizure onset presented significantly earlier and showed significantly higher rates of drug-resistant epilepsy compared with the late onset group, although there were no significant differences in the initial symptoms. The subjects with severe epileptic conditions tended to have more severe clinical dysfunction and more severe organ involvement.

Both focal and generalized seizures occurred in patients with MELAS. Epilepsy in this population is drug resistant, but a certain degree of clinical seizure reduction was achievable with antiepileptic drugs, with more favorable outcomes than historically expected. Close observation and active epilepsy treatment of individuals with MELAS episodes and earlier seizure onset might improve the prognosis.

From the article

Epilepsy is quite common throughout the MELAS disease course,  but not all individuals initially manifest with seizures. Our data are consistent with previous studies in terms of age at first presentation and at first seizure.  Twelve of our 22 patients (54.5%) initially presented with seizures, reconfirming that epileptic seizures were the most common presenting symptom in patients with MELAS. Subsequently, all subjects experienced seizure events…

MELAS may respond to traditional antiepileptic drugs but is generally refractory.  Epileptic seizures in MELAS can be difficult to treat for several reasons, including recurrent unexpected acute lesions induced by stroke-like episodes with resultant neuronal hyperexcitability, focal hyperemia, inflammation, necrosis, edema,  and epileptogenetic primary mitochondrial dysfunction.  The choice of antiepileptic drugs is complicated because of the high potential of mitochondrial toxicity associated with valproic acid, carbamazepine, phenytoin, and phenobarbital.  Most studies focused on describing EEG characteristics or showing progressive ongoing courses of each case series.  Lee et al.  reported detailed treatment outcomes of a combination of antiepileptic drugs in 46 infants with syndromic and nonsyndromic mitochondrial diseases. When we further investigated, partial to complete seizure reduction for more than 1 year was achievable with combinations of more than two antiepileptic drugs, somewhat more favorable than historically expected and relatively better than the study by Lee et al.  Four of 22 patients (18.2%) achieved complete seizure freedom for at least one year, 16 of 22 patients (72.7%) achieved ≥50% seizure reduction, and only two patients (9.1%) showed no change from baseline at the last clinic visit, appearing quite promising. Treatment of drug-resistant epilepsy requires complex decision making to balance the risks and benefits of applying multiple drugs in this complicated patient population with ongoing multiorgan involvement; however, our data suggest active epilepsy treatment is possible, which may lead to better quality of life for both patients and their caregivers.

Having determined that temporary partial to complete seizure reduction is achievable by antiepileptic treatment, we further investigated factors that may affect outcomes, including the age of seizure onset and initial presenting symptom. The subgroup analyses confirmed heterogeneity of seizure types and EEG abnormalities, which was not affected by the age of seizure onset or initial presenting symptoms. Patients with earlier seizure onset presented at significantly younger ages (5.4 ± 2.4 vs 11.1 ± 2.8 years, P < 0.001) and showed significantly higher rates of drug-resistant epilepsy (83% vs 40%, P = 0.017). There was no significant difference in initial presenting symptoms. Patients with earlier seizure onset also tended to take higher numbers of antiepileptic drugs and exhibited lower rates of clinical seizure reduction with treatment, yet with no statistical significance. From these results, we may assume that in the pediatric MELAS population, seizures at a younger age might indicate underlying brain dysfunction at an earlier age, as demonstrated by our EEG results, and which subsequently leads to earlier diagnosis. An earlier beginning to the epileptic process and ongoing encephalopathy may also result in worse treatment outcomes, as in our data. Special attention and active epilepsy treatment is thus required in children presenting with seizure at earlier ages. Physicians who treat children with MELAS should be prepared to detect early signs of clinical seizures and plan subsequent treatment for best management.

Saturday, February 18, 2017

Ketogenic diet in resistant myoclono-astatic epilepsy

Elodie Stenger, Mickael Schaeffer, Claude Cances, Jacques Motte, Stéphane Auvin, Dorothée Ville, Hélène Maurey, Rima Nabbout, Anne de Saint-Martin.  Efficacy of a ketogenic diet in resistant myoclono-astatic epilepsy: A French multicenter retrospective study.  Epilepsy Research.  In press.

•A Ketogenic diet has a strong anticonvulsant effect in myoclono–astatic epilepsy
•Early introduction of a ketogenic diet after three antiepileptic drugs allows for a high rate of remission
•A good cognitive outcome is correlated with an early introduction of a ketogenic diet.

Recent studies have suggested that the early introduction of a ketogenic diet (KD) could improve seizure control in myoclono-astatic epilepsy (MAE). This multicenter study sought to identify the benefits of KD use on seizure control and epilepsy and on developmental outcomes in children with resistant MAE.

Fifty children who were diagnosed with severe MAE in the French network of Reference Centers for Rare Epilepsies and who were treated with KD between 2000 and 2013 were included in this study. The seizure frequency and EEG recordings were assessed two weeks before KD introduction, 2 and 6 months after, and during the last follow-up, which also included an assessment of developmental outcome.

Patients had a median follow up of 52 months (range 13 −136) and received 4.3 antiepileptic drugs [2-9] before KD introduction. Fifty-four percent (54%) of our patients were seizure-free after 6 months of KD or more, and 86% experienced more than a 70% seizure reduction after 2 months of KD. Forty-four percent (44%) of them had a clear benefit of early KD treatment (after four AEDs failed). Early KD treatment did not result in a greater seizure reduction (p = 0.055), but significantly resulted in remission (p < 0.028). Fifty percent of patients with resistant MAE had normal development outcomes. Earlier KD treatment, after three AEDs failed, was correlated with a better cognitive outcome (p < 0.01).

Early introduction of KD treatment in resistant MAE has a strong, persistent anticonvulsant effect with long-term remission and better cognitive outcomes.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/02/17/myoclono-astatic-epilepsy-doose-syndrome-ketogenic/7061201/?category=latest&page_id=1

Pediatric SUDEP

Morse AM, Kothare SV. Pediatric Sudden Unexpected Death in Epilepsy. Pediatr Neurol. 2016 Apr;57:7-16.

Epilepsy is a common neurological disorder among children and adolescents that is associated with increased mortality for numerous reasons. Sudden unexpected death in epilepsy is a critically important entity for physicians who treat patients with epilepsy. Many pediatric neurologists are hesitant to discuss this condition with patients and families because of the lower risk in the pediatric age group.
We searched for studies published between January 2000 and June 2015 by means of a PubMed search and a cumulative review of reference lists of all relevant publications, using the keywords "sudden unexpected death in epilepsy patients," "pediatric SUDEP," "sudden unexpected death in epilepsy patients and children," "sudden unexpected death in children" and "sudden infant death syndrome."
SUDEP is a rare condition in children. Its mechanism is poorly understood and may have a distinct pathogenesis from adult sudden unexpected death in epilepsy. Limited comfort, experience, and knowledge to provide appropriate education about sudden unexpected death in epilepsy leads to fewer physicians discussing this subject leading to less informed and less prepared patients and families.

We provide a detailed review of the literature on pediatric SUDEP, including the definition, classification, and proposed mechanisms of sudden unexpected death in epilepsy in children, as well as discuss the incidence in the pediatric population and risk factors in children, concluding with possible prevention strategies.

From the article:

Many researchers have attempted to identify the underlying pathophysiology for SUDEP but without conclusive success. Most of the proposed mechanisms for SUDEP are based on adult studies. Some studies performed in children demonstrate overlap with adult pathophysiology, but others suggest that it may be a phenomenologically different process. It has been suggested that SUDEP in children may be caused by similar mechanisms as postulated in adult SUDEP, but the pattern of seizure-related cardiopulmonary disturbances differ.  Ryvlin et al. performed a retrospective analysis of 133,788 subjects from 147 epilepsy monitoring units: 70% adults and 30% children with video electroencephalography (EEG), evaluating cardiorespiratory deaths encountered during monitoring. They suggested that the main mechanism leading to SUDEP starts with an early, centrally mediated, severe alteration of both respiratory and cardiac functions after generalized tonic-clonic seizures.  However, no differences between the adult and pediatric cohorts were addressed in this study. In general, there are several proposed mechanisms of SUDEP that may occur either independently, such as cardiac, pulmonary, or autonomic dysregulation, or in combination.

Cardiac mechanisms are likely related to cardiac dysrhythmia precipitated by seizures. Sevcencu and Struijk  outlined the spectrum of cardiac effects in adults related to epilepsy include subtle changes in heart rate variability to ictal sinus arrest, and from QT-interval shortening to atrial fibrillation. Transient bradycardia, sinus tachycardia,  various arrhythmias, and prolongation of the QT interval are often seen in children during seizure.  Temporal lobe complex partial seizures are more likely to cause cardiovascular dysregulation as compared with seizures from an extratemporal origin. 
Respiratory mechanisms suggested to play a role in SUDEP include respiratory arrest, neurogenic pulmonary edema, and asphyxiation. Another possible mechanism is severe postictal laryngospasm.   Respiratory dysfunction is likely a result of abnormal neuronal activation and deactivation of the respiratory center in the brainstem during both generalized and focal seizures.  Although central apnea and neurogenic pulmonary edema  are the two major proposed pathways linking seizures to SUDEP, most studies performed were in adults, with mostly case reports found in children. 

Cardiac and respiratory abnormalities commonly overlap, resulting in an exacerbation of the detrimental effects of each. Pavlova et al. evaluated the relationship of cardiorespiratory abnormalities and EEG changes during seizures according to age in patients with epilepsy. The results suggested that there may be an age-related effect on cardiorespiratory changes with EEG abnormalities associated with seizures with higher rates of apnea and bradycardia in children, but a much higher prevalence of postictal generalized EEG suppression (PGES) of longer duration in adults.  However, it is important to note that the children in the study more commonly had frontal-onset seizures, whereas the adult patients had a temporal onset. This finding suggests a possible relationship of seizure foci to cardiorespiratory changes. Singh et al.  also identified potentially life-threatening cardiopulmonary abnormalities, such as bradycardia, apnea, and hypoxemia, in pediatric epileptic seizures are associated with predictable patient and seizure characteristics, including seizure subtype and duration.

PGES, which is EEG amplitude less than 10 μV at the end of a seizure lasting more than 50 seconds, was identified by Lhatoo et al. in a series of 10 adult patients as a risk factor to development of SUDEP in the future. PGES is an EEG phenomenon linked to the end of a tonic, not clonic, phase of generalized tonic-clonic seizures  and observed after the seizure is over. Moseley et al. was the first to identify a relationship between PGES and SUDEP in children. In fact, their study revealed that PGES is not uncommon in children, as it occurred in almost a third of the children evaluated and appeared to have a positive correlation with a higher score on the SUDEP 7 inventory. The magnitude of both sympathetic and parasympathetic changes corresponds to the duration of EEG suppression after tonic-clonic seizures in children (tachycardia/bradycardia, prolonged QTc, heart rate variability).  These changes were measured by a special device worn, for 3-7 days, on the wrist by 11 patients utilizing a unique algorithm to calculate these abnormalities.  There are age-specific differences for PGES in adults and children. Freitas et al.  found that the mean PGES duration was eight times longer in adults and recovery duration twice as long as found in children.

Autonomic alterations during seizures occur independently or secondary to both cardiac and respiratory dysfunction as a cascade of complex, multifactorial, and often bidirectional changes with dominance of one autonomic system over the other in most patients.  Autonomic failure has been postulated to be the ultimate driving force toward PGES with cerebral shutdown leading to SUDEP.

Mosely et al.  found that SUDEP accounts for 12% of all epilepsy-related deaths in children. It is estimated that the rate of SUDEP in children is approximately two per 10,000 patient-years based on retrospective studies.

Rufinamide dosing in Lennox-Gastaut syndrome

Sanjeev Kothare,  Gerhard Kluger, Rajesh Sachdeo, Rajesh Sachdeo, Betsy Williams, Omar Olhaye, Carlos Perdomo, Francesco Bibbiani.  Dosing Considerations for Rufinamide in Patients With Lennox-Gastaut Syndrome: Phase III Trial Results and Real-World Clinical Data.  European Journal of Epilepsy.  In press.

Lennox-Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged ≥1year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies.

Rufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared.

Results demonstrated that a rapid titration schedule (7 or 14days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic-atonic seizures, with efficacy and tolerability sustained over 3years. The most common AEs during the Phase III study—somnolence, vomiting, pyrexia—occurred during the first 3weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings.

A lower dose and slower titration schedule (“low and slow”) may reduce incidence of AEs without compromising efficacy of rufinamide in LGS.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/02/17/rufinamide-dosing-antiepileptic-drug-lennox-gastaut/7060452/?category=latest&page_id=1