Ketogenic diet in refractory childhood epilepsy

Lambrechts DA, de Kinderen RJ, Vles JS, de Louw AJ, Aldenkamp AP, Majoie HJ. A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy. Acta Neurol Scand. 2016 Mar 29. doi: 10.1111/ane.12592. [Epub ahead of print]Abstract

OBJECTIVE:

To evaluate the efficacy and tolerability of the ketogenic diet (KD) during the first 4 months of a randomized controlled trial (RCT) in refractory epilepsy patients aged 1-18 years.

METHODS:

Children and adolescents with refractory epilepsy, not eligible for epilepsy surgery, were included. Following 1 month at baseline, patients were randomized to either the KD or to care as usual (CAU).Primary outcome is the proportion of patients with at least 50% reduction in seizure frequency at 4 months. Secondary outcomes are mean percentage of baseline seizures, seizure severity, and side effects.

RESULTS:

Fifty-seven patients were randomized; nine dropped out, leaving 48 for analysis (i.e., 26 KD, 22 CAU). In an intention-to-treat analysis, 13 patients (50%) treated with the KD and four patients (18.2%) of the CAU group were responders.Mean seizure frequency at 4 months compared to baseline, after removal of two outliers in the KD group, was significantly lower (P = 0.024) in the KD group (56%) (95% CI: 36-76) than in the CAU group (99%) (95% CI: 65-133%).Twice as many patients in the KD group had a relevant decrease in seizure severity score (P = 0.070).Patients treated with the KD had a significantly higher score for gastrointestinal symptoms (P = 0.021) without an increase in the total score of side effects.

CONCLUSIONS:

This trial provides class I evidence that the KD is an effective therapy in children and adolescents with refractory epilepsy compared with CAU. Most often reported side effects are gastrointestinal symptoms.The study has been registered with the Netherlands Trial Registry (NTR2498).

Courtesy of:  http://www.mdlinx.com/neurology/medical-news-article/2016/04/07/children-ketogenic-diet-rct-refractory-epilepsy/6606405/?category=sub-specialty&page_id=1&subspec_id=317

Zika virus and ADEM

The Zika virus may be associated with an autoimmune disorder that attacks the brain's myelin similar to multiple sclerosis, according to a small study that is being released today and will be presented at the American Academy of Neurology's 68th Annual Meeting in Vancouver, Canada, April 15 to 21, 2016.

"Though our study is small, it may provide evidence that in this case the virus has different effects on the brain than those identified in current studies," said study author Maria Lucia Brito Ferreira, MD, with Restoration Hospital in Recife, Brazil. "Much more research will need to be done to explore whether there is a causal link between Zika and these brain problems."...

Of the six people who had neurologic problems, two of the people developed acute disseminated encephalomyelitis (ADEM), an attack of swelling of the brain and spinal cord that attacks the myelin, which is the coating around nerve fibers. In both cases, brain scans showed signs of damage to the brain's white matter. Unlike MS, acute disseminated encephalomyelitis usually consists of a single attack that most people recover from within six months. In some cases, the disease can reoccur. Four of the people developed Guillain-Barré syndrome (GBS), a syndrome that involves myelin of the peripheral nervous system and has a previously reported association with the Zika virus.

When they were discharged from the hospital, five of the six people still had problems with motor functioning. One person had vision problems and one had problems with memory and thinking skills.

Tests showed that the participants all had Zika virus. Tests for dengue and chikungunya were negative.

"This doesn't mean that all people infected with Zika will experience these brain problems. Of those who have nervous system problems, most do not have brain symptoms," said Ferreira. "However, our study may shed light on possible lingering effects the virus may be associated with in the brain."

"At present, it does not seem that ADEM cases are occurring at a similarly high incidence as the GBS cases, but these findings from Brazil suggest that clinicians should be vigilant for the possible occurrence of ADEM and other immune-mediated illnesses of the central nervous system," said James Sejvar, MD, with the Centers for Disease Control and Prevention in Atlanta and a member of the American Academy of Neurology. "Of course, the remaining question is 'why'-why does Zika virus appear to have this strong association with GBS and potentially other immune/inflammatory diseases of the nervous system? Hopefully, ongoing investigations of Zika virus and immune-mediated neurologic disease will shed additional light on this important question."

https://www.sciencedaily.com/releases/2016/04/160411082335.htm

Polymicrogyria, thalamic hypoplasia and epilepsy with CSWS

Bartolini E, Falchi M, Zellini F, Parrini E, Grisotto L, Cosottini M, Posar A,Parmeggiani A, Ambrosetto G, Ferrari AR, Santucci M, Salas-Puig J, Barba C,Guerrini R. The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsywith CSWS. Neurology. 2016 Mar 29;86(13):1250-9.

Abstract
OBJECTIVE:We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy.
METHODS:We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS.
RESULTS:CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p = 0.0021 for hemispheres; p = 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm(3) for malformed hemispheres or 4,616 mm(3) for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm(3) reduction of the polymicrogyric hemispheres and by 15% for every 100 mm(3) reduction of ipsilateral thalami.
CONCLUSIONS:The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS.

ADHD and the leaky thalamus

Wells MF, Wimmer RD, Schmitt LI, Feng G, Halassa MM. Thalamic reticular
impairment underlies attention deficit in Ptchd1(Y/-) mice. Nature. 2016 Mar 23.
doi: 10.1038/nature17427. [Epub ahead of print]

Abstract

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ~1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.
________________________________________________________________________

The co-authors also suggested that their findings could eventually lead to a new disease category that includes the autism spectrum and intellectual disability as well as ADHD. “To our knowledge, this is the first study to detail the biology behind thalamic dysfunction in cognitive disorders…,” said senior investigator Michael M. Halassa MD, PhD, an assistant professor of neuroscience at NY Langone. “We believe that this work defines a new disease category based on common biological signatures….”

In their research on what they called a “leaky thalamus,” the scientists looked at what happens when a specific gene, Ptchd1, is deleted to genetically alter mice. The scientists found that Ptchd1 plays a role in modulating the amount of SK (small conductance calcium-dependent potassium currents) that help the thalamus communicate with other parts of the brain and inhibit inattention and hyperactivity

Mice without Ptchd1 made three times as many concentration errors in concentration tests as unaltered mice and had difficulties screening out distractions, the study said. These mice also were insensitive to treatment with stimulants, the study added, which suggested that the ADHD in the people who don’t respond to stimulants may have a disorder with a different origin. The authors noted that “ADHD symptoms are frequently observed in patients with Ptchd1 mutations.”

The researchers did have success in improving the thalamus signaling in the genetically altered mice with the drug 1-ethyl-benzimidazolinone, but said it’s not useable humans. Nonetheless, the effectiveness of that drug suggested that scientists should look for a medication that has the same effect on humans, the authors added.

http://www.hcplive.com/medical-news/is-leaky-thalamus-to-blame-for-adhd

ACTA1 mutations

Nowak KJ, Ravenscroft G, Laing NG. Skeletal muscle α-actin diseases (actinopathies): pathology and mechanisms. Acta Neuropathol. 2013 Jan;125(1):19-32.

Abstract

Mutations in the skeletal muscle α-actin gene (ACTA1) cause a range of congenital myopathies characterised by muscle weakness and specific skeletal muscle structural lesions. Actin accumulations, nemaline and intranuclear bodies, fibre-type disproportion, cores, caps, dystrophic features and zebra bodies have all been seen in biopsies from patients with ACTA1 disease, with patients frequently presenting with multiple pathologies. Therefore increasingly it is considered that these entities may represent a continuum of structural abnormalities arising due to ACTA1 mutations. Recently an ACTA1 mutation has also been associated with a hypertonic clinical presentation with nemaline bodies. Whilst multiple genes are known to cause many of the pathologies associated with ACTA1 mutations, to date actin aggregates, intranuclear rods and zebra bodies have solely been attributed to ACTA1 mutations. Approximately 200 different ACTA1 mutations have been identified, with 90 % resulting in dominant disease and 10 % resulting in recessive disease. Despite extensive research into normal actin function and the functional consequences of ACTA1 mutations in cell culture, animal models and patient tissue, the mechanisms underlying muscle weakness and the formation of structural lesions remains largely unknown. Whilst precise mechanisms are being grappled with, headway is being made in terms of developing therapeutics for ACTA1 disease, with gene therapy (specifically reducing the proportion of mutant skeletal muscle α-actin protein) and pharmacological agents showing promising results in animal models and patient muscle. The use of small molecules to sensitise the contractile apparatus to Ca(2+) is a promising therapeutic for patients with various neuromuscular disorders, including ACTA1 disease.

Goebel HH, Laing NG. Actinopathies and myosinopathies. Brain Pathol. 2009

Jul;19(3):516-22.

Abstract

The currently recognized two forms of "anabolic" protein aggregate myopathies, that is, defects in development, maturation and final formation of respective actin and myosin filaments encompass actinopathies and myosinopathies. The former are marked by mutations in the ACTA1 gene, largely of the de novo type. Aggregates of actin filaments are deposited within muscle fibers. Early clinical onset is often congenital; most patients run a rapidly progressive course and die during their first 2 years of life. Myosinopathies or myosin storage myopathies also commence in childhood, but show a much more protracted course owing to mutations in the myosin heavy chain gene MYH7. Protein aggregation consists of granular material in muscle fibers and few, if any, filaments.

Feng JJ, Marston S. Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies. Neuromuscul Disord. 2009 Jan;19(1):6-16.

Abstract

Mutations in the skeletal muscle actin gene, ACTA1 are responsible for up to 20% of congenital myopathies with a variety of pathologies that includes nemaline myopathy, intranuclear rod myopathy, actin myopathy and congenital fibre type disproportion. In their review of 2003, Sparrow et al. considered how these actin mutations might affect muscle function at the molecular level and thus cause the disease. Since then several laboratories have taken up the challenge of investigating genotype-phenotype relationships experimentally. The objective of this review is to assess the current state of our understanding of the molecular mechanisms of skeletal myopathies and the prospects for future therapies based on this knowledge. Thirty congenital myopathy-causing ACTA1 mutations have been studied using a range of biochemical and in vitro approaches. They showed diverse molecular defects, and there is no obvious pattern seen in mutations resulting in the same histopathology.

Inspired by a patient.

Epileptiform K-complexes and sleep spindles

Seneviratne U, Cook M, DʼSouza W. Epileptiform K-Complexes and Sleep Spindles:  An Underreported Phenomenon in Genetic Generalized Epilepsy. J Clin Neurophysiol. 2016 Apr;33(2):156-61.

Abstract

PURPOSE:

To study the frequency of epileptiform K-complexes and sleep spindles as well as clinical variables influencing those abnormalities.

METHODS:

We prospectively performed 24-hour ambulatory EEGs in a cohort of patients with genetic generalized epilepsy diagnosed and classified according to the International League against Epilepsy criteria. Overlapping of epileptiform discharges with K-complexes and sleep spindles was defined as epileptiform K-complexes and epileptiform sleep spindles. The presence of epileptiform K-complexes and sleep spindles was tabulated for each patient, and frequencies were calculated. We performed multiple regression analysis to study the influence of clinical predictors on the occurrence of epileptiform K-complexes and sleep spindles. The predictor variables tested in the model were seizure-free duration, epilepsy duration, genetic generalized epilepsy syndrome, number of antiepileptic drugs, use of sodium valproate, and use of lamotrigine.

RESULTS:

A total of 107 patients (37 males and 70 females) were studied. The mean age was 28.5 ± 10.7 years (range, 13-58). Juvenile absence epilepsy was the most common epilepsy syndrome in the cohort (31.8%), followed by generalized epilepsy with tonic-clonic seizures only (26.2%), juvenile myoclonic epilepsy (26.2%), and childhood absence epilepsy (14%). Epileptiform K-complexes and sleep spindles were seen in 65.4% and 10.3% of patients, respectively. None of the clinical variables had any significant impact on the occurrence of epileptiform K-complexes and sleep spindles in our multivariable analysis.

CONCLUSIONS:

Epileptiform K-complexes are common in the sleep EEGs of patients diagnosed with genetic generalized epilepsy. This underreported phenomenon highlights the important association of arousals and epileptiform discharges in genetic generalized epilepsy.

Cortical and sub-cortical excitability during spindles and K-complexes, putative attractors of epileptic activity Ioannides AA 1 , Liu L 1 1AAI Scientific Cultural Services Ltd, Lab for Human Brain Dynamics, Nicosia, Cyprus

Purpose: The ARMOR project (www.armor-project.eu) is developing a platform for home monitoring of epilepsy patients. During sleep stage II (SS2) the frequency of specific types of epileptic activity is high. It is believed that large graphoelements of SS2, spindles and K-complexes act as attractors of epileptic activity.

Method: We studied high quality whole night sleep MEG recordings of four normal subjects [1]. The brain activity during K-complexes and spindles was compared with activity shortly during targeted baseline periods that included periods before (1-2 seconds) the graphoelements, quiet core periods of sleep stages [1], including SS2 and the awake state, with separate comparisons performed in the time and frequency domains.

Results: We showed widely distributed cortical foci of activity with hot spots during spindles around the central sulcus, parietal and prefrontal cortex, and during K-complexes the strongest hot spots in the anterior and motor cingulate. The statistical comparisons between periods of large K-complex and spindle activity with targeted baseline periods confirmed these findings with very high statistical significance (p< 0.0001) for each subject. However, the same comparisons showed distinct sub-cortical areas for each baseline period, suggesting significant changes in sub-cortical excitation in different sleep stages, even in the quiet periods, consistent with our earlier study [1].

Conclusion: Our results highlight the need to monitor epileptic activity during sleep with simultaneous characterization of sleep stages. This need will be satisfied by the output of the ARMOR project that has home monitoring capability, allowing such a characterization to be followed over extended periods and thus probe the evolution of epilepsy with unprecedented detail. 

Acknowledgment: The work was partially funded by the European Commission under the Seventh Framework Program with grant ARMOR, agreement number 287720.

References: [1] Ioannides AA et al. (2009) MEG identifies dorsal medial brain activations during sleep, NeuroImage 44: 455-68.

http://armor.tesyd.teimes.gr/documents/10184/16090/Montreal_abstract.pdf/5dfcb580-e0f1-4ad5-b0cb-e67e839f3f85

Note polyspikes overlapping on the ascending limb of the surface negative wave of the K-complex.

Note polyspike-wave discharges admixed with the terminal part of a sleep spindle.

Note polyspike-wave discharges in the middle of a sleep spindle. This is best realized in the central electrodes

Tourette and comorbid psychiatric disorders

Hirschtritt ME, Lee PC, Pauls DL, Dion Y, Grados MA, Illmann C, King RA,

Sandor P, McMahon WM, Lyon GJ, Cath DC, Kurlan R, Robertson MM, Osiecki L, Scharf

JM, Mathews CA; Tourette Syndrome Association International Consortium for

Genetics. Lifetime prevalence, age of risk, and genetic relationships of comorbid

psychiatric disorders in Tourette syndrome. JAMA Psychiatry. 2015

Apr;72(4):325-33.

Abstract

IMPORTANCE:

Tourette syndrome (TS) is characterized by high rates of psychiatric comorbidity; however, few studies have fully characterized these comorbidities. Furthermore, most studies have included relatively few participants (<200), and none has examined the ages of highest risk for each TS-associated comorbidity or their etiologic relationship to TS.

OBJECTIVE:

To characterize the lifetime prevalence, clinical associations, ages of highest risk, and etiology of psychiatric comorbidity among individuals with TS.

DESIGN, SETTING, AND PARTICIPANTS:

Cross-sectional structured diagnostic interviews conducted between April 1, 1992, and December 31, 2008, of participants with TS (n = 1374) and TS-unaffected family members (n = 1142).

MAIN OUTCOMES AND MEASURES:

Lifetime prevalence of comorbid DSM-IV-TR disorders, their heritabilities, ages of maximal risk, and associations with symptom severity, age at onset, and parental psychiatric history.

RESULTS:

The lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had 2 or more psychiatric disorders. The mean (SD) number of lifetime comorbid diagnoses was 2.1 (1.6); the mean number was 0.9 (1.3) when obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) were excluded, and 72.1% of the individuals met the criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15-19 years for both). Tourette syndrome was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95% CI, 1.0-1.9; P = .04) and decreased risk of substance use disorders (OR, 0.6; 95% CI, 0.3-0.9; P = .02) independent from comorbid OCD and ADHD; however, high rates of mood disorders among participants with TS (29.8%) may be accounted for by comorbid OCD (OR, 3.7; 95% CI, 2.9-4.8; P < .001). Parental history of ADHD was associated with a higher burden of non-OCD, non-ADHD comorbid psychiatric disorders (OR, 1.86; 95% CI, 1.32-2.61; P < .001). Genetic correlations between TS and mood (RhoG, 0.47), anxiety (RhoG, 0.35), and disruptive behavior disorders (RhoG, 0.48), may be accounted for by ADHD and, for mood disorders, by OCD.

CONCLUSIONS AND RELEVANCE:

This study is, to our knowledge, the most comprehensive of its kind. It confirms the belief that psychiatric comorbidities are common among individuals with TS, demonstrates that most comorbidities begin early in life, and indicates that certain comorbidities may be mediated by the presence of comorbid OCD or ADHD. In addition, genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to TS. 

From the manuscript:

The heritability estimates confirm previous research showing that TS, OCD, and ADHD are highly genetically related. However, for the first time, we also provide evidence of a strong genetic relationship between these TS-related phenotypes and mood, anxiety, and DBD. Of particular interest, our analyses suggest that the observed genetic correlations between TS and these disorders are better accounted for by an underlying genetic relationship with ADHD and, in the case of mood disorders, by an underlying genetic relationship with both ADHD and OCD. In non-TS samples, there is considerable evidence to support shared genetic variance between ADHD and DBD, and some data to support a shared genetic diathesis underlying ADHD and major depressive disorder. Genetic relationships between OCD and mood disorders have not previously been examined. Our findings are in line with a previous study that found no increased rates of ADHD or other non-OCD disorders such as anxiety, affective, substance abuse and psychotic disorders, among parents of probands with TS compared to controls, suggesting that these disorders segregate independently from TS. Our findings that parental history of ADHD predicts psychiatric disorder burden in TS-affected offspring, independent of parental history of TS and OCD, provides additional support for the observed genetic relationships between psychiatric disorders and ADHD...

This study provides important new data regarding the prevalence, predictors, and ages of highest risk for psychiatric illness among individuals affected with TS, as well as for the first time formally evaluating the etiological relationships between disorders other than OCD and ADHD. The key clinical findings, that mood, anxiety, and DBD are very common among TS-affected individuals, tend to begin early in life, and are highly associated with comorbid OCD and ADHD, are of direct and immediate relevance for practitioners. The genetic analyses advance our understanding of the etiological relationships between TS and other psychiatric disorders, and provide a framework for future studies aimed at better understanding the biology of these complex, inter-related syndromes.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446055/

Inspired by the conference I am attending.