Sunday, April 30, 2017

A 22q11.2 potpourri

Wither RG, Borlot F, MacDonald A, Butcher NJ, Chow EWC, Bassett AS, Andrade DM. 22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy. Epilepsia. 2017 Apr 27. doi: 10.1111/epi.13748. [Epub ahead of print]

Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents. In this study we investigated the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population.
The medical records of 202 adult patients with 22q11.2DS were retrospectively reviewed for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings. Epilepsy status was assigned in accordance with 2010 International League Against Epilepsy Classification.
Of 202 patients, 32 (15.8%) had a documented history of seizure. Of these 32, 23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use. Nine patients (9/32, 28%; 9/202, 4%) met diagnostic criteria for epilepsy. Two patients had genetic generalized epilepsy; two patients had focal seizures of unknown etiology; two had epilepsy due to malformations of cortical development; in two the epilepsy was due to acquired structural changes; and in one patient the epilepsy could not be further classified.

Similarly to children, the prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population. Hypocalcemia continues to be a risk factor for adults, but differently from kids, the main cause of seizures in adults with 22q11.2DS is exposure to antipsychotics and antidepressants. Further prospective studies are warranted to investigate how 22q11.2 microdeletion leads to an overall decreased seizure threshold. 

Researchers aimed to examine the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population. In adults with 22q11.2DS, the prevalence of epilepsy and acute symptomatic seizures is higher, similarly to children than in the general population. For adults, hypocalcemia continues to be a risk factor, but differently, from kids, in adults with 22q11.2DS the main cause of seizures is exposure to antipsychotics and antidepressants.


The researchers retrospectively reviewed the medical records of 202 adult patients with 22q11.2DS for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings.

They assigned epilepsy status in accordance with 2010 International League Against Epilepsy 


In this study, 32 patients (15.8%) had a documented history of seizure, out of 202 patients.
23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use among these 32.

For epilepsy, 9 patients (9/32, 28%; 9/202, 4%) met diagnostic criteria.

As per the outcomes, 2 patients had genetic generalized epilepsy; 2 patients had focal seizures of unknown etiology; 2 had epilepsy due to malformations of cortical development; in 2 the epilepsy was due to acquired structural changes; and in 1 patient the epilepsy could not be further classified.

Suksawat Y, Sathienkijkanchai A, Veskitkul J, Jirapongsananuruk O, Visitsunthorn N, Vichyanond P, Pacharn P. Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome. J Clin Immunol. 2017 Apr 20. doi:10.1007/s10875-017-0394-6. [Epub ahead of print]

Patients with 22q11.2 deletion syndrome have a variable decrease in immunological parameters, especially regarding T cell counts. The aim of this study was to investigate immunological change over time and factors associated with immunological recovery among patients with 22q11.2 deletion syndrome.
Patients with 22q11.2 deletion syndrome diagnosed by fluorescence in situ hybridization (FISH) were studied. Immunological parameters were evaluated every 6 months until patients returned to normal. Infection and vaccination histories were recorded and analyzed, and Kaplan-Meier survival curves were plotted to describe resolution of immunodeficiency.
Forty-nine patients with an age range of 4 to 222 months were included. Twenty-five (51%) patients were female. In hypocalcemia, the odds ratio for CD4 lymphopenia was 17.03 (95%CI 1.82-159.23; p value = 0.01). Thirty patients (61.2%) exhibited decreased CD4+ T cell numbers, which returned to normal level in 18 (60%) patients. Median age of CD4+ T cell resolution was 2.5 years. T cell functions were abnormal in three patients. T cell functions returned to normal in all patients at a median age of 1.1 years. Six patients (13.5%) had abnormal serum immunoglobulin levels, with levels improving in four patients at 1.4 years of age. The most common infection was pneumonia (69.4%). BCG vaccination was administered in 47 of 49 patients at birth. Among 32 patients who had T cell defect, one patient developed BCGitis and one developed disseminated BCG.
Immunodeficiencies identified among patients with 22q11.2 deletion syndrome were T cell defect (65.3%) and decreased immunoglobulin levels (12.2%). Median age of CD4 resolution was 2.5 years.

Maggadottir SM, Sullivan KE. The diverse clinical features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J Allergy Clin Immunol Pract. 2013 Nov-Dec;1(6):589-94.

A 2-year-old boy with chromosome 22q11.2 deletion syndrome was referred for recurrent sinopulmonary infections. He was diagnosed shortly after birth by a fluorescence in situ hybridization test that was performed due to interrupted aortic arch type B. He had no hypocalcemia, and his recovery from cardiac repair was uneventful. He had difficulty feeding and gained weight slowly, but, otherwise, there were no concerns during his first year of life. At 15 months of age, he began to develop significant otitis media and bronchitis. He was hospitalized once for pneumonia at 18 months of age and has never been off antibiotics for more than 1 week since then. He has not had any previous immunologic evaluation. Recurrent sinopulmonary infections in a child with chromosome 22q11.2 deletion syndrome can have the same etiologies as in any other child. Atopy, anatomic issues, cystic fibrosis, and new environmental exposures could be considered in this setting. Early childhood can be problematic for patients with chromosome 22q11.2 deletion syndrome due to unfavorable drainage of the middle ear and sinuses. Atopy occurs at a higher frequency in 22q11.2 deletion syndrome, and these children also have a higher rate of gastroesophageal reflux and aspiration than the general population. As would be appropriate for any child who presents with recurrent infections at 2 years of age, an immunologic evaluation should be performed. In this review, we will highlight recent findings and new data on the management of children and adults with chromosome 22q11.2 deletion syndrome.

McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, Zackai EH, Emanuel BS, Vermeesch JR, Morrow BE, Scambler PJ, Bassett AS. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015 Nov 19;1:15071.

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness - all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

Trientine tetrahydrochloride for treatment of Wilson's disease

Trientine tetrahydrochloride (Cuprior, gmp-orphan SA) has been recommended for approval in Europe for the treatment of Wilson's disease in adults, adolescents, and children aged 5 years and older who are intolerant to d-penicillamine.

The positive opinion, from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP), is for a hybrid medicine: a drug that is similar to an authorized medicine containing the same active substance but that differs in characteristics such as strength, indication, or pharmaceutical form. Hybrid applications rely in part on the results of preclinical tests and clinical trials for a reference product and in part on new data.

Wilson's disease is a rare genetic storage disease caused by a defect in a copper transporter gene, leading to copper accumulation in the liver, brain, eye, and peripheral nerves.

Trientine is a copper-chelating agent that removes copper from the body by forming a stable complex that is eliminated through urinary excretion. Trientine may also inhibit copper absorption from the intestinal tract.

Cuprior is a hybrid of trientine dihydrochloride, which has been on the market in Europe since 1985.  
Cuprior works in the same way as the reference product but, unlike the reference product, the trientine salt in Cuprior (tetrahydrochloride) does not need to be stored in the refrigerator.

Cuprior has had orphan status since 2015. It will be available in 150-mg tablets.

"The benefits with Cuprior are its ability to decrease serum copper levels in patients with Wilson's disease," the EMA said in a statement.
Nausea is the most commonly reported adverse reaction with trientine. Serious iron deficiency anemia and severe colitis may occur during treatment, the agency notes.

Epilepsy in Koolen-de Vries syndrome

Myers KA, Mandelstam SA, Ramantani G, Rushing EJ, de Vries BB, Koolen DA, Scheffer IE. The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients. Epilepsia. 2017 Apr 25. doi:10.1111/epi.13746. [Epub ahead of print]

This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1.
We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure.
Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma.
The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.

This study's goal was to explain the spectrum of epilepsy phenotypes in Koolen–de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1. The authors concluded that the typical epilepsy phenotype of KdVS involves childhood–onset focal seizures that are prolonged and have prominent autonomic features. The typical EEG pattern is multifocal epileptiform discharges and structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery ought to be undertaken with care given the widespread neuroanatomic abnormalities; though, tumors are a rare, yet important, occurrence.


The authors were welcomed to take part in a large gathering of individuals with KdVS and their families.

At that time, they enlisted individuals with KdVS and seizures and performed thorough phenotyping.
Extra subjects were included who approached them after the family support group brought attention to the research via social media.

In this study, inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least 1 seizure.


The authors studied 31 individuals, aged 2–35 years.

At seizure onset, median age was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset.
The most frequent seizure type were focal impaired awareness seizures occurring in 20 of 31, usually with prominent autonomic features.

They found prolonged seizures in 21 patients and, at times, refractory status epilepticus.
Electroencephalography (EEG) demonstrated focal/multifocal epileptiform discharges in 20 of 26.
They reviewed MRI studies of 13 patients, and all had structural anomalies.

Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, while periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also seen.

For a lesion, 1 patient underwent epilepsy surgery that proved to be an angiocentric glioma.


About 10 percent of people diagnosed with Angelman syndrome do not have a clear genetic cause, even with the availability of advanced genomic technologies. A study published 29 January in the American Journal of Medical Genetics2 encourages clinicians to consider similar disorders, which all present with speech difficulties and delays, when diagnosing these children.

For example, Koolen-de Vries syndrome has some characteristics in common with Angelman syndrome: developmental delay, intellectual disability, severe speech and language delays and a friendly, happy demeanor. However, people with Koolen-de Vries syndrome have more advanced language skills than those with Angelman syndrome, and distinctive physical features such as a broad forehead and unusually loose joints. 

Friday, April 28, 2017

Cannabidiol reduces drop seizures in Lennox-Gastaut

Adding cannabidiol (CBD) to antiepileptic drug (AED) therapy significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome (LGS), results of a phase 3 placebo-controlled study have shown.

Although the add-on therapy resulted in more adverse events than placebo, it was generally well tolerated, researchers report.

The new data are "exciting" because they represent another possible step toward US Food and Drug Administration (FDA) approval of this agent and give "new hope" to patients with LGS, lead researcher, Anup Patel, MD, associate professor of neurology and pediatrics, Nationwide Children's Hospital and The Ohio State University Medical Center, Columbus, told Medscape Medical News.  "If approved, we will have another option to use in a disease state that tends to be very treatment-resistant," he said.

The study results were released April 18 and will be presented in full at the American Academy of Neurology 2017 Annual Meeting (AAN) in Boston, Massachusetts…

The multicenter study included 225 patients with LGS, with a mean age of 16 years (30% were adults; the oldest was 55 years old). These patients had experienced eight or more drop seizures during a 4-week baseline period, with failure of at least one AED.

Their median monthly drop seizure frequency was 85. A median of six AEDs had previously failed, and patients were currently taking a median of three AEDs.

Researchers randomly assigned patients to receive CBD (Epidiolex; GW Pharmaceuticals), 20 mg/kg/day; CBD, 10 mg/kg/day; or placebo. After a 2-week titration period, patients continued on therapy for 12 weeks…

The primary efficacy endpoint was percentage change from baseline in drop seizures, which tend to be the most prevalent type of seizures in patients with LGS, according to Dr Patel.

"More importantly, they are the most disabling type of seizures and have a greater risk of injury," he said.

Of the total, 9 patients in the 20-mg/kg CBD group and 2 each in the 10-mg/kg CBD and placebo groups withdrew from the study early.

The analysis found that compared with placebo (with a percentage change of 17%), the reduction in drop seizure frequency was significantly greater for CBD 20 mg/kg (42%; P = .0047) and CBD 10 mg/kg (37%; P = .0016).

Adverse events occurred in 94% of the 20-mg/kg CBD group, 84% of the 10-mg/kg CBD group, and 72% of the placebo group. Most of these were mild or moderate. The two most common adverse events, occurring in greater than 10% of patients, were somnolence and decreased appetite.
Treatment-related serious adverse events were reported in 5 patients receiving CBD 20 mg/kg, 2 receiving CBD 10 mg/kg, and 0 receiving placebo.

Overall, 13 patients had elevated aminotransferase levels, which may indicate liver problems. But Dr Patel pointed out that 10 of these patients were also taking the AED valproic acid, which may have contributed to this elevation…

Dr Patel pointed out that those in the placebo group as well as those taking the active agent had a high rate of adverse events.

"Obviously, the rate was higher in the treatment arms, but it was very similar to the overall percentage of [adverse events] noted in other trials of patients with LGS," he said. "This is a very sick population of patients and they often have other problems."

He also stressed that the number of patients who dropped out of the study was small.

Of the 212 completers, 99% entered the open-label extension study.

Study results of the drug in LGS have been released before, but what's new here, said Dr Patel, is that researchers have added results on responder rates (a 50% or greater reduction in monthly drop seizures) and from the Caregiver Global Impression of Change (CGI) questionnaire, which is a sort of "marker for quality of life."

The drug outperformed placebo on both these outcomes, said Dr Patel.

The responder rate was 15% in the placebo group vs  36% in the lower-dose CBD group (P = .0030) and 40% in the higher-dose group (P = .0006).

As for the CGI, 66% of patients taking the lower dose and 57% taking the higher dose reported an improvement in overall condition compared with 44% for placebo (P < .05 for both comparisons)…
Commenting on these findings for Medscape Medical News, Amy Brooks-Kayal, MD, chief and Ponzio Family Chair in Pediatric Neurology, University of Colorado, Denver, and former president of the American Epilepsy Society (AES), pointed out that these results are similar to the seizure reductions reported in several abstracts presented in December 2016 at the AES meeting in Houston, Texas.

"These results suggest that CBD may be an effective adjunctive therapy in treatment-resistant epilepsy, and can be effective in reducing seizure frequency, but with a high rate of adverse effects and low rate of seizure freedom," she said.

Treatments for the prevention of sudden unexpected death in epilepsy

Maguire MJ, Jackson CF, Marson AG, Nolan SJ. Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev. 2016 Jul 19;7:CD011792.

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of people with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus and in whom postmortem examination does not reveal a structural or toxicological cause for death. SUDEP has a reported incidence of 1 to 2 per 1000 patient years and represents the most common epilepsy-related cause of death. The presence and frequency of generalised tonic-clonic seizures (GTCS), male sex, early age of seizure onset, duration of epilepsy, and polytherapy are all predictors of risk of SUDEP. The exact pathophysiology of SUDEP is currently unknown, although GTCS-induced cardiac, respiratory, and brainstem dysfunction appears likely. Appropriately chosen antiepileptic drug treatment can render around 70% of patients free of all seizures. However, around one-third will remain drug refractory despite polytherapy. Continuing seizures place patients at risk of SUDEP, depression, and reduced quality of life. Preventative strategies for SUDEP include reducing the occurrence of GTCS by timely referral for presurgical evaluation in people with lesional epilepsy and advice on lifestyle measures; detecting cardiorespiratory distress through clinical observation and seizure, respiratory, and heart rate monitoring devices; preventing airway obstruction through nocturnal supervision and safety pillows; reducing central hypoventilation through physical stimulation and enhancing serotonergic mechanisms of respiratory regulation using selective serotonin reuptake inhibitors (SSRIs); reducing adenosine and endogenous opioid-induced brain and brainstem depression.
To assess the effectiveness of interventions in preventing SUDEP in people with epilepsy by synthesising evidence from randomised controlled trials of interventions and cohort and case-control non-randomised studies.
We searched the following databases: Cochrane Epilepsy Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2015) via the Cochrane Register of Studies Online (CRSO); MEDLINE (Ovid, 1946 onwards); SCOPUS (1823 onwards); PsycINFO (EBSCOhost, 1887 onwards); CINAHL Plus (EBSCOhost, 1937 onwards);; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. The date of the last search was 12 November 2015. We checked the reference lists of retrieved studies for additional reports of relevant studies and contacted lead study authors for any relevant unpublished material. We identified duplicate studies by screening reports according to title, authors' names, location, and medical institute, omitting any duplicated studies. We identified any grey literature studies published in the last five years by searching: Zetoc database; ISI Proceedings; International Bureau for Epilepsy (IBE) congress proceedings database; International League Against Epilepsy (ILAE) congress proceedings database; abstract books of symposia and congresses, meeting abstracts, and research reports.
We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs; prospective non-randomised cohort controlled and uncontrolled studies; and case-control studies of adults and children with epilepsy receiving an intervention for the prevention of SUDEP. Types of interventions included: early versus delayed pre-surgical evaluation for lesional epilepsy; educational programmes; seizure-monitoring devices; safety pillows; nocturnal supervision; selective serotonin reuptake inhibitors (SSRIs); opiate antagonists; and adenosine antagonists.
We aimed to collect data on study design factors and participant demographics for included studies. The primary outcome of interest was the number of deaths from SUDEP. Secondary outcomes included: number of other deaths (unrelated to SUDEP); change in mean depression and anxiety scores (as defined within the study); clinically important change in quality of life, that is any change in quality of life score (average and endpoint) according to validated quality of life scales; and number of hospital attendances for seizures.
We identified 582 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 211 duplicate records and screened 381 records (title and abstract) for inclusion in the review. We excluded 364 records based on the title and abstract and assessed 17 full-text articles. We excluded 15 studies: eight studies did not assess interventions to prevent SUDEP; five studies measured sensitivity of devices to detect GTCS but did not directly measure SUDEP; and two studies assessed risk factors for SUDEP but not interventions for preventing SUDEP. One listed study is awaiting classification.We included one case-control study at serious risk of bias within a qualitative analysis in this review. This study of 154 cases of SUDEP and 616 controls ascertained a protective effect for the presence of nocturnal supervision (unadjusted odds ratio (OR) 0.34, 95% confidence interval (CI) 0.22 to 0.53) and when a supervising person shared the same bedroom or when special precautions, for example a listening device, were used (unadjusted OR 0.41, 95% CI 0.20 to 0.82). This effect was independent of seizure control. Non-SUDEP deaths; changes to anxiety, depression, and quality of life; and number of hospital attendances were not reported.
We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

Sudden unexpected death in epilepsy incidence rates and risk factors

Harden C, Tomson T, Gloss D, Buchhalter J, Cross JH, Donner E, French JA, Gil-Nagel A, Hesdorffer DC, Smithson WH, Spitz MC, Walczak TS, Sander JW, Ryvlin P. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2017 Apr 25;88(17):1674-1680.

To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified.
Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus.
Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0-17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16-0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64-2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence).
Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.
A new practice guideline on sudden unexpected death in epilepsy (SUDEP) has been released by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES).

For the document, the writing committee sought to establish incidence rates of SUDEP and identify any risk factors.

"We found that SUDEP is relatively rare in children, affecting 1 in 4500 children with epilepsy per year; that's according to moderate evidence," said coauthor Elizabeth Donner, MD, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada, and chair of the AES SUDEP Task Force.

SUDEP was more common in adults than in children, typically affecting 1 in 1000 adults living with epilepsy per year, Dr Donner said.

The major risk factor was generalized tonic-clonic seizures. "People with three or more of this type of seizure…were 15 times more likely to die suddenly than people who did not have this seizure type, so that's a very significant finding," Dr Donner said. "In total, this translates to up to 18 in 1000 deaths per year for people with epilepsy with frequent generalized tonic-clonic seizures."

"Our guideline brings clarity to the discussion, giving healthcare providers information they can use to help people with epilepsy reduce their risk," said lead author, Cynthia Harden, MD, Department of Neurology, Mount Sinai Health System, New York, New York, during a press conference here.
The guideline was co-developed by AAN and AES, and is endorsed by the International Child Neurology Association. It is published online April 24 in Neurology and was presented during a press conference here at the American Academy of Neurology 2017 Annual Meeting (AAN)…

A previous study showed that patients and their families prefer to be informed of individual risk for an event like SUDEP, they note, but after being informed of an adverse event, they tend to overestimate the risk for that adverse event affecting them.

"Overestimation can be lessened by presenting the risk as a probability of both having and not having the event, and by using numbers in addition to words and frequencies rather than percentages to convey the risk," the authors write.

Accordingly, they suggest some language physicians may use to inform patients in a balanced way.
"Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children with epilepsy; therefore, annually 4,499 of 4,500 children will not be affected," they write (Level B).

Similarly, "Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected (Level B)."…

The major risk factors they found were the presence and frequency of generalized tonic-clonic seizure (GTCS). People with three or more of these seizures per year had a 15-fold increased SUDEP risk.

"The large SUDEP risk increase from GTCS, coupled with epilepsy monitoring unit evidence demonstrating that a GTCS was always the precipitating event of SUDEP, strongly suggests that GTCS are not just associated with SUDEP but, rather, are in the causal path to SUDEP," the authors note. "From this, it seems reasonable to infer that improved control of an individual's GTCS will result in a reduced risk of SUDEP. Thus, a reduction in SUDEP risk is an additional benefit to the many benefits resulting from improved seizure control."…

In terms of recommendations, then, they suggest that for patients who continue to have GTCS, "clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of the new approach."
They also suggest that clinicians inform their patients that seizure freedom, "particularly freedom from GTCS (which is more likely to occur with medication adherence), is strongly associated with a decreased SUDEP risk."…

Children with Dravet syndrome have an unusually high risk for SUDEP, they add. "Mutations in sodium channel gene SCN1A are the most common cause of Dravet syndrome and this gene is expressed in brain and heart. It is possible that these mutations render patients more susceptible to cardiac arrhythmias in the setting of a seizure.

Thursday, April 27, 2017

Cerliponase alfa for late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease

The US Food and Drug Administration (FDA) has approved cerliponase alfa (Brineura, BioMarin International Ltd) to treat symptomatic children aged 3 years and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a form of Batten disease.

CLN2 is a rare fatal lysosomal storage disorder characterized by a deficiency in enzyme tripeptidyl peptidase-1 (TPP1), which leads to a build-up of protein deposits in the cells, including nerve cells. This damages tissues and leads to progressive degeneration of the brain and retina. Most children with CLN2 lose their ability to walk and talk by the age of 6 years. Often children with CLN2 die between 8 and 12 years of age.

Cerliponase alfa is a recombinant form of TPP1 that replaces the missing enzyme.

Cerliponase alfa had orphan drug and breakthrough therapy designations and received priority review. It's the first drug approved by the FDA to slow loss of walking ability in children with CLN2.

"The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options," Julie Beitz, MD, director, Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research, said in a statement. 

"Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition."

Cerliponase alfa is administered into the cerebrospinal fluid (CSF) by infusion via an intraventricular access device. The recommended dose is 300 mg given once every other week, followed by an infusion of electrolytes. The complete treatment takes approximately 4.5 hours. Patients should receive antihistamines with or without antipyretics or corticosteroids 30 to 60 minutes before the start of the infusion, the FDA said.

The efficacy of cerliponase alfa was demonstrated in a nonrandomized, single-arm dose-escalation clinical study involving 22 symptomatic children with CLN2 disease and 42 untreated children with CLN2 disease from a natural history cohort.

After taking into account age, baseline walking ability, and genotype, patients treated with cerliponase alfa had fewer declines in walking ability compared with untreated patients, the FDA said.

The most common adverse reactions in patients treated with cerliponase alfa include fever, electrocardiogram (ECG) abnormalities (including bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma, headache, irritability, pleocytosis, device-related infection, feeling jittery, and low blood pressure.

Cerliponase alfa should not be administered if there are signs of acute intraventricular access device–related complications, such as leakage, device failure, or signs of device-related infection (eg, swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device).

If intraventricular access device complications do occur, clinicians should discontinue cerliponase alfa infusion and refer to the device manufacturer's labeling for further instructions, the FDA said.
Clinicians should also routinely test CSF samples to detect device infections. Cerliponase alfa should not be used in patients with ventriculoperitoneal shunts.

In addition, clinicians should monitor vital signs before the infusion starts, periodically during infusion, and after infusion, and they should perform ECG monitoring during infusion in patients with a history of bradycardia, conduction disorder, or structural heart disease, the FDA said.

Hypersensitivity reactions have been reported in cerliponase alfa–treated patients. Because of the potential for anaphylaxis, appropriate medical support should be readily available when the drug is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated, the FDA said.

The FDA will require the manufacturer to further evaluate the safety of cerliponase alfa in patients with CLN2 younger than age 2 years. In addition, a long-term safety study will assess cerliponase alfa–treated patients for a minimum of 10 years.

Earlier this month, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of cerliponase alfa for CLN2 disease.

Wednesday, April 26, 2017

“We are here to help you die, if that is your wish — and we truly believe it is.”

The Lifelines story in Mishpacha's Peasch issue, “Living with Dignity,” illustrates graphically how physician-assisted suicide statutes completely transform the mindset of health-care providers. (The story was actually sent to me by the narrator/daughter of the patient in question, who heard I was researching the Canadian statute.[see earlier in the link about the Canadian statute])

Every single physician and nurse in the story, with the sole exception of the Orthodox “Dr. Sharon Finer,” who insists that the mother’s condition is “completely treatable,” appears to view their duty with respect to a terminally ill patient as to expedite their departure from the world.

First, the doctor at the hospital in which the 84-year-old cancer patient is being treated tells her that her cancer has metastasized to her bones and stomach lining, and that she has only a day or two to live. She is sent home to die. By prematurely ending treatment, the hospital caused her needless pain by failing to detect calcium leaking from her bones into her blood.

After she was admitted to a second hospital via the emergency room, that hospital too soon gives up on medical treatment, and keeps sending teams of palliative specialists to ask whether she would like increased doses of morphine, which can often trigger a fatal heart attack. Those same professionals next recommend cessation of hydration, which will lead inevitably to death.

Only after the elderly cancer patient realizes that death is not as imminent as she was told, does she insist on lowering her pain medication so she can resume normal activities. For her efforts, she is visited by a series of psychiatrists who try to convince her to die already. One asks her, “Do you have any meaning in life?” Even after being assured that she does, he keeps conveying the same message: “We are here to help you die, if that is your wish — and we truly believe it is.”

Another young resident completely misreads a CT scan and tells the patient that the situation is hopeless. The resident then falsely writes on her chart that the patient expressed a desire to cease treatment.

Today, more than half a year after the first prediction of death, the narrator’s mother goes to the gym every day to work out on the elliptical machine and lift weights, reads prodigiously, and greets her children, grandchildren, and great-grandchildren with a smile.

Sometimes, even under medical regimes that appropriate to themselves the ability to assess the “quality of life,” the merchants of death strike out.

Autism spectrum disorders and cerebral palsy

Delobel-Ayoub M, Klapouszczak D, van Bakel MME, Horridge K, Sigurdardottir S, Himmelmann K, Arnaud C. Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy. Dev Med Child Neurol. 2017 Apr 25. doi: 10.1111/dmcn.13436. [Epub ahead of print]

To evaluate the prevalence of co-occurring autism spectrum disorders (ASDs) among children with cerebral palsy (CP), and to describe their characteristics.
The data of 1225 CP cases from four population-based registers (Iceland, Sweden, and two in France) and one population-based surveillance programme (North East England, UK) participating in the Surveillance of Cerebral Palsy in Europe Network (SCPE) were analysed. The ASD diagnoses were systematically recorded using category F84 of the International Classification of Diseases, 10th Revision. The registers provided data on children born between 1995 and 2006, while the cross-sectional survey in the UK concerned children aged 0 to 19 years, registered in 2010.
Among the children with CP, 107 had an associated diagnosis of ASD - i.e., 8.7% of the study population (95% confidence interval 7.2-10.5). This proportion varied across centres from 4.0% to 16.7% but was independent of CP prevalence. Male sex, co-occurring epilepsy, intellectual disability, and better walking ability were associated with the coexistence of ASD.
Our findings support the need for a multidisciplinary approach to management of children with CP to adequately identify and address all facets of presentation, including ASD.

Courtesy of:

Tuesday, April 25, 2017

Our son's special bar mitzvah

If one day could encapsulate the highs and lows of raising a child with Down's syndrome, the day our son, Yehuda, was called to the Torah as a bar mitzvah would be that day.

My wife and I thought it would be a good challenge for Yehuda to not only have an aliyah and recite the blessings over the Torah, but to actually read from the Torah, like most of the “regular” boys do to celebrate their bar mitzvah.

We decided he should do it during Chol Hamoed Pesach in the 7:00 AM minyan when there would be less people at shul and less pressure if he’d back out at the last minute…

The shul was packed. We were surprised to see how many close friends and family made the effort to come so early in the morning. Right before his aliyah, I put my talis on Yehuda and reminded him, “You’ve got this. Remember: slow, loud and clear.” His name was about to be called and this was it, his moment of decision: do I tackle my fear and go up there or simply walk out of shul and head home for some potato chips?

His name was ceremoniously called and everyone went silent. Yehuda quickly went up to the bima, holding the silver yad, Torah pointer, that would help ensure he read every word as opposed to recite it from memory (which would not be sufficient according to Jewish law).

He aced it! Once he cleared his throat and took a second to find his groove, he did a perfect job, reading clearly, with aplomb and confidence. The feeling of nachas my wife and I experienced is hard to put into words. My kids said they had never seen me smile like that. But more importantly, Yehuda was beaming, feeling so proud of his accomplishment. [video at link]

And the accomplishment was deservedly his. We didn’t coddle him. We didn’t manufacture an ersatz experience to make Yehuda feel good. He took on the challenge, put in the necessary work and showed himself capable of accomplishing something to that which he set his mind…

The story could end here, and we’d all feel good reading about how one special boy with Down syndrome overcame his limitations, yada yada yada…

But the truth isn’t as rosy.

We looked forward to capping off such a triumphant day having dinner with my in-laws at the Jerusalem hotel where they were staying for Passover. This is an annual all-you-can-eat bash for our family of hearty eaters. I naively thought that after Yehuda’s spectacular and mature performance, he would behave himself at the hotel despite his viewing it as a massive playground, replete with elevator rides and a zillion secret spots in which to hide.

Within the first moment of sitting down at the table, Yehuda was already missing. My wife and I were more annoyed than alarmed. This was rather typical behavior, Yehuda knew exactly where to find us and we figured he would eventually get tired of exploring and come join us at the table (after all, one of Yehuda’s most favorite activities is eating).

We went into crisis mode, launching a futile effort looking for Yehuda who was probably joyriding in one of the elevators.

But the other guests at the table didn’t feel this way, especially my father-in-law who was getting increasingly agitated and distressed with every passing minute. So we went into crisis mode, my wife and I launching a more or less futile effort looking for Yehuda who was probably joyriding in one of the elevators. I spoke to hotel security who said they’d be on the lookout.

By the time Yehuda nonchalantly walked down the big spiral staircase in the hotel to join the family for dinner, my limited patience had been depleted and I was seething (not the right reaction, I know). My wife and I had decided that there had to be a clear consequence for his actions. I quickly ran up the stairs before he could come down and told him, “You blew it, big time. We are going straight home and you’ll grab something to eat at home.”

Yehuda then pulled his dreaded move of firmly planting himself on the floor and turning himself into an unmovable mountain. I had no interest in engaging in an all-out battle of wills in front on my in-laws who were already incredulous at Yehuda’s behavior and our evident lack of parenting skills. I had to get him out and into the car right away, before the meal was over and the extended family and hotel guests would start pouring out in to the hotel lobby.

Yehuda is a big boy; I can’t pick him up. Suffice it to say getting him to the car was not a pretty sight. Yehuda and I both made mistakes and it certainly was not the way I had envisioned ending such a milestone day.

However it does reflect a more realistic day in the life of raising a child with special needs. Yehuda is not an angel. He is boy full of conflicting wants and desires, and in raising him, there are times of great joy and accomplishment, and times of total frustration, bewilderment and anger.

Just like raising any child.

Monday, April 24, 2017

Seizures in preterm neonates

Hannah C. Glass, MDCM, Renée A. Shellhaas, MD, MS, Tammy N. Tsuchida, MD, PhD, Taeun Chang, MD, Courtney J. Wusthoff, MD, Catherine J. Chu, MD, M. Roberta Cilio, MD, PhD, Sonia L. Bonifacio, MD, MAS, Shavonne L. Massey, MD, Nicholas S. Abend, MD, Janet S. Soul, MDCM On behalf of the Neonatal Seizure Registry study group.  Seizures in Preterm Neonates: A Multicenter Observational Cohort Study. Pediatric Neurology.  In press.

The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society’s neonatal electorencephalogram monitoring guideline.

Study Design
Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N=18), very preterm (28 to <32 weeks, N=18), and moderate/late preterm (32 to <37 weeks, N=56) and compared to term neonates.

Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for etiology in >50% of preterm neonates. Hypothermia therapy was administered in 15 moderate/late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) were similar when comparing preterm and term neonates. However, exclusively subclinical seizures were more common in preterm than term neonates (24% versus 14%). Phenobarbital was the most common initial medication for all gestational age groups and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% versus 15%).

Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates.

This study's goal was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society’s neonatal electorencephalogram monitoring guideline. For preterm, subclinical seizures were more common and mortality was higher than term neonates. In preterm neonates, these data emphasize the importance of electroencephalographic monitoring and the potential for improved management.


The clinicians enrolled 611 neonates with seizures (92 (15%) were born preterm).

They evaluated seizure characteristics by gestational age at birth for extremely preterm (<28 weeks, N=18), very preterm (28 to <32 weeks, N=18), and moderate/late preterm (32 to <37 weeks, N=56) and compared to term neonates.


In >50% of preterm neonates, hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for etiology.

The clinicians administered hypothermia therapy in 15 moderate/late preterm subjects with encephalopathy.

When comparing preterm and term neonates, the presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar.
However, in preterm, exclusively subclinical seizures were more common than term neonates (24% vs. 14%).

The most common initial medication for all gestational age groups was phenobarbital and failure to respond to an initial loading dose was 63% in both preterm and term neonates.

Among the 3 preterm gestational age groups, mortality was similar.

However, preterm mortality was more than twice that of term infants (35% vs. 15%).

Saturday, April 22, 2017

Intranasal exosomes prevent damage from status epilepticus

Long Q, Upadhya D, Hattiangady B, Kim DK, An SY, Shuai B, Prockop DJ, Shetty AK. Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci U S A. 2017 Apr 10. pii: 201703920. doi: 10.1073/pnas.1703920114. [Epub ahead of print]


Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrow-derived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.

Courtesy of Doximity

Tourette syndrome and medical marijuana

Mother Of Teen With Tourette’s Pushes For Medical Cannabis In Schools

Since the passage of the medical marijuana bill in Minnesota, patients across the state have been helped.

Joy Mitchell says her 16-year-old son Josh went from being violent and often pulled from school to being able to control himself. But the law is still holding the Crosby teenager back.

Even a few months ago, a quiet concentrated game of chess would have been out of the question for Josh Mitchell. The 16-year-old has autism and was diagnosed with Tourette syndrome.

“He’d bang his head really hard on the floor, he took a planter outside on the deck and threw it at the sheriff,” Joy Mitchell said.

“It was not good,” admitted Josh Mitchell.

The decision to try medical marijuana came last year when mom Joy was at her wit’s end.

“A year ago I went to his case worker with the county and I said you need to remove him and put him in a home somewhere,” Joy Mitchell said.

It was her last resort.

“He had threatened my older son with a knife and was escalating and getting too strong for me to restrain, having more episodes and I didn’t know what else to do, we had tried everything we could think of,” Joy Mitchell said.

Doctors prescribed Josh this cannabis oil for his Tourette’s. He takes the medication every two hours.

“I just open up my mouth and I squirt it underneath my tongue. Just one squirt usually. It helped me calm down more and relax more and stuff. I make these noises and it helped stop that too,” Josh Mitchell said.

Joy Mitchell attributes the behavior change to, “the cannabis oil. It’s the only change we’ve made. I mean it was very drastic, very fast. He used to yell I hate my life, F my life all the time. It went from I hate my life to I love my life.”

Last year educators told his parents they couldn’t handle him anymore. The medication has allowed Josh to go back to school. Now he’s progressing, but he only goes to school for half the day. Federal law prohibits medical cannabis from being on school grounds.

“He has a hard time with school as it is and then when he doesn’t have this it makes things more difficult,” Joy Mitchell said.

Josh can only miss one dose before he starts getting agitated.

“If I could have it at school that would help out a lot with my work and everything too,” Josh Mitchell said.

Joy Mitchell wants her son to have as full a life as possible, and that includes going to school all day.

“I mean they keep other medications locked up at school I don’t see why they couldn’t just keep it locked up,” Joy Mitchell said.

A handful of states passed strict legislation allowing medical cannabis use on school campuses.

The chief sponsor of the original bill in Minnesota told WCCO, now that it has been brought to his attention, this should be an easy technical tweak to make here. DFL Senator Scott Dibble is drafting a bill in hopes of introducing it this week to be passed this legislative session.

The Minnesota School Boards Association said its best advice for now is that medical marijuana must be stored and administered off school grounds.

Todd Lyscio, Executive Director at Crosslake Community School where Josh attends school said, “As a public school, we need to follow all laws as they apply to public schools. According to MN Statute 152.23, no school in Minnesota is permitted to have medical cannabis on school grounds. Consequently, since it is not permitted on school grounds, buses, etc. we cannot administer it.”
Video at link

Courtesy of a colleague.

Friday, April 21, 2017

Half a brain does not make for half a mind

The woman joking with me across the table was born with only half her brain. Something catastrophic happened while she was in her mother's womb, though no one knows what for sure. It wasn't a stroke, because stroke destroys healthy tissue, and Michelle Mack's left hemisphere simply never developed. Her doctors speculated that her left carotid artery, which supplies blood to the left hemisphere, may have become blocked while Michelle was still a fetus, preventing that hemisphere from forming. At birth the doctors gave her the usual tests and told her mother, Carol, that she was a normal baby. Even today a neurologist would not likely guess, without a brain scan, that a whole hemisphere is missing. I find myself wondering how many others have lived out their lives with half a brain, without themselves or anyone knowing it…

Though she has only a right hemisphere, Michelle is not a desperate creature barely surviving on life support. She is twenty-nine years old. Her blue eyes peer through thick glasses. She wears blue jeans, sleeps in a blue bedroom, and speaks fairly normally. She holds a part-time job, reads, and enjoys movies and her family. She can do all this because her right hemisphere took over for her left, and such essential mental functions as speech and language moved to her right. Her development makes it clear that neuroplasticity is no minor phenomenon operating at the margins; it has allowed her to achieve massive brain reorganization…

Michelle has some extraordinary calculating skills—savant skills—that she employs at lightning speed. She also has special needs and disabilities. She doesn't like to travel and gets easily lost in unfamiliar surroundings. She has trouble understanding certain kinds of abstract thought. But her inner life is alive, and she reads, prays, and loves. She speaks normally, except when frustrated. She adores Carol Burnett comedies. She follows the news and basketball and votes in elections. Her life is a demonstration that the whole is more than the sum of its parts and that half a brain does not make for half a mind…

Michelle's experience reminds us how ignorant we are about some of the most basic aspects of human brain functions. What happens when the functions of both hemispheres must compete for the same space? What, if anything, must be sacrificed? How much brain is needed for survival? How much brain is required to develop wit, empathy, personal taste, spiritual longing, and subtlety? If we can survive and live without half our brain tissue, why is it there in the first place?...

On the right I can see the gray convolutions of a normal right hemisphere. On the left, except for a thin, wayward peninsula- of gray brain tissue—the minuscule amount of left hemisphere that developed—there is only the deep black that denotes emptiness. Michelle has never looked at the film.

She calls this emptiness "my cyst," and when she speaks of "my cyst" or "the cyst," it sounds as though it has become substantial for her, an eerie character in a science fiction movie. And indeed, peering at her scan is an eerie experience. When I look at Michelle, I see her whole face, her eyes and smile, and cannot help but project that symmetry backward into the brain behind. The scan is a rude awakening…

But because Michelle has no left hemisphere, she has trouble seeing things coming from her right and is blind in the right visual field. Her brothers used to steal her french fries from her right side, but she'd catch them because what she lacks in vision, she has made up for with supercharged hearing. Her hearing is so acute that she can clearly hear her parents talking in the kitchen when she is upstairs at the other end of the house. This hyperdevelopment of hearing, so common in the totally blind, is another sign of the brain's ability to adjust to a changed situation. But this sensitivity has a cost.
In traffic, when a horn blares, she puts her hands over her ears, to avoid sensory overload. At church she escapes the sound of the organ pipes by slipping out the door. School fire drills frightened her because of the noise and confusion.

She is also supersensitive to touch. Carol cuts the tags off Michelle's clothing so she won't feel them. It's as though her brain lacks a filter to keep out excess sensation, so Carol often "filters" for her, protecting her.  If Michelle has a second hemisphere, it is her mother…

But at two she still couldn't crawl, so Wally, who knew that she loved music, would play her favorite record, and when the song was over, Michelle would cry, "Hmnun, hmmm, hmmm, want it again!" Then Wally would insist she crawl to the record player before he'd play it again. Michelle's overall learning pattern was becoming clear—a significant delay in development; a message from the clinicians to her parents to get used to it; and then somehow Michelle would pull herself out of it. Carol and Wally became more hopeful…

Though she can repeat Dr. Grafman's explanation that her right hemisphere now handles such left-brain activities as speaking, reading, and math, she sometimes speaks of the cyst as though it has substance, as though it were a kind of alien being with a personality and will, rather than an emptiness inside her skull, where a left hemisphere should have been. This paradox displays two tendencies in her thought. She has a superior memory for concrete details but difficulty with abstract thought. Being concrete has some advantages. Michelle is a great speller and can remember the arrangement of letters on the page, because like many concrete thinkers, she can record events in memory and keep them as fresh and vivid as the moment when she first perceived them. But she can find it difficult to understand a story illustrating an underlying moral, theme, or main point that is not explicitly spelled out, because that involves abstraction…

I began to suspect Michelle was a savant with some extraordinary mental abilities when, in our conversations, almost as an aside, she would unobtrusively, but with uncommon accuracy and confidence, correct her mother about the date of a particular event…

Because she said that she often could remember days back into the mid-1980s without using a formula, I tried to push her past her recall and asked her the day of the week for August 22, 1983.
This time she took half a minute and was clearly calculating, whispering to herself, instead of remembering.

"August 22, 1983, um, that was a Tuesday"

"That was harder because?"

"Because in my mind I only go back to the fall of 1984. That's when I remember things well." She explained she had a clear memory of each day and what happened on it during the period she was in school, and that she used those days as an anchor.

Grafman's theory provides an explanation of how Michelle's brain evolved. Michelle's loss of brain tissue occurred before there could have been any significant commitment of her right hemisphere. Since plasticity is at its height in the earliest years, what probably saved Michelle from certain death was that her damage occurred so early. When her brain was still forming, her right hemisphere had time to adjust in the womb, and Carol was there to care for her.

It is possible that her right hemisphere, which normally processes visual-spatial activities, was able to process speech because, being partially blind and barely able to crawl, Michelle learned to speak before she learned to see and walk. Speech would have trumped visual-spatial needs in Michelle, just as visual-spatial needs had trumped arithmetical needs in Paul…

People with right-prefrontal lesions have impaired foresight. They can watch a movie, but they can't get the main point or see where the plot is going. They don't plan well, since planning involves ordering a series of events so that they lead toward a desired outcome, goal, or main point. Nor do people with right frontal lesions execute their plans well. Unable to keep to the main point, they are easily distracted. They are often socially inappropriate because they don't get the main point of social interactions, which are also a series of events, and they have difficulty understanding metaphors and similes, which require extracting the main point or theme from various details. If a poet says, "A marriage is a battle zone," it is important to know that the poet doesn't mean the marriage consists of actual explosions and dead bodies; rather, it is a husband and wife fighting intensely.

All the areas Michelle has difficulty with—getting the main point, understanding proverbs, metaphors, concepts, and abstract thought—are right prefrontal activities. Grafman's standardized psychological testing confirmed that she has difficulty planning, sorting out social situations, understanding motives (a version of getting the main theme, applied to social life), and also some problems empathizing with and forecasting the behavior of others.  Her relative absence of foresight, Grafman  thinks, increases her level of anxiety and makes it harder for her to control her impulses. On the other hand, she has a savant's ability to remember individual events and the exact dates they occurred—a left-prefrontal function…

There is a theme to her preferences, tastes, and longings. The Baby-Sitters Club, Carol Burnett's harmless humor, the toy bear collection, and everything else I saw in Michelle's blue room were part of that phase of development called "latency," the relatively calm period that precedes the storm of puberty, with its erupting instincts. Michelle, it seemed to me, showed many latency passions, and I found myself wondering whether the absence of her left lobe had affected her hormonal development even though she was a fully developed woman. Perhaps these tastes were the result of her protected upbringing, or perhaps her difficulty understanding the motives of others led her to a world in which the instincts are quieted and where humor is gentle…

I see the smile—an overflow of inner peace. In Michelle's heaven are all the things she's striving for—more human contact, vague hints of increased but safely circumscribed relations between men and women, all that has given her pleasure. Yet all this occurs in an afterworld where, though she is more independent, she can find the parents she so loves not too far away. She has no medical problems, nor does she wish for the other half of her brain. She's fine there just as she is.

From Norman Doidge, MD, The Brain that Changes Itself  .Penguin Books 2007

Thursday, April 20, 2017

CHAMP1 mutations

Inspired by a patient

Hempel M, Cremer K, Ockeloen CW, Lichtenbelt KD, Herkert JC, Denecke J, Haack TB, Zink AM, Becker J, Wohlleber E, Johannsen J, Alhaddad B, Pfundt R, Fuchs S, Wieczorek D, Strom TM, van Gassen KL, Kleefstra T, Kubisch C, Engels H, Lessel D. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment. Am J Hum Genet. 2015 Sep 3;97(3):493-500.

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.

From the article

Taken together, all five individuals with a de novo deleterious CHAMP1 mutation are affected by ID[intellectual disability] and delayed motor development with a particularly severe delay in speech development. Whereas the motor development improved over time, speech impairment remained. All individuals suffered from muscular, in particular truncal, hypotonia. Orofacial hypotonia was observed in four probands. Similar dysmorphic features, including a short philtrum, tented upper lip, and everted lower lip were observed in all individuals. Three individuals presented with upslanting palpebral fissures, low-set ears, and a long face and pointed chin. A friendly behavior was described in all individuals. Decreased pain sensation, feeding difficulties during the neonatal period, hyperopia, and a high arched palate were noted in four individuals. Three individuals displayed stereotypic movements. Three individuals showed microcephaly. Before identifying the causative CHAMP1 mutations, a number of different specific genetic tests had been performed. The most important genetic differential diagnoses were Prader-Willi (PWS) and Angelman syndromes (AS). PWS was suspected in three probands because of feeding difficulties. At toddler age, the severely delayed speech development, the microcephaly, and ataxic gait made Angelman syndrome an important differential diagnosis, which was tested in three probands. ARX analysis was performed because of ID and speech delay in two male probands…

The findings in altogether seven independent individuals thus confirm that mutations in CHAMP1 are a monogenic cause of ID/GDD. In line with this assumption, there is no single loss-of-function CHAMP1 variant deposited in the ExAC database, including more than 110,000 sequenced alleles at this locus, which argues strongly for a deleterious effect of CHAMP1 mutations. Notably, the Residual Variation Intolerance (RVI) score, which quantifies gene intolerance to functional mutations7 of CHAMP1, is −0.75 (13.71th percentile) and thus even lower than the average RVI score for genes involved in developmental disorders (0.56; 19.54th percentile). This suggests that the degree of intolerance to deleterious variants of CHAMP1 is significantly more pronounced than the average degree of intolerance to deleterious variants of genes known to have mutations that cause developmental disorders.

CHAMP1 is located at chromosome 13q34 and contains a single coding exon (as well as two 5′-untranslated exons) encoding for a zinc-finger protein of 812 amino acids. CHAMP1 was shown to interact with the mitotic control protein MAD2L2 and is required for its spindle localization. CHAMP1 localizes to chromosomes and the mitotic spindle and regulates localization of CENPE and CENPF to kinetochores. Furthermore, it regulates kinetochore-microtubule attachment and therefore proper chromosome alignment.5 Mutations affecting genes encoding for proteins that regulate chromosome alignment and/or spindle assembly are a well-established cause of a variety of syndromic and non-syndromic developmental disorders.

Wednesday, April 19, 2017

The automatic identification of craniosynostosis using 3D stereophotogrammetry.

Meulstee JW, Verhamme LM, Borstlap WA, Van der Heijden F, De Jong GA, Xi T, Bergé SJ, Delye H, Maal TJ. A new method for three-dimensional evaluation of the cranial shape and the automatic identification of craniosynostosis using 3D stereophotogrammetry. Int J Oral Maxillofac Surg. 2017 Apr 6. pii:S0901-5027(17)31362-0. doi: 10.1016/j.ijom.2017.03.017. [Epub ahead of print]


Craniosynostosis is a congenital defect which can result in abnormal cranial morphology. Three dimensional (3D) stereophotogrammetry is potentially an ideal technique for the evaluation of cranial morphology and diagnosis of craniosynostosis because it is fast and harmless. This study presents a new method for objective characterization of the morphological abnormalities of scaphocephaly and trigonocephaly patients using 3D photographs of patients and healthy controls. Sixty 3D photographs of healthy controls in the age range of 3-6 months were superimposed and scaled. Principal component analysis (PCA) was applied to find the mean cranial shape and the cranial shape variation in this normal population. 3D photographs of 20 scaphocephaly and 20 trigonocephaly patients were analysed by this PCA model to test whether cranial deformities of scaphocephaly and trigonocephaly patients could be objectively identified. PCA was used to find the mean cranial shape and the cranial shape variation in the normal population. The PCA model was able to significantly distinguish scaphocephaly and trigonocephaly patients from the normal population. 3D stereophotogrammetry in combination with the presented method can be used to objectively identify and classify the cranial shape of healthy newborns, scaphocephaly and trigonocephaly patients.

Courtesy of:

Saturday, April 15, 2017

Unprofessional content on Facebook accounts of US urology residency graduates

Koo K, Ficko Z, Gormley EA. Unprofessional content on Facebook accounts of US urology residency graduates. BJU Int. 2017 Apr 9. doi: 10.1111/bju.13846. [Epub ahead of print]

To characterize unprofessional content on public Facebook accounts of contemporary US urology residency graduates.
Facebook was queried with the names of all urologists who graduated from US urology residency programmes in 2015 to identify publicly accessible profiles. Profiles were assessed for unprofessional or potentially objectionable content using a prospectively designed rubric, based on professionalism guidelines by the American Urological Association, the American Medical Association, and the Accreditation Council for Graduate Medical Education. Content authorship (self vs other) was determined, and profiles were reviewed for self-identification as a urologist.
Of 281 graduates, 223 (79%) were men and 267 (95%) held MD degrees. A total of 201 graduates (72%) had publicly identifiable Facebook profiles. Of these, 80 profiles (40%) included unprofessional or potentially objectionable content, including 27 profiles (13%) reflecting explicitly unprofessional behaviour, such as depictions of intoxication, uncensored profanity, unlawful behaviour, and confidential patient information. When unprofessional content was found, the content was self-authored in 82% of categories. Among 85 graduates (42%) who self-identified as a urologist on social media, nearly half contained concerning content. No differences in content were found between men and women, MD and DO degree-holders, or those who did or did not identify as a urologist (all P > 0.05).
The majority of recent residency graduates had publicly accessible Facebook profiles, and a substantial proportion contained self-authored unprofessional content. Of those identifying as urologists on Facebook, approximately half violated published professionalism guidelines. Greater awareness of trainees' online identities is needed.

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From the article

Table 2. Unprofessional or potentially objectionable content on urologists’ public Facebook accounts (n = 201)
Content category*

Unprofessional content
Any unprofessional content

Uncensored profanity (T)

References to alcohol intoxication (T)

Appearing intoxicated (I)

Unprofessional behaviour at work or in a professional capacity (I)

Protected health information (I/T)

Unlawful behaviour (I/T)

Offensive comments about colleagues at own hospital (T)

Offensive comments about colleagues at other hospital (T)

Offensive comments about a specific patient (T)

Any profile
Excluding profiles with unprofessional content

1.        I, image; T, text; P, page, link, or other posted content. *Categories are not exclusive; total may sum to > 100%.
Potentially objectionable content
Any potentially objectionable content
Holding alcohol (I)
Politics or content of a political nature (P)
Religion or content of a religious nature (P)
Inappropriate or offensive attire (I)
Comments about politics or of a political nature (T)
Comments about religion or of a religious nature (T)
Consuming alcohol (I)
Censored profanity (T)
References to sex or sexual behaviour (T)
Appearing in sexually suggestive attire or circumstances (I)
Comments about controversial social topics (T)
Controversial social topics (P)