Saturday, March 30, 2019

Diagnostic value of oligoclonal bands in children

Magnus Spangsberg Boesen, Alfred Peter Born,Poul Erik Hyldgaard Jensen, Finn Sellebjerg, MortenBlinkenberg, Magnus Christian Lydolph, Mikala Klok Jørgensen, Lene Rosenberg, Jesper Qvist Thomassen, Malene Landbo Børresen.  Diagnostic value of oligoclonal bands in children: A nationwide population-based cohort study.  Pediatric  Neurology.  In press. 


To evaluate the diagnostic value of cerebrospinal fluid oligoclonal bands (OCBs) in children (<18 years).

In a nationwide population-based setting, we retrieved data on 2,055 children’s OCB examination including concordant cerebrospinal fluid biomarkers during 1994–2017. Case ascertainment was by review of medical records and diagnostic codes. We used Fisher’s exact test to explore distribution differences of OCB positivity in acquired demyelinating syndromes (ADS) before and after 12 years of age and calculated sensitivity, specificity, positive predictive value, and negative predictive value of OCBs to distinguish ADS from the other diagnostic groups.

Median age at OCB examination was 15.2 years (range=1.8–18.0), and 10% had presence of cerebrospinal fluid OCB. OCB positivity was the highest in ADS (52%), but it was age-dependent: 21% in children with ADS before age 12 years and 68% in children 12–17 years (p<0.0001) due to the higher incidence of multiple sclerosis in the latter. Cerebrospinal fluid OCBs were not predictive of ADS before age 12 years compared with the other diagnostic groups. However, cerebrospinal fluid OCBs in children aged 12–17 years were highly predictive of ADS compared with CNS infections and non-ADS immune-mediated CNS diseases (positive predictive value: 0.89; 95% confidence interval=0.82–0.94; p<0.0001), but negative OCBs were not discriminatory (negative predictive value: p=0.17).

In a clinical setting, cerebrospinal fluid OCB examination may be of higher yield in children aged 12–17 years if there is clinical suspicion of multiple sclerosis, and in such circumstances a positive test supports a diagnosis of multiple sclerosis.

Courtesy of Doximity

Successful pregnancy in maple syrup urine disease

Grünert SC, Rosenbaum-Fabian S, Schumann A, Schwab KO, Mingirulli N, Spiekerkoetter U. Successful pregnancy in maple syrup urine disease: a case report and review of the literature. Nutr J. 2018 May 12;17(1):51

Maple syrup urine disease (MSUD) is an autosomal recessive disorder of branched-chain amino acid metabolism. Patients with MSUD are at risk of life-threatening metabolic decompensations with ketoacidosis and encephalopathy. These episodes are often triggered by physiological stress. Only few cases of pregnancies in MSUD mothers have been reported so far.

We present the favorable outcome of a pregnancy in a woman with classical MSUD. She presented in the metabolic outpatient clinic in week 7 of gestation. Branched-chain amino acid concentrations were measured at least weekly to adjust dietary leucine intake. Despite excellent compliance, leucine concentrations frequently exceeded the target value of < 300 μmol/L during the first trimester. From the second trimester until delivery, protein and leucine intake increased continuously to about threefold compared to pre-pregnancy values. To maximize patient safety during delivery and the postpartum period, a detailed plan including peripartal infusion therapy, dietary recommendations and monitoring parameters was developed. Primary Caesarean section was performed in week 38 of gestation, and the patient gave birth to a healthy girl. Lactation was successfully implemented. Leucine levels were maintained within the target range throughout the complete postpartum period. In addition to our case, we give an overview about all cases of pregnancies in MSUD mothers published so far.

Management of pregnancy, delivery, postpartum period and lactation may be challenging in patients with MSUD. Careful monitoring and interdisciplinary collaboration is essential to minimize the risk of metabolic crisis, especially after delivery.

Impaired CO(2)-Induced arousal in SIDS and SUDEP

Buchanan GF. Impaired CO(2)-Induced Arousal in SIDS and SUDEP. Trends Neurosci. 2019 Mar 8. pii: S0166-2236(19)30018-9. doi:10.1016/j.tins.2019.02.002. [Epub ahead of print]

Premature, sudden death is devastating. Certain patient populations are at greater risk to succumb to sudden death. For instance, infants under 1year of age are at risk for sudden infant death syndrome (SIDS), and patients with epilepsy are at risk for sudden unexpected death in epilepsy (SUDEP). Deaths are attributed to these syndromic entities in these select populations when other diagnoses have been excluded. There are a number of similarities between these syndromes, and the commonalities suggest that the two syndromes may share certain etiological features. One such feature may be deficiency of arousal to CO2. Under normal conditions, CO2 is a potent arousal stimulus. Circumstances surrounding SIDS and SUDEP deaths often facilitate CO2 elevation, and faulty CO2 arousal mechanisms could, at least in part, contribute to death.

Every parent’s worst fear is not being able to keep their child safe. And a mysterious condition known as sudden infant death syndrome (SIDS) is enough to keep any new parent awake at night.

What’s so troubling about SIDS is that no one really understands why a seemingly healthy baby goes to sleep and never wakes up. But a new opinion review paper suggests that SIDS and other forms of sudden death syndromes — which impact people of all ages and seem to strike without warning or cause — may share a common, neurological cause.

Some individuals may be prone to sudden death syndromes because they are born with a neurological difference that can be fatal under the right circumstances, explains Gordon Buchanan, a neurologist and epileptologist at the University of Iowa who authored the opinion review paper in Trends in Neurosciences. Among these people, there seems to be a problem with the part of the brain that controls breathing and waking during sleep…

Buchanan thinks that individuals who succumb to sudden death syndromes may have malfunctioning serotonin receptors in their brains. These receptors are part of our brain’s “suffocation alarm system” and help to ensure that blood oxygen and carbon dioxide (CO2) levels are healthy. But Buchanan thinks that a rare neurological difference causes some people’s brains to be bad at detecting when blood CO2 levels get too high — which is a signal to our bodies that we could be suffocating. Instead of waking up like most people would, those with this defect stay asleep and are seemingly powerless against what’s happening to them…

“The possibility that SIDS and SUDEP lie on a sudden death continuum of sorts has been known in the SUDEP community for some time … using known mechanisms for SIDS as a starting point for understanding SUDEP seemed like a good place to start,” he said. “Defects in the brain stem serotonin system have been identified in the brains of several cohorts of babies that have dies of SIDS. Similar anatomical defects are starting to be identified in pathological and imaging studies of people who have died of SUDEP.”…

Researchers have made some recent progress in understanding what causes complex syndromes like SIDS. Last year, a team of researchers found a genetic mutation affecting respiratory muscle function was associated with a subset of SIDS cases. Another recent study found that smoking just one cigarette per day during pregnancy can double a baby’s risk of SIDS. But more research is needed to paint a more precise picture of what’s behind these bewildering cases and how to test for them.

For now, Buchanan recommends that at-risk populations, like people with epilepsy and parents of infants, follow preventive measures against sudden death. Parents should place the babies on their backs to sleep and take care to reduce plush toys, pillows, blankets, and loose-fitting clothing in the crib. People with epilepsy can also take precautions, such as ensuring their condition is properly managed, sleeping on their back, and using a seizure alarm or monitor to alert family or neighbors if they have a seizure at night.

Courtesy of Doximity

Thursday, March 28, 2019

Necessity of intracranial imaging in infants and children with macrocephaly

Sampson MA, Berg AD, Huber JN, Olgun G. Necessity of Intracranial Imaging in Infants and Children With Macrocephaly. Pediatr Neurol. 2019 Apr;93:21-26.

Macrocephaly is frequently encountered in pediatrics and often leads to imaging. There are no recommendations from the American Academy of Pediatrics or the American College of Radiology providing imaging guidelines for macrocephaly. The goal of this study is to identify risk factors for pathologic macrocephaly and to aid the clinician in identifying patients that would benefit from imaging.

We conducted a medical record review throughout a multistate health care system, Sanford Health, from January 1, 2012 to December 31, 2016. Patients with macrocephaly were identified by problem list in children aged less than 36 months. Data collection included basic demographics, imaging modality, developmental delay, prematurity, seizures, focal neurological symptoms, family history of macrocephaly, sedation used, and sedation complications.

A total of 169 patients were included in the analysis. Imaging modalities included 39 magnetic resonance imagings (23.1%), 47 cranial computed tomographies (27.8%), and 83 head ultrasounds (49.1%). Imaging results demonstrated 13 abnormal studies with five of those studies being abnormal with high clinical yield. Patients with abnormal studies were more likely to have developmental delay (P = 0.04) or neurological symptoms (P = 0.015). Positive family history of macrocephaly was predictive of normal imaging (P = 0.004). There were no sedation complications.

Intracranial imaging does not appear to be necessary in children with no risk factors and or a positive family history of macrocephaly. Risk factors such as developmental delay or neurological symptoms could identify children at risk for imaging abnormalities that require further management.

Ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms

Dressler A, Benninger F, Trimmel-Schwahofer P, Gröppel G, Porsche B, Abraham K, Mühlebner A, Samueli S, Male C, Feucht M. Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: A single-center parallel-cohort randomized controlled trial. Epilepsia. 2019 Mar;60(3):441-451.

To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome.

In this parallel-cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high-dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow-up, adverse effects, and developmental progress.

One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow-up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age-appropriate psychomotor development and adaptive behavior were similar. Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow-up was similar. In infants with prior VGB, seizure freedom at last follow-up was 48% (KD) and 21% (ACTH, P = 0.05).

The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short-term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second-line treatment after VGB.

Monday, March 25, 2019

Sleeping beauty syndrome

A college student said she suffers from a rare syndrome that causes her to sleep for weeks at a time, and has even napped through her exams. Rhoda Rodriguez-Diaz, 21, was allegedly diagnosed with “Sleeping Beauty syndrome” which can cause her to sleep for up 22 hours per day, only waking in a dream-like trance to eat junk food, drink and go to the bathroom.

At its worst, her sleeping episodes allegedly last three weeks, which caused her to fail the second year of college after she slept through crucial end-of-year exams.

As a child Rodriguez-Diaz was diagnosed with hyperinsomnia, characterized by extreme tiredness, by her general physician. But it wasn't until last September that doctors finally discovered the psychology student had the one-in-a-million Kleine-Levin syndrome.

She goes months at a time without experiencing an episode, but when they strike, she is totally wiped out.

"Life goes on whilst I'm sleeping,” Rodriguez-Diaz, of Leicester, England said. “Reality hits me when I wake up and realize I've missed like a week of my life. I feel a huge setback when it does happen. I miss out on so much. That's the hardest part of it.”

"It's hard to explain to people where I have been. Because it's so rare a lot of people struggle to understand,” she said. "It's really annoying when people call me lazy. I do struggle to deal with the effects of it.”

“But I'm determined to not let it have a big impact on my life,” she said. “It is one part of me and not who I am. It's frustrating because people think I'm just lazy. But I'm not, I can't help it."

Rodriguez-Diaz said that as a child, she was unable spend as much time with friends as she would have liked.

"When I was 4 or 5 would sleep for two or three weeks at a time and the doctors had no idea what it was,” she said. "It was quite bad when I was a child. But then it didn't happen again until I was a teenager. When I was 15 or 16 I remember finding myself sleeping more and more. Even at school I would fall asleep in the study area.”

"I forced myself to go to school. I didn't get teased but I found it very frustrating,” she said. "I was really into my sports but I couldn't do as much as I wanted to because I was constantly tired. I had to force myself to do every day activities and found myself mentally tired all of the time.”

"When I wake up after a few days I feel normal again,” she said. “My friends say they can tell when I have an episode coming on because my mood changes. I get worked up and my behavior changes drastically."

Between February and June last year, Rodriguez-Diaz went through a period of suffering from a number of episodes, which left her unable to spend enough time on her studies.

She said she was dismissed from her course in July last year when she failed to show for a number of exams and missed coursework deadlines because she was asleep.

After a visit to the doctor, in May last year, Rodriguez-Diaz was sent to see specialists at St. Thomas' Hospital and finally got her diagnosis in September.

"It's not as bad as it used to be but I feel like I'm always playing catch up,” she said. "I was sleeping a lot in my first year too but because it didn't have too much of an impact on my work I didn't go to the doctors. It was when I was missing work that I went to my GP. I tried to explain to uni that I had a condition that was stopping me from doing work.”

"But because I wasn't diagnosed until September I had nothing to back it up,” she said. "I didn't have enough credits to pass the year and I was dismissed."

Rodriguez-Diaz last experienced an episode around three months ago when she slept for over 60 hours in just three days. She said she typically snacks on junk food during nap breaks and often puts on weight during an episode.

She has now re-enrolled to resume her studies, and is sitting her second year again. 

"I missed so many exams. 60 percent of my course is exams and I missed half of them,” she said. "It wasn't my fault. But they said this is an 'exceptional case' so I am allowed to go back. It's a big relief but I have to redo a lot of work I did in second year. It was difficult for me."

Patients diagnosed with Kleine-Levin Syndrome are known to grow out of the condition eventually, and Rodriguez-Diaz says has learnt to manage her condition in adult life.

"I'm more aware of it now. I know when I'm going to have an episode,” she said. "It used to feel like I was in a dream. It's such a surreal feeling. It feels like you're not really there. This is just a hiccup in my life and I am just waiting until it fades out. I want to be taken serious in life and this isn't helping."

Hussain S, Al Jarman K, Hussain S. Sleeping beauty syndrome presenting with insomnia. BMJ Case Rep. 2018 Oct 12;2018.

A young man previously diagnosed with Kleine-Levin syndrome (KLS) presented with abnormal behaviour over the last 8 days. This included decreased sleeping hours and appetite, hypersexuality, aggressiveness and visual hallucinations. All blood tests and investigations in the emergency department yielded normal results. A preliminary diagnosis of a KLS episode with psychosis was made and the patient was started on a regimen of aripiprazole 10 mg once daily along with lorazepam 2 mg intravenously in two divided doses in the event of agitation or insomnia. On discharge 5 days later, the patient had returned to his premorbid level of functioning and was willing to follow up in the neurology clinic. He was discharged on aripiprazole 10 mg once daily and lorazepam 2 mg two times daily as needed for 2 weeks to help with his agitation and insomnia, as well as lithium carbonate 400 mg at night.

Nebhinani N, Suthar N. Sleeping Beauty Syndrome: A Case Report and Review of Female Cases Reported from India. Indian J Psychol Med. 2017 May-Jun;39(3):357-360.

Kleine-Levin syndrome (KLS), also called "Sleeping beauty syndrome" is a rare, disorder predominantly reported in adolescent males, characterized by recurrent episodes of hypersomnia and to various degrees, hyperphagia, cognitive disturbances, and hypersexuality. Here, we are reporting a case of a middle-aged female, with 16 years delay in diagnosing KLS, poor response to most of the psychotropics, except good response to a combination of lithium, sertraline, and modafinil for last 12 months and also reviewing other female cases with KLS reported from India.

Mudgal S, Jiloha RC, Kandpal M, Das A. Sleeping beauty: kleine-levin syndrome. Indian J Psychiatry. 2014 Jul;56(3):298-300.

Kleine-Levin syndrome (KLS) alias sleeping beauty syndrome, is a rare sleep disorder. Clinically presenting as episodes of hypersomnolence, behavioral and cognitive disturbances, hyperphagia and hypersexuality. KLS may have an idiopathic onset or may be precipitated by neurological event or infection. Until date, no definite underlying cause is established and neither there are any definitive management guidelines. It remains a diagnosis of exclusion after other psychiatric and neurological causes have been ruled out. Coloring of presentation with behavioral and mood elements makes it important for a psychiatrist to be well-informed about the condition to avoid the erroneous diagnosis. KLS is a devastating illness, which robs the patient of time, experiences, and relationships. An early diagnosis and effective management can help patient escape from the morbidity caused by this disorder. Armodafinil and oxcarbamazepine have found to be effective in two of the case. The emphasis of this report is to add to the existing clinical knowledge of neurologists, psychiatrists and physicians. In the future, research is needed on genetic etiology and management of this disorder.


Friday, March 22, 2019

Transcranial magnetic stimulation for treatment of Tourette syndrome

Singh S, Kumar S, Kumar N, Verma R. Low-frequency Repetitive Transcranial Magnetic Stimulation for Treatment of Tourette Syndrome: A Naturalistic Study with 3 Months of Follow-up. Indian J Psychol Med. 2018 Sep-Oct;40(5):482-486.

The objective of this study is to report the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) in three patients with medication-refractory Tourette syndrome (TS) and over 3-month follow-up. A review of literature on the use of rTMS for the treatment of TS is also presented. Three patients with severe, medication-refractory TS and comorbid obsessive-compulsive disorder (OCD) in two of them, received an open-label trial of rTMS at 1 Hz frequency for 4-week duration. The first two cases of TS-OCD showed, on average, around 57% improvement in Yale Global Tic Severity Scale (YGTSS) scores (65% and 50%) and 45% improvement in Yale-Brown Obsessive-compulsive Scale (Y-BOCS) scores; however, the third case of pure-TS showed marginal improvement of 10% only. The improvement in TS-OCD patients with rTMS treatment was maintained at the end of 3-month follow-up, with an average reduction of about 49% (58% and 40%) and 36% observed in YGTSS and Y-BOCS scores, respectively. The present study supports the use of low-frequency rTMS to improve tics and OCD symptoms in patients with severe, medication-refractory TS-OCD. Further, the beneficial effects of rTMS treatment were maintained substantially over 3-month follow-up period.

Behler N, Leitner B, Mezger E, Weidinger E, Musil R, Blum B, Kirsch B, Wulf L, Löhrs L, Winter C, Padberg F, Palm U. Cathodal tDCS Over Motor Cortex Does Not Improve Tourette Syndrome: Lessons Learned From a Case Series. Front Behav Neurosci. 2018 Aug 24;12:194.

Introduction: Current pathophysiological hypotheses of Gilles de la Tourette Syndrome (GTS) refer to temporally abnormal neuronal activation in cortico-striato-thalamo-cortical (CSTC) networks. Modifying cortical activity by non-invasive brain-stimulation appears to be a new treatment option in GTS. Background: Previous studies suggested therapeutic effects of cathodal transcranial direct current stimulation (tDCS) to pre-supplementary motor areas (SMA), however, treatment modalities concerning electrode placement, current intensity and stimulation-rate have not been systematically explored. Aim of this study was to assess efficacy of an alternative stimulation regime on GTS symptoms in a pilot study. To test a treatment protocol with tDCS twice a day, we administered 10 sessions over 5 days of bilateral cathodal tDCS (30 min, 2 mA) over the pre-SMA in three patients with severe GTS. Tic severity as well as obsessive-compulsive (OC) symptoms and affective scales were rated before and after tDCS treatment. Discussion: Only one out of three patients showed a 34.5% reduction in tic severity. The two other patients showed an increase in tic severity. All patients showed a mild increase in positive affect and a reduction in negative affect, OC symptom changes were heterogeneous. Our results do not support earlier findings of extensive therapeutic effects of cathodal tDCS on tics in patients with GTS and show that prediction of stimulation effects on a targeted brain area remains inaccurate. Concluding Remarks: Future research will have to focus on the determination of most effective stimulation modes regarding site, polarity and frequency of tDCS in GTS patients.

Grados M, Huselid R, Duque-Serrano L. Transcranial Magnetic Stimulation in Tourette Syndrome: A Historical Perspective, Its Current Use and the Influence of Comorbidities in Treatment Response. Brain Sci. 2018 Jul 6;8(7).

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder consisting of impairing motor and vocal tics which often persists adolescent and adult years. In this older refractory group, standard treatments such as pharmacotherapy and psychotherapeutic interventions may only have limited effects. Based on electrical cortical dysregulation in individuals with TS, a novel approach has employed brain stimulation strategies to modulate the putative aberrant neural electrical activity in pathways that may underlie tics, such as insula-supplementary motor area (SMA) connectivity.

This review will examine all published clinical trials employing transcranial magnetic stimulation (TMS) to ameliorate tics, and discuss a framework for the pathophysiology of TS in relation to electrical brain activity. A framework for future research in tic disorders using TMS and imaging targeting neuroplasticity will be discussed.

Therapeutic electrical brain activity modulation with TMS has been carried out in stroke neuro-rehabilitation and neuropsychiatry, including trials in TS. Eleven trials document the use of TMS in TS targeting several brain areas, a positive effect is seen for those trials targeting the SMA. In particular, it appears that younger individuals with concurrent attention-deficit hyperactivity disorder (ADHD) benefit the most.

TMS can be used as an effective tool to explore the psychophysiology of TS and potentially provide a therapeutic option. Ultimately, translational research using TMS in TS needs to explore connectivity differences pre- and post-treatment in individuals with TS that are linked to improvement in tic symptoms, with an emphasis on approaches using functional neuroimaging as well as other probes of neuroplasticity.

Hsu CW, Wang LJ, Lin PY. Efficacy of repetitive transcranial magnetic stimulation for Tourette syndrome: A systematic review and meta-analysis. Brain Stimul. 2018 Sep - Oct;11(5):1110-1118.

While previous studies have investigated the effect of repetitive transcranial magnetic stimulation (rTMS) in treating Tourette syndrome (TS), the results remain inconclusive.

We aim to systematically review the existing literature related to the efficacy of rTMS in TS and synthesize the results through meta-analysis.

We searched for PubMed, Embase, Cochrane Library, and databases without language restriction through January 1, 2018, and included randomized-controlled and open-label trials that assessed the treatment effect of rTMS for tic symptoms. We used a random-effects model to pool effect sizes, which were expressed as Hedges' g and 95% confidence intervals (CIs). The outcomes include symptom improvement of tic, obsessive-compulsive (OC), and attention-deficit hyperactivity disorder. Distribution of sex, age, and differences of rTMS protocol were examined as potential moderators.

Eight studies were included in the meta-analysis. rTMS significantly improved tic (g = -0.61; CI: -0.94 to -0.29) and OC (g = -0.48; CI: -0.83 to -0.14) symptoms in TS patients, compared to baseline. However, active rTMS was not effective in tic or OC symptoms among patients with TS when controlled for placebo. Furthermore, stimulation of the bilateral supplementary motor areas was more effective in tic symptoms than that of other areas (g = -0.70; CI: -1.11 to -0.30 vs. g = -0.36; CI: -0.84 to 0.14). Moreover, a younger age was associated with a better treatment effect (coefficient = 0.03, p = 0.027).

Current study indicates that rTMS has a significant effect on tic and OC symptoms in TS patients.

Wednesday, March 20, 2019

Mutations in valyl-tRNA synthetase gene VARS causing epleptic encephalopathy

Friedman J, Smith DE, Issa MY, Stanley V, Wang R, Mendes MI, Wright MS, Wigby K, Hildreth A, Crawford JR, Koehler AE, Chowdhury S, Nahas S, Zhai L, Xu Z, Lo WS, James KN, Musaev D, Accogli A, Guerrero K, Tran LT, Omar TEI, Ben-Omran T, Dimmock D, Kingsmore SF, Salomons GS, Zaki MS, Bernard G, Gleeson JG. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nat Commun. 2019 Feb 12;10(1):707.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

An international effort led by physician-scientists at Rady Children's Institute for Genomic Medicine (RCIGM), in collaboration with a team at the Montreal Children's Hospital of the McGill University Health Centre (MCH-MUHC), has identified the cause of a devastating pediatric brain disorder paving the way for the first step in developing potential therapies for this rare neurodegenerative condition.

Investigators performed advanced genetic tests on blood samples from seven children with neuro-development disabilities who were evaluated by doctors in San Diego, Montreal and Cairo. This led to the discovery of mutations in the VARS gene, which had not previously been linked to human disease.

"These children showed epileptic seizures and abnormalities evident on brain MRI scans," said Joseph Gleeson, MD, director of neurodevelopmental genetics at RCIGM and professor of neuroscience and pediatrics at UC San Diego School of Medicine. "Although no treatment currently exists for this condition, the results are important as the first step in guiding research directed at targeted therapies."
The genetic mutations identified in the study led to a defect in the enzyme responsible for generating proteins containing the amino acid valine which is necessary for cellular health. Genetic variations that damage these types of enzymes are associated with a variety of human diseases including microcephaly and neuropathy.

In this study, the team found that, enzymatic activity was significantly reduced in cells from the young patients. The findings suggest that children with this disorder may benefit from treatments to support the synthesis of new valine containing proteins in the brain…

Both whole exome and whole genome testing were conducted as part of this study. These tests search an individual's genetic code for imperfections that are the source of disease.

Diagnostic utility of whole exome sequencing in the neuromuscular disease

Waldrop MA, Pastore M, Schrader R, Sites E, Bartholomew D, Tsao CY, Flanigan KM. u. Neuropediatrics. 2019 Jan 21. doi: 10.1055/s-0039-1677734. [Epub ahead of print]

Next-generation sequencing is a powerful diagnostic tool, yet it has proven inadequate to establish a diagnosis in all cases of congenital hypotonia or childhood onset weakness. We sought to describe the impact of whole exome sequencing (WES), which has only recently become widely available clinically, on molecular diagnosis in the Nationwide Children's Hospital Neuromuscular clinics. We reviewed records of all patients in our clinic with pediatric onset of symptoms who had WES done since 2013. Patients were included if clinical suspicion was high for a neuromuscular disease. Clinical WES was performed in 30 families, representing 31 patients, all of whom were seen for hypotonia, weakness, or gait disturbance. Probands had between 2 and 12 genetic diagnostic tests prior to obtaining WES. A genetic diagnosis was established in 11 families (37%), and in 12 patients (39%), with mutations in 10 different genes. Five of these genes have only been associated with disease since 2013, and were not previously represented on clinically available disease gene panels. Our results confirm the utility of WES in the clinical setting, particularly for genetically heterogeneous syndromes. The availability of WES can provide an end to the diagnostic odyssey for parents and allow for expansion of phenotypes.

Traditionally, diagnosis of neuromuscular disorders follows a pattern: review the clinical phenotype and narrow down the likely options; run a targeted test for the suspected disorder; diagnose. In cases with challenging phenotypes or unresolved diagnoses after these initial assessments, many neuromuscular clinics resort to a range of additional tests, including microarray, electromyography, a muscle or nerve biopsy and next generation gene panel testing — a broader genetic screen capturing more of the possible single-gene neuromuscular diseases.

For patient families with inconclusive results throughout this battery of tests, it used to be the end of the road. Over the past several years, however, whole exome sequencing (WES) has become a clinically available test, offering physicians the chance to cast a much broader net in the search for genetic alterations at the root of a child’s symptoms. To find out whether the test offers clinically meaningful diagnostic utility, physician-scientists at Nationwide Children’s Hospital reviewed the results of four years of WES testing among patients in their Neuromuscular Disorders Clinic.,,
Twelve of the patients (39%) received a confirmed diagnosis based on WES findings, most commonly for genetic syndromes associated with myopathy or congenital myopathy (n=8), including three children (including two siblings) with the ultra-rare Vici syndrome. Two patients were diagnosed with central nervous system disorders. WES led to changes in the clinical management of numerous patients, including one who had had a long-standing presumptive diagnosis of mitochondrial disease.

“These were patients in whom our standard genetic testing algorithm did not show a result,” says Kevin Flanigan, MD, director of the Neuromuscular Disorders program at Nationwide Children’s and senior author on the paper. “WES is now a mature technology, and we think that, when it’s properly applied, WES can rapidly and economically shorten the diagnostic odyssey for parents and add to our understanding of the range of clinical phenotypes associated with mutations in given genes.”

Drs. Flanigan and Waldrop also suspect that using WES after initial failed gene panel tests, rather than moving on to invasive tests in between, is likely more cost-effective and beneficial for families. It should be noted, however, that WES is only useful in cases of single-gene disorders, rather than for broad syndromes that result in similar phenotypes. This may account for the substantial proportion of children who remain undiagnosed even after WES.

For some of these patients, Drs. Flanigan and Waldrop request whole genome sequencing — an expanded genomic screen analyzing billions of pieces of genetic code instead of the thousands studied by WES. The test is extremely resource intensive both in manpower and computational technology. While not yet available clinically due to its expense and experimental nature, it is offered through the Institute for Genomic Medicine as part of a research program for children who remain undiagnosed after exhausting all other options.

Sunday, March 17, 2019

I have no clue how someone could shake half of a baby’s brain

The defense’s expert witness spent Monday afternoon in DeKalb County court trying to disprove that Katie Petrie shook a 6-month-old, causing permanent brain damage.

“I have no clue how someone could shake half of a baby’s brain,” Joseph Scheller, a child neurologist from Baltimore, testified Monday.

About three years ago, Ryker Newhouse was in Petrie’s care at her Cortland home and day care, when prosecutors said she violently shook him, causing injuries resulting in likely permanent brain damage. Petrie, 36, of the 900 block of 14th Street in DeKalb, could face six to 30 years in prison if convicted of aggravated battery to a child.

Petrie’s defense claims that whatever caused Ryker’s brain injury, it was not shaking, but an impact with a solid object, which could have occurred days before Dec. 15, 2015, when Petrie reported the child was having a seizure at her home.

Scheller blamed an impact injury for Ryker’s developmental setbacks, impaired vision and limited use of his right arm. He showed images of CAT scans taken of Ryker’s brain Dec. 15, 2015, and explained how an impact would have caused a subdural hematoma that hugged the left side of his brain but ultimately left the right side unharmed.

“The left side suffered and withered, due to lack of circulation,” he said. “Unfortunately, it doesn’t recover when it’s suffered this degree of atrophy or withering.”

He repeated that Ryker being shaken was out of the question.

“You can’t shake half the brain,” Scheller said. “I have no clue how someone could shake half of a baby’s brain.”

He likened it to shaking a jar with an apple in it.

“The skull is the jar,” he said. “The brain is the apple.”

Doctors testified Nov. 14 for the prosecution – DeKalb County State’s Attorney Rick Amato and First Assistant State’s Attorney Stephanie Klein – that the left side of Ryker’s skull had been fractured.

Scheller said a hematoma – a swelling of clotted blood – caused by such a fracture could have happened a couple of days before symptoms presented.

“You know [Ryker’s injury] happened relatively recently, but you can’t date it exactly,” he said.

Under cross-examination, Klein pointed out that Scheller did not treat Ryker, and that he had to review about 4,500 pages of records and dozens of images to draw his conclusions, which he reported he arrived at in five or six hours. She pressed Scheller that there are many ways a baby can be shaken. “You could shake a baby and slam it down to the ground,” she said.

“That’s correct,” Scheller said.

She also asked him why he didn’t include in his report that a skull fracture makes suffering a hematoma more likely.

“I didn’t think it was that important,” Scheller said.

On Nov. 14, in addition to doctors, prosecutors called Ryker’s parents. They testified that Ryker had a cold leading up to Dec. 15, 2015, but that he was happy that day. A video was shown of Ryker giggling and smiling at his mother about 36 hours before prosecutors say Petrie caused Ryker irreparable harm.

Witnesses established last month that Ryker took a nap then ate well Dec. 15, 2015, before he threw up, causing Petrie to grab some wipes, and she said that when she turned back to Ryker, he was having a seizure.

Scheller was the only witness to take the stand in Petrie’s defense. She opted not to testify.

The defense rested about 4:15 p.m., and the prosecution, which had rested Nov. 15, recalled Rockford-based pediatrician Raymond Davis, to rebut Scheller’s testimony.

Davis testified, as he did Nov. 14, that the nature of Ryker’s hematoma suggests it was caused by his brain repeatedly accelerating and decelerating. He said in many case studies, nerve damage has occurred, but hasn’t been detectable by a CAT scan.

Under cross-examination by Petric’s lawyer, Peter Buh, Davis testified that it also is possible for a shaken baby to suffer damage to only half the brain – a direct rebuttal of Scheller’s testimony.

Amato said closing arguments will be made Tuesday afternoon, and a verdict is expected from DeKalb County Judge Philip Montgomery on Wednesday.

“I know we’re all anxious to see a conclusion to this trial,” Montgomery said, “but I’m going to take time tomorrow after closing arguments and make my ruling at 1:30 Wednesday.”

A Cortland woman, who was found guilty of causing brain damage to a child, will be sent to prison for around a decade after prosecutors alleged two other children had broken bones after being in her care.

In DeKalb County Court on Tuesday, our sister station WLBK reports Judge Philip Montgomery sentenced 36-year-old Katie Petrie to 11 years in prison.

She could’ve received up to 30 years after being found guilty in December of Aggravated Battery to a Child. While it’s not known if then-six-month-old Ryker Newhouse was shaken, hit or thrown, the boy has needed multiple surgeries since being taken to the hospital from Petrie’s at-home daycare in 2015, including another surgery just last month.

Niemann-Pick type C treated with VTS-270

It started at Karson “K.J.” Ross’ 9-month-old pediatric well-baby visit.

Pretty routine stuff for a family that’s had two older kids go through those types of regular checkups. Log the baby’s height and weight. Check ears, eyes and throat. Administer vaccines.

“But they said it felt like his spleen was enlarged,” recalled Ashley Ross, K.J.’s mom.

The cause, though, was puzzling.

After that appointment in the fall of 2017 came an ultrasound, followed by test after test at Akron Children’s Hospital. Sixty-seven in all, by the family’s count. Along the way, doctors ruled out cancer, but began to suspect a rare hereditary disease, Niemann-Pick.

“We prayed that it wasn’t,” Ashley Ross said.

She and her husband, Matt, who live in southwest Canton, Googled everything there was to Google about Niemann-Pick. 

It wasn’t good. There’s no cure. And one variety can kill a child by age 4.

The official word came on Aug. 22, 2018.

It was Niemann-Pick type C. It’s a genetic mutation that causes cholesterol and fats to build up inside a child’s liver, spleen or lungs — and ultimately affects the brain, too. The disease is sometimes referred to as “childhood Alzheimer’s.”

Medical research has found only 500 cases diagnosed worldwide each year.

Symptoms include learning delay, lack of muscle strength, loss of coordination. The disease causes trouble in a child’s ability to walk and talk and can include seizures and jerking muscles and a sudden loss of muscle tone.

To this day, 2-year-old K.J. Ross’ vocabulary is limited to “dad.”

He’s barely over 2-feet and weighs 21 pounds.

After the diagnosis, Ashley Ross wasn’t about to give up hope. Using social media, she connected with parents across the country in a similar situation. One told her to contact Dr. Elizabeth M. Berry-Kravis, a pediatric neurologist at Rush University Medical Center in Chicago.

“I emailed her and she got right back to me,” Ashley Ross said.

Berry-Kravis had been administering an experimental drug VTS-270, from Mallinckrodt Pharmaceuticals, in Niemann-Pick type C patients. The drug is given through a spinal tap.

Studies have shown the drug can stabilize the disease for extended periods, according to an article published last year in “Pediatric Neurology” and co-authored by Berry-Kravis.

In late September, K.J. Ross went to Chicago for his first treatment. He and his parents make the flight every two weeks, and will continue to do that for the foreseeable future.

Ultimately, the Ross family would like to see VTS-270 earn U.S. Food and Drug Administration approval, which could make it available more locally, or for another treatment to develop.

The non-profit Patient AirLift Services provides the free flights. And Ashley and Matt Ross recently secured federal Social Security benefits to support K.J.

His siblings, Matthew Ross Jr., a first-grader at Our Lady of Peace Catholic School, and Jazminn, a fifth-grader at the same school, often call their little brother “Beanie.” 

It’s a nickname that seemed to fit and they’ve stuck with it.

Parishioners at Christ the Servant Parish at Our Lady of Peace Church, which operates the school, have also chipped in with donations to help the family.

“Everyone always wants to know ‘how is K.J. doing?’” said Monsignor Lewis F. Gaetano. “We’ve all tried to do what we can ... the mission is outside of these four walls.”


Saturday, March 16, 2019

A pediatric case of narcolepsy treated with sodium oxybate

Miskoff JA, Chaudhri M. A Pediatric Case of Narcolepsy Presenting as Syncope. Cureus. 2018 Dec 31;10(12):e3801.


Narcolepsy is a chronic genetic  and sleep disorder that is caused by a protein deficiency. This may affect the patients' sleep architecture and the brain's ability to control circadian rhythms. Individuals with this condition feel rested after waking but then feel tired and sleepy as the day progresses. Typical onset is during adolescence, but there is often a significant delay in diagnosis, which may markedly hinder an individual's quality of life. This case provides an opportunity to shed light on this often underdiagnosed or misdiagnosed condition by presenting a case of a remarkable individual who has persevered to be successful with the help of a timely diagnosis and aggressive off-label therapy.
The patient was treated with sodium oxybate and modafinil. Sodium oxybate was approved by the FDA for narcolepsy in patients 18 years of age and older; a decision was taken by the treating clinician to start the therapy off-label at a reduced dose for this patient.

From the article:

A 13-year-old female visited a physician in January 2007 for the evaluation of passing out associated with laughing. According to the records, the patient underwent a magnetic resonance imaging (MRI) of the brain with and without contrast, along with an electroencephalogram (EEG), in October 2007 for an evaluation pertaining to a chronic headache and generalized weakness resulting in syncopal episodes triggered by laughter. The results of these diagnostic studies were unremarkable. The patient was seen by a neurologist on September 26, 2007, for persistent symptoms of losing muscle tone triggered by a strong emotional response. The neurologist suggested that the patient should undergo a magnetic resonance angiogram (MRA) of carotid arteries because the symptom of “laughter leading to loss of muscle tone, resulting in the patient losing control and falling” may suggest syncope of a cardiovascular etiology. Furthermore, neurologist records suggest that the patient experienced four episodes of laughter leading to loss of muscle tone while she was at Disneyland, a week later. Lastly, the neurologist concluded his consultation by suggesting that no further workup was needed. Subsequently, the patient underwent an echocardiogram on October 1, 2007, to investigate her continued “syncopal episodes.” According to records, the cardiologist felt that the patient might have vasovagal syncope thus requiring an MRA and MRI of the neck followed by a Holter monitor. The results were all within normal limits as reported by the patient and her mother. Although the cardio-neuro workup was inconclusive, the patient continued to have chronic symptoms and, therefore, sought initial consultation with a sleep specialist.

The patient was seen by our practice on January 11, 2008, and was referred for a nocturnal polysomnogram (NPSG) and a multiple sleep latency test (MSLT) to investigate a probable diagnosis of narcolepsy due to exhibited signs of narcolepsy with cataplexy, sleep paralysis, excessive daytime sleepiness and hypnagogic hallucinations. The PSG results suggested a total sleep of 436.7 minutes with a sleep efficiency of 93 percent (n=89%). Moreover, rapid eye movement (REM) and sleep latencies were 94.5 minutes (n=136-156) and 10 minutes, respectively. The PSG revealed that the patient experienced one obstructive apnea lasting for 11 seconds, five central apneas, and 11 hypopneas with an apnea/hypopnea index of 2.3, which is normal. The patient verbalized not being able to move or talk during sleeping. The patient underwent an MSLT study in February 2008, which revealed a mean sleep latency (MSL) of 4.3 minutes on three 20-minute naps. The diagnostic criterion requires an MSL of ≤8 minutes and ≥2 sleep onset REM periods (SOREMPs) on MSLT. Since our patient satisfied the MSL and SOREMP components on three naps, continuing the study was not needed. Records indicate that the patient had an average sleep lasting 15 minutes, REM sleep lasting five minutes, and eight minutes average latency to REM sleep on the MSLT. A normal REM cycle occurs every 90 minutes after sleep onset, the first REM period lasts 10 minutes with each recurring REM stage lengthening. In addition to the sleep study, laboratory workup for HLA-DR15 and DQ0602 was positive, thus further supporting the diagnosis of narcolepsy.

As the patient was undergoing further studies to confirm her diagnosis, her condition and symptoms became common knowledge among her peers, which led her to be ostracized by fellow students. The situation escalated quickly to the point of feeling like she was bullied on a daily basis. Ultimately, she switched school, which added emotional stress to her life…

As with most patients, a trial and error of sodium oxybate were needed to titrate up to the therapeutic dose. The patient was started on 1.5 milligram (mg) sodium oxybate to be taken twice; however, the dose was decreased to 0.75 mg due to intolerance. In addition, the patient was prescribed 200 mg modafinil to be taken in the morning and an additional dose to be taken in the afternoon if needed. Over time, her sodium oxybate dose was increased to 4 grams taken once at bedtime. Typically, in adults, sodium oxybate is started at 2.25 grams (g) at bedtime and repeated three to four hours later due to its short half-life for a total of 9 g. Most titrations take several weeks to months at times. Along with medication, non-pharmacologic interventions, such as not being able to swim, not being able to enjoy riding a bicycle with her friends, requesting access to medication at all times, and needing extra time for exams, along with many other interventions, were instituted. Basically, she had to avoid all activities where laughter may induce cataplexy, which may increase the risk of bodily harm.

In a recent visit, the patient stated that she is tolerating her sodium oxybate and modafinil at a dose of 4 grams taken once per night without any complications and that her condition has stabilized. Timely management of her condition has improved her day-to-day functionality along with improving her quality of life.


Evaluation of age of death in Niemann-Pick disease, type C

Bianconi SE, Hammond DI, Farhat NY, Dang Do A, Jenkins K, Cougnoux A, Martin K, Porter FD. Evaluation of age of death in Niemann-Pick disease, type C: Utility of disease support group websites to understand natural history. Mol Genet Metab. 2019 Feb 15. pii: S1096-7192(18)30794-7. doi: 10.1016/j.ymgme.2019.02.004. [Epub ahead of print]

Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disease affecting the visceral organs and the central nervous system. The age of initial presentation varies from fetal to adult onset, although childhood onset is most common. The life expectancy for the full spectrum of NPC patients is not well defined, and it is unknown if current supportive care impacts the natural history. In order to assess age of death for a large cohort of NPC patients, we "crowd-sourced" age and year of death from information posted on disease support group website memorial walls. We analyzed data from 338 individuals who died between 1968 and 2018. In addition to age of death, gender can be inferred from given names and photographs. The median age of death was 13 years with a range from 0.1-69 years. Although sex significantly affects survival of NPC1 mutant mice, we did not observe a gender dependent survival difference in NPC patients. Median age of survival across time increased between the earliest patients and the most recently deceased patient; however, we found no significant change in survival over the last 20 years. These data suggest that supportive medical care has not impacted survival in the recent past and provides support for the use of historic controls in evaluating therapeutic interventions.

Friday, March 15, 2019

I'm just mad about saffron

The popular and expensive spice saffron (Crocus sativus L), appears to be as effective as the stimulant methylphenidate (MPH) in treating symptoms in youngsters with attention deficit hyperactivity disorder (ADHD), new research suggests.

In a randomized 6-week trial, a team of investigators from Tehran University of Medical Sciences in Iran, found there were no significant differences in efficacy or adverse events in the saffron vs MPH group.

"From this preliminary study, the main point is that we can consider saffron as an alternative [to stimulants] in patients with ADHD," senior author Shahin Akhondzadeh, PhD, FBPhS, DSc, professor of clinical psychopharmacology, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Iran, told Medscape Medical News.

"Short-term efficacy of saffron demonstrated the same efficacy as methylphenidate, although larger, controlled studies with longer treatment periods are necessary to verify the findings," he said. "Many antidepressants have been used as alternatives to stimulants in patients with ADHD that cannot tolerate Ritalin or do not respond to Ritalin," Akhondzadeh said.

However, antidepressants are also associated with adverse events, with results that are "often unsatisfactory," the authors note.

This leaves an "empty place to be filled by alternative medications, in particular herbal medications," they add.

Saffron has traditionally been used for a variety of medicinal purposes, including its antispasmodic, antiseptic, anticancer, and anticonvulsant effects. 

Saffron and its active constituents appear to increase the reuptake inhibition of dopamine and norepinephrine and are N-methyl D-aspartic acid (NMDA) receptor antagonists and GABA-α agonists.

"As you may know, my country is the main producer of saffron and about 90% of saffron is from Iran — indeed, saffron is a Persian herb with history as long as the Persian Empire," Akhondzadeh noted.

"There are solid documents in the Persian traditional medicine about the psychotropic effects of saffron, but we need evidence-based medicine in traditional medicine as well.

"My research group at Roozbeh Psychiatry Hospital has studied the psychotropic effects of saffron since early 2000, and we have documented its antidepressant effects," he added…

No significant difference was found in Parent ADHD Rating Scale scores at baseline between the saffron and the MPH groups (34.20 ± 4.69 vs 33.56 ± 6.48, respectively; mean difference [MD], 0.64; 95% confidence interval [CI], –2.58 to 3.86; t = –0.400; df = 48; P = .691).

Moreover, general linear model repeated measures also showed no significant effect for treatment (between-subject factor; F = 0.672; df = 1; P = .416).

A time × treatment calculation showed a similar trend of the two treatment groups across time in both hyperactivity and inattention.

Moreover, a significant effect of both treatments on improving Parent ADHD Rating Scale scores was demonstrated (P < .001).

Post hoc comparisons of the Parent ADHD Rating Scale showed a significant reduction as soon as week 3 (P < .001) in both groups, and there was no significant difference between the treatment groups at endpoint (P = .975).

Similar findings were obtained in the Teacher ADHD-RS-IV scores, with no significant difference in baseline total scores between the saffron and the MPH groups (24.16 ± 8.32 vs 23.64 ± 8.16, respectively; MD, 0.52; 95% CI, –4.16 to 5.20; t = ­–0.223; df = 48; P = 0.824), time to improvement, and reduction in symptoms at study endpoint.

No serious adverse event was recorded in any of the patients, and non-serious events (eg, headache, dry mouth, insomnia, decreased appetite) were similar between the two groups.

"This study provides evidence for satisfactory outcomes with saffron in treatment of ADHD," the authors write.

However, Akhondzadeh acknowledged that the cost of saffron is a concern.

"Although saffron is the most expensive spice, the daily dosage that we used in this study is equal to 60 mg pure saffron," he reported…

Although saffron is available as a spice in the United States, "there is no guaranty that it will have the same medicinal effect if used in a meal, since the main component of our extract is crocin," he added.

Commenting on the study for Medscape Medical News, Patricia L. Gerbarg, MD, assistant clinical professor in psychiatry, New York Medical College, Valhalla, and Richard P. Brown, MD, associate professor in clinical psychiatry at Columbia University College of Medicine, New York, NY, called it a "credible" and "well-done randomized controlled trial."

The authors "appropriately note that this is positive preliminary evidence and that additional trials are needed to replicate these initial very positive findings," Gerbarg and Brown, who were not involved with the study, told Medscape Medical News via email.

The study was conducted in Iran, "where ethnic populations may have genetic variants that enable them to respond more positively or more robustly to saffron than other populations," which has been "noted with other herbs."

It is therefore "particularly important to replicate this study in a population that is not Iranian, to verify efficacy in other countries," noted Brown and Gerbarg, who are coeditors of Complementary and Integrative Treatments in Psychiatric Practice (Washington, DC: American Psychiatric Association Publishing; 2017), which has a chapter on saffron.

"Each practitioner must decide whether they feel that this evidence is promising enough to justify a trial of optimized saffron on a case-by-case basis [that] takes into account the observation that saffron is very low in side effects, so the risks are minimal," they said.

Moreover, "if the saffron is beneficial, it may be possible to reduce the dose or discontinue a prescription stimulant, which could spare the patient who may be experiencing side effects," Gerbarg and Brown add.

Batya Swift Yasgur. Popular Spice Rivals Stimulant for ADHD - Medscape - Mar 11, 2019.

Baziar S, Aqamolaei A, Khadem E, Mortazavi SH, Naderi S, Sahebolzamani E, Mortezaei A, Jalilevand S, Mohammadi MR, Shahmirzadi M, Akhondzadeh S. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019 Feb 11. doi: 10.1089/cap.2018.0146. [Epub ahead of print]


Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood and adolescence. About 30% of patients do not respond to stimulants or cannot tolerate their side effects. Thus, alternative medication, like herbal medicine, should be considered. The aim of this trial is to compare the safety and efficacy of Crocus sativus (saffron) versus methylphenidate in improving symptoms of children with ADHD.

In a 6-week randomized double-blind study, 54 patients (children 6-17 years old) with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomly assigned to receive either 20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg) methylphenidate (MPH) or 20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg). Symptoms were assessed using the Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) at baseline and weeks 3 and 6.

Fifty patients completed the trial. General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores (F = 0.749, df = 1.317, p = 0.425, and F = 0.249, df = 1.410, p = 0.701, respectively). Changes in Teacher and Parent ADHD Rating Scale scores from baseline to the study end were not significantly different between the saffron group and the MPH group (p = 0.731 and p = 0.883, respectively). The frequency of adverse effects was similar between saffron and MPH groups.

Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate. Nevertheless, larger controlled studies with longer treatment periods are necessary for future studies.

Thursday, March 14, 2019

Ictal vomiting

Aungaroon G, Vawter-Lee M. Teaching Video NeuroImages: Ictal vomiting in a child. Neurology. 2018 Nov 6;91(19):e1836-e1837.

A 22-month-old boy presented with repetitive vomiting. The vomiting was occasionally associated with behavioral arrest, right arm jerking, and rightward head deviation. Video EEG revealed ictal vomiting localized to the left temporal head region (video at link above). The MRI showed left hemisphere polymicrogyria, particularly in the left temporal lobe. The seizures remained intractable despite multiple antiepileptic medications (levetiracetam, oxcarbazepine, and lacosamide). Ictal vomiting is a rare seizure semiology with a few distinctive features. It is reported in 2.7% of children and hypothesized to be associated with insular cortex involvement during a seizure.

Pediatric epilepsy readmissions

Vawter-Lee M, Lutley A, Lake SW, Fledderjohn S, King A, Horn PS, Wesselkamper KR. Pediatric Epilepsy Readmissions: The Who, When, and Why. Pediatr Neurol. 2018 Dec 25. pii: S0887-8994(18)30895-6. doi: 10.1016/j.pediatrneurol.2018.12.007.[Epub ahead of print]


Prior studies have demonstrated a pediatric epilepsy readmission rate of 6% to 10% but have not described details of the readmitted patients. We report the characteristics of pediatric patients admitted for epilepsy who were readmitted to the hospital within 30 days of discharge.

An interdisciplinary team was established to individually review and characterize the 30-day readmissions of patients admitted for epilepsy from May 2014 to October 2016. The team contained both inpatient and outpatient neuroscience nurses, care managers, a quality outcomes manager, and child neurology physicians.

Over a 30-month period we had an all-cause 30-day readmission rate of 8.0%, which was 219 pediatric epilepsy readmissions from 169 patients. We found that 21.5% of readmissions were scheduled, 37% were for progression of chronic epilepsy, 9.6% were for recently diagnosed epilepsy, and 14.6% were for unrelated diagnoses. We classified 21.5% of readmissions as preventable and 64.9% as not preventable. Thirty-five percent of readmissions occurred within seven days of the initial discharge, including 29 of 47 (61.7%) preventable readmissions. The most common reasons for preventable readmissions were problems with the discharge care plan or medication management.

We demonstrate that 21.5% of pediatric epilepsy readmissions were scheduled and 21.5% were judged to be preventable. The majority of preventable readmissions occurred within seven days of index discharge. Characterizing epilepsy readmissions is the first step in being able to reduce readmissions.

From the article:

Problems with the discharge care plan (readmission category 3) led to 6.4% of readmissions. Examples included not providing clear medication plans, not providing medication refills when discharging over the weekend, discharging before parents being comfortable going home, retrospective feeling from the reviewing team that the patient was discharged too quickly, and not recognizing feeding intolerance. Another example is that multiple patients were discharged before the electroencephalogram (EEG) being read from the epilepsy monitoring unit after undergoing 24-hour monitoring to evaluate for electrical status epilepticus during sleep (ESES). After the EEG was interpreted as showing ESES, each of these patients was readmitted to start treatment.

Problems with medications (readmission category 4) led to 4.1% of readmissions. Examples include several patients with known nonadherence to recommended medical treatment (including some with open medical neglect cases due to seizure medication nonadherence) and a specialty pharmacy shipping an inadequate dosage of a medication, resulting in readmission until the pharmacy shipped the remaining dosages.

We determined that 21.5% (n = 47) of all-cause 30-day readmissions were preventable (scores of 4 or 5) (95% confidence interval 16.5% to 27.4%, Wilson's score exact procedure) ( Table 2 ). The majority, 64.8% (n = 142), of readmissions were not preventable (scores of 1 or 2). Of the 18 readmissions deemed definitely preventable (score 5), 11 were readmissions occurring because of the discharge care plan. The second most common reason for definitely preventable readmissions was medication management (n = 3).

Of the 29 more likely preventable readmissions (score 4), 19 were due to acute or chronic disease progression. The acute disease progression patients were newly diagnosed with epilepsy, and the readmissions were judged to be preventable due to concern that at the time of index discharge the medications were not yet clearly controlling the seizures or the parents were not yet prepared to manage seizures at home.

Patients who were readmitted were initially discharged across all days of the week ( Supplementary Table 1 ). There was no statistical significance between the day of initial discharge and preventability of future readmissions ( P = 0.78, chi-square with six degrees of freedom). Patients were readmitted on all days of the week ( Supplementary Table 1 ). In terms of preventability, there was no statistical significance between the day of readmission and preventability of the readmission ( P = 0.38, chi-square with six degrees of freedom).

Index admission length of stay ranged from less than 24 hours to 28 days ( Supplementary Figure 1 ). The mean index length of stay was 3.1 days, while the mode was 1 day (n = 74). Readmission length of stay ranged from one day to 53 days ( Supplementary Figure 2 ). The mean readmission length of stay was 4.1 days, while the mode was 1 day (n = 68).

Thirty-five percent of readmissions occurred within seven days. Of the 21.5% (n = 47) of readmissions that were preventable (scores 4 or 5), 61.7% (n = 29) were readmitted in zero to seven days. Further analysis showed that time to readmission was shorter for patients with a preventability score of 4 or 5 (mean = 8.5 days, S.D. = 8.2 days), versus patients with a preventability score of 3 (mean = 11.3 days, S.D. = 7.6 days) or patients whose readmissions we judged were not preventable (score of 1 or 2) (mean = 15.7 days, S.D. = 8.8 days). Based on the preventability scores, these three groups were all significantly different from each other with Wilcoxon rank sum P values = 0.02 (scores 1 or 2 versus score 3), P < 0.001 (scores 1 or 2 versus scores 4 or 5), and P = 0.04 (score 3 versus scores 4 or 5)…

By manually reviewing all 219 readmissions over 30 months, the group concluded that 21.5% of all-cause readmissions were preventable. This percentage is similar to the preventability reported by Toomey et al. and Hain et al. in Pediatrics.  Our study demonstrated that the majority of preventable readmissions (61.7%) occurred zero to seven days following index discharge. These are important data to note, as they allow programs to focus on a smaller subset of readmissions.

Our results showed that discharge care plan problems led to most of our preventable readmissions. Identifying this, our team worked to improve our discharge process by emphasizing medication reconciliation accuracy, creating discharge instruction templates with clear escalation plans for common pediatric neurology disorders (such as seizures, migraines, infantile spasms, febrile seizures, idiopathic intracranial hypertension, ketogenic diet, and psychogenic nonepileptic spells) and ensuring appropriate health literacy level of discharge instructions.

After recognizing that we had multiple readmissions for ESES, our division changed how EEGs are ordered for suspected ESES. These patients are now scheduled in such a way that if the first night of EEG monitoring shows ESES the treatment is started before discharge home. Since making this change we have had zero patients readmitted for initiation of ESES treatment, which has saved families both money and the burden of a second hospitalization.

Some preventable readmissions were due to medication management problems. Solutions for the problems we noted included verifying prescriptions were filled and picked up before discharge and having families do teach-back education with nursing staff to demonstrate understanding of how to measure and administer medications. The importance of medication accuracy at discharge has been examined in multiple other studies, both pediatric and adult, that have examined the role of pharmacists in the discharge process and how this affects readmission rates. 

Patients with acute disease progression, who were newly diagnosed with epilepsy, were noted to have a significant number of more likely preventable readmissions. For some of these readmissions, there was concern that at time of index discharge parents were not yet prepared to manage seizures at home. There have been several pediatric studies examining the child and parent perspectives on readmissions and discharges, including how to determine when a family is ready to be discharged and if parents felt a readmission was preventable.  An overall theme is open communication with families to make sure instructions are clear and that families understand the treatment plan.

Many times children with chronic epilepsy are readmitted for breakthrough seizures, and providers assume it is an unavoidable readmission. However, we found that 11% of these (nine of 81) chronic epilepsy readmissions were preventable. These data reflect a not insignificant number of readmissions that should not be dismissed.

Docosahexaenoic acid (DHA) for spinocerebellar ataxia 38 (SCA38) treatment

MartaManes, Antonella Alberici, Eleonora Di Gregorio, Loredana Boccone, Enrico Premi, Nico Mitro, Maria Pia Pasolini, Claudia Pani, Barbara Paghera, LauraOrsi, Chiara Costanzi, Marta Ferrero, FilippoTempia, DonatellaCaruso, AlessandoPadovani, Alfredo Brusco, Barbara Borroni. Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.  Parkinsonism & Related Disorders.  Available online 7 March 2019. rights and content

Spinocerebellar Ataxia 38 (SCA38) is caused by mutations within ELOVL5 gene, which encodes an enzyme involved in the metabolism of very long fatty acids. 
In this open label extension clinical trial we evaluated the long-term safety and efficacy of oral docosahexaenoic acid (DHA) supplementation. 
DHA replacement therapy is an effective long-term treatment in SCA38.


Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study.

Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3.

We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded.

Long-term DHA supplementation is an eligible treatment for SCA38.

Spinocerebellar ataxia 38 (SCA38)CerebellumAtaxiaDocosahexaenoic acid (DHA)Clinical trial

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Wednesday, March 13, 2019

The problem of delayed diagnosis of pediatric stroke

Fitzsimons BT, Fitzsimons LL, Sun LR. Laney’s Story: The Problem of Delayed Diagnosis
of Pediatric Stroke. Pediatrics. 2019;143(4):e20183458

Recounting the days of Laney’s first transient ischemic attacks (TIAs) and strokes and the horror and confusion that accompanied that time is something I would never wish on any parent. But if this article can help even 1 child receive a faster stroke diagnosis, then it is worth every painful word that I type.

First, I want you to know Laney. She had flowing auburn hair, an infectious smile with a gap in her front teeth, and an uncanny elegance for a 3-year-old girl. But a 3-year-old girl she was. She loved jumping in muddy puddles, “flying” around the house as Supergirl, and running around in circles until she was dizzy. She could put together a puzzle faster than some adults I know, manipulate a chocolate from her enchanted parents, and melt your heart with her big brown eyes. She was our whole life. In our minds, we were the happiest family on Earth.

It all began on May 7, 2016. We had recently returned from vacation, where Laney hiked miles every day in Sedona, Arizona. We will always remember these days as our best days. Laney, at 3.5 years old, was taking a bath when she suddenly started speaking with a slight slur. It was subtle, and we attributed it to her being tired.

Two weeks passed. We were in the kitchen when Laney started speaking with a slur and developed a facial droop. We called 9-1-1, and Laney was taken to a local emergency department (ED) where the doctor suspected she was having seizures. Laney was transported to another hospital where an overnight EEG revealed “seizure-like” activity, and the doctors recommended an MRI. Because this was a Sunday morning, with no anesthesiologists available, we were given the choice of keeping Laney in the hospital until Monday or taking her home and scheduling the MRI soon. We took Laney home to save her from the distressing hospital setting. There was no mention of stroke during either of these hospital visits.

Three days later, Laney experienced the same symptoms (slurred speech, drooping mouth and face, and trouble walking) but more severe. We rushed her to a different ED and showed the doctors and even a neurologist a video of the event. She was again diagnosed with seizures and discharged with a prescription for oxcarbazepine. There was no mention of stroke.

A week later, at Laney’s first neurology appointment, we showed the neurologist the video and described her symptoms. The neurologist diagnosed Laney with complex partial seizures and told us to continue oxcarbazepine. He said we could wait 3 months for the MRI to give Laney a break.

Laney’s Neurologist
Months before I met her, Laney had a series of TIAs consisting of dysarthria, facial droop, and inability to walk. In any adult, these would have been immediately recognized as a warning sign of impending stroke. But because Laney was 3 years old, they were misdiagnosed as complex partial seizures… 

Laney’s Father
Tragically, Laney had a severe reaction to oxcarbazepine. We took her back to the hospital, where doctors, in consultation with her neurologist, gave her lorazepam instead and discharged her.

After the hospital, we took Laney to the nearby Chuck E. Cheese’s. We ate pizza, took pictures, and played games. We won more tickets that day than we had in all our other visits combined. We were deliriously happy, if just for a moment. That was the last time we ever spent with our healthy little girl. I think about those joyful hours every day.

The following morning, almost a month since Laney’s initial symptoms, Laney woke up unable to stand, speak, eat, or drink. She wanted so badly to communicate, but the words would not come out as tears rushed down her cheeks. We called 9-1-1. The medics arrived as Laney was writhing on the floor. They did not consider stroke but instead administered epinephrine. In hysteria, Laney was transported back to the hospital. She was unable to stand or speak. Her heart rate climbed to 190 beats per minute, and I ran throughout the ED floor looking for a doctor to help Laney, who appeared to be dying in front of our eyes.

Our little girl was not talking and was barely moving. Laney was transferred to a larger hospital where doctors concluded that she was tired from her seizures. She had high blood pressure (which we now know was to help perfuse blood to her brain to prevent stroke), and they gave her medicine to lower it. Again, because no anesthesiology staff was available over the weekend, they could not do an MRI. There were no wheelchairs available, so I carried Laney’s limp body across the hospital to radiology for a head computed tomography scan. I will never forget that long walk.

Finally, on Monday, June 6, 2016, Laney underwent an MRI. The doctors informed us that Laney has suffered multiple acute strokes and had severe brain damage. This was the first time we had heard the word “stroke” since Laney’s symptoms began. We were devastated and frantically wanted to help her. We did not yet realize that this damage was permanent and that the Laney we knew and loved was gone…

Over the next months, Laney continued to have strokes as doctors struggled to stabilize her. Those days were filled with innumerous horrors. We never left Laney’s side and did not leave the hospital grounds for the entire summer. After months in the hospital and brain surgery, Laney was transferred to inpatient rehabilitation. She worked valiantly in speech, occupational, and physical therapy. Laney’s therapists were wonderful, and she began to laugh, smile, and regain strength. Laney was discharged that fall and continued in intensive outpatient rehabilitation. She worked so hard and even learned how to communicate with buttons and sit up on her own. Laney would even hold her little sister, whom she loved fiercely.

Laney’s Neurologist
I only met Laney after her prolonged hospitalization and inpatient rehabilitation, but she captivated me immediately despite being devastated by moyamoya disease, a cerebral vasculopathy that, in Laney’s case, was relentless and caused multiple strokes that stole her ability to move and speak. Reviewing Laney’s course, it was easy to identify in retrospect the delays in stroke recognition and cognitive biases, including anchoring, that contributed to the delayed diagnosis. But hindsight is 20/20, and given how common seizures are in children, it is not hard to imagine a thoughtful, capable pediatrician or neurologist making the misdiagnosis. Laney’s case is unfortunately not an exception. Multiple studies have revealed that the average time to diagnosis of childhood ischemic stroke is >22 hours. In 1 study, arterial ischemic stroke was only considered as a possible diagnosis in a quarter of cases of childhood stroke despite focal deficits being a part of the presentation in 86% of cases.…

Laney’s Father
Tragically, in December 2016, Laney suffered another stroke. After multiple failed medical interventions and visits to several medical centers, Laney was placed on hospice care. Our little girl finally succumbed and died on March 27, 2017. We kissed her little face and body until the second the funeral-home transport took her away…

Laney’s parents established the Laney Jaymes Foundation in 2017 with the missions of expanding pediatric stroke awareness, supporting research, and providing adaptive equipment to children who have suffered from stroke. Together, we identify clinical and research priorities that merge the goals of physicians and scientists with those of patients and families. For example, with guidance from Laney’s doctors, the foundation is actively funding research to better understand childhood cerebral vasculopathy, the most common cause of childhood stroke, and specifically moyamoya disease, the type of vasculopathy from which Laney suffered. The foundation both funds the research and helps guide its trajectory (with consistent collaboration between parents and physician scientists), incorporating both viewpoints and sets of priorities as we work toward the common goal of helping children like Laney.