Friday, May 31, 2019

Smartphone-controlled wearable for migraine pain


Yarnitsky D, Dodick DW, Grosberg BM, Burstein R, Ironi A, Harris D, Lin T, Silberstein SD. Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Headache. 2019 May 9. doi: 10.1111/head.13551. [Epub ahead of print]

Abstract

OBJECTIVE:
To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine.

BACKGROUND:
There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine.

METHODS:
This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints.

RESULTS:
Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499).

CONCLUSIONS:
REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.
_________________________________________________________________________

The US Food and Drug Administration (FDA) has cleared a noninvasive neuromodulation device (Nerivio Migra, Theranica) for the relief of acute migraine pain.

Nerivio Migra is a "first-in-category product," according to the company. It is worn on the upper arm and uses smartphone-controlled electronic pulses to relieve migraine through conditioned pain modulation — an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions.

The device is indicated for the acute treatment of migraine with or without aura in adults who do not have chronic migraine.

The FDA cleared Nerivio Migra on the basis of results of a prospective, randomized, double-blind, placebo-controlled study involving 252 patients who experienced two to eight migraines per month...
"The clinical data of this innovative therapeutic device is of very high quality. It indicates that the device can provide patients with significant relief of pain and other migraine symptoms without the side effects presented by drugs," neuroscientist Messoud Ashina, MD, PhD, of the Danish Headache Center, who is president-elect of the International Headache Society, said in a news release from the manufacturer.

"This study followed the latest edition of the guidelines from the International Headache Society for controlled trials of acute treatment of migraine attacks in adults," added Brian Grosberg, MD, director of the Hartford Healthcare Headache Center in Connecticut, who was principal investigator of the study.

"The results of the study demonstrate a high efficacy ratio for single as well as multiple attacks, both at 2 and 48 hours after treatment," said Grosberg.

The company plans to launch Nerivio Migra in the United States later this year "at an affordable price," Alon Ironi, CEO and cofounder of Theranica, said in the release. "We have identified at least 7 different painful conditions that may be relieved by this noninvasive, drug-free technology after appropriate clinical development," he added.

https://www.medscape.com/viewarticle/913538

Thursday, May 30, 2019

Characterization of the basal ganglia in children with self-injurious behavior and tuberous sclerosis complex


Gipson TT, Poretti A, Kelley SA, Carson KA, Johnston MV, Huisman TAGM. Characterization of the Basal Ganglia Using Diffusion Tensor Imaging in Children with Self-Injurious Behavior and Tuberous Sclerosis Complex. J Neuroimaging. 2019 May 6. doi: 10.1111/jon.12628. [Epub ahead of print]

Abstract

BACKGROUND AND PURPOSE:
Tuberous sclerosis complex (TSC) is a rare, genetic disease that is associated with multiple manifestations including epilepsy and autism. Self-injurious behaviors (SIBs) also occur in a subset of patients. This study used diffusion tensor imaging (DTI) in children with TSC for quantitative and volumetric analysis of brain regions that have been associated with SIB in other genetic conditions.

METHODS:
We used DTI to compare 6 children with TSC-associated SIB and 10 children with TSC without SIB. Atlas-based analysis of DTI data and calculation of number of voxels; fractional anisotropy (FA); and mean, axial, and radial diffusivity were performed for multiple regions; DTI measures were summarized using medians and interquartile ranges and were compared using Wilcoxon rank sum tests and false discovery rates (FDRs).

RESULTS:
Analysis showed that children with TSC and SIB had reduced numbers of voxels (median) in the bilateral globus pallidus (right: 218 vs. 260, P = .008, FDR = .18; left: 222 vs. 274, P = .002, FDR = .12) and caudate nucleus (right: 712 vs. 896, P = .01, FDR = .26; left: 702 vs. 921, P = .03, FDR = .44) and reduced FA in the bilateral globus pallidus (right: .233 vs. .272, P = .003, FDR = .12; left: .223 vs. .247, P = .004, FDR = .12) and left caudate nucleus (.162 vs. .186, P = .03, FDR = .39) versus children without SIB. No other statistically significant differences were found.

CONCLUSIONS:
These data support a correlation between lower volumes of the globus pallidus and caudate with SIB in children with TSC.

Courtesy of:  https://www.mdlinx.com/journal-summaries/tuberous-sclerosis-complex-diffusion-tensor-imaging/2019/05/07/7566165?spec=neurology

Angiomyolipoma and tuberous sclerosis


Gipson TT. Consequences of delay in screening, monitoring, and treatment of angiomyolipoma and tuberous sclerosis: A case report.  Clin Nephrol. 2018 Jul;90(1):71-75.

Abstract 

BACKGROUND:
Tuberous sclerosis complex (TSC) is a multisystem disorder that results in tumor growth in various organs. TSC can affect the kidneys in the form of renal angiomyolipomas and cysts that can lead to chronic kidney disease.

CASE PRESENTATION:
A 38-year-old woman was referred to Kennedy Krieger Institute for comprehensive TSC management. Before referral, the patient had gone most of her life without a definite diagnosis of TSC despite visually-prominent signs such as forehead plaques, facial angiofibromas, and ungual fibromas. Eventually, complications of the disease led to the patient requiring hemodialysis at age 34 and a complete bilateral nephrectomy at age 36. However, the patient was not diagnosed with TSC until an evaluation at the National Institutes of Health at age 37. After becoming a patient at our clinic, a multidisciplinary approach was taken to provide comprehensive care by including various disciplines such as nephrology, neurology, pulmonology, ophthalmology, dentistry, dermatology, and cardiology.

DISCUSSION AND CONCLUSION:
TSC consensus recommendations aid in diagnosis, monitoring, and treatment of TSC and its associated manifestations, including those involving the kidneys. Our case underscores the importance of early identification of TSC to prevent future complications and promotes use of a multidisciplinary team to provide comprehensive care.

http://childnervoussystem.blogspot.com/2015/04/renal-disease-in-tuberous-sclerosis.html

Tuesday, May 28, 2019

Epileptic phenotypes in children with early onset mitochondrial diseases


Matricardi S, Canafoglia L, Ardissone A, Moroni I, Ragona F, Ghezzi D, Lamantea E, Nardocci N, Franceschetti S, Granata T. Epileptic phenotypes in children with early onset mitochondrial diseases. Acta Neurol Scand. 2019 May 18. doi: 10.1111/ane.13130. [Epub ahead of print]

Abstract
OBJECTIVES:
To determine the prevalence of epilepsy in children with early onset mitochondrial diseases (MDs) and to evaluate the epileptic phenotypes and associated features.

MATERIALS & METHODS:
Children affected by MD with onset during the first year of life were enrolled. Patients were classified according to their mitochondrial phenotype and all findings in patients with epilepsy versus patients without were compared. The epileptic features were analyzed.

RESULTS:
The series includes 129 patients (70 females) with median age at disease onset of 3 months. The median time of follow-up was 5 years. Non-syndromic mitochondrial encephalopathy and pyruvate dehydrogenase complex deficiency were the main mitochondrial diseases associated with epilepsy (p<0.05). Seizures occurred in 48%, and the presence of epilepsy was significantly associated with earlier age at disease onset, presence of perinatal manifestations, and early detection of developmental delay and regression (p<0.001). Epileptic encephalopathy (EE) with spasms and EE with prominent focal seizures were the most detected epileptic syndromes (37% and 27.4%). Several seizure types were recorded in 53.2%, with the unusual association of generalized and focal epileptic pattern. Disabling epilepsy was detected in 63%, and was associated with early seizure onset, presence of several seizure types, epileptic syndrome featuring EE, and the recurrence of episodes of status epilepticus and epilepsia partialis continua (p<0.05).

CONCLUSIONS:
Epilepsy in children with early onset MD may be a presenting or a prominent symptom in a multisystemic clinical presentation. Epilepsy-related factors could determine a worst seizure outcome, leading to a more severe burned[brunt?] of the disease.


Monday, May 27, 2019

Chiari malformation


Claudia Martinez, 28, is a walking miracle. She's also a fourth-year medical student at the same hospital that has treated her throughout six brain surgeries.

The Brawley, Calif., native who was raised in Houston, Texas wanted to be a doctor since she was a little girl but she never could have imagined the journey it would take her on, which she now describes as  "a blessing in disguise."

Martinez received a devastating diagnosis as an undergraduate student at the University of Houston. Plagued by headaches and blackouts, Martinez was told her debilitating condition was called Chiari Malformation, which involves brain tissue extending into the spinal cord. It could cause paralysis. But despite the diagnosis, surgeries, and going in and out of hospitals, Martinez graduated with a 4.0 and got accepted into her dream medical school, the University of Texas at Houston, where she was being treated.

"My journey has been long and at times has felt impossible, but what keeps me going is my future patients," Martinez told Fox News. "I've learned we don't necessarily need a cure. We need inclusion, we need patience, we need accessibility, and we need individuals who are willing to work with us to give us the reasonable accommodations that, by law, we are entitled to."

Martinez suffered a seizure during her first year of medical school and had to undergo experimental surgery. During her third year, she suffered a stroke that left her unable to function from the neck down. She was transferred to TIRR Memorial Hermann Hospital for intense neuro-rehabilitation where she learned to walk, feed, dress, and bathe once again.

Martinez has organized the Conquer Chiari 5k Walk three times, raising over $55,000 for Chiari research, and plans to hold the fourth walk this year.

"Yes, I'm here to advocate for myself, but more importantly for those who do not yet have a voice, for those coming after me, and for my future patients," she added. "If I can set a trail to guide others so they don't have to suffer as much as I have, then it will all be worth it."

Martinez has shared her journey on Instagram, inspiring others through her honesty and fight.

                                                           From Instagram

"I thank God every day for what I’ve gone through, [because] it is how I’ve found my calling," Martinez wrote on her Instagram. "I’ve officially decided to pursue a residency in PM&R (Physical Medicine and Rehabilitation)."

She added: "I want to be on the side of medicine that most people don’t see. I want to work with a population of individuals whose worth and potential is often overlooked and be their advocate. I want to help them see that even though it may be a little different, life can be beautiful again."
But Martinez doesn't use med school or being a patient as an excuse.

She also mentors college students, especially underrepresented minorities who are interested in pursuing medicine, through programs like Aspirations in Medical Professions, SMDEP Mentorship Program, Pre-Jamp symposium, and on her own.

The 28-year-old volunteers with RSVP (Rehabilitation Services Volunteer Project), a non-profit that provides physical rehabilitation services and medical equipment to underinsured individuals in Houston with disabilities.

And if that isn't enough, Martinez is in the process of starting her own non-profit that will work to give patients adaptive medical equipment and make adjustments to their home to make them ADA compatible.

She is set to graduate in May 2020.

https://www.foxnews.com/health/texas-medical-student-hospital-doctor-miracle

Sunday, May 26, 2019

Refractory Tourette syndrome

https://www.youtube.com/watch?v=Q1gPC85TU_Y

Novel tool used to mine clinical data and identify causative gene in childhood epilepsy


A team of researchers at Children's Hospital of Philadelphia (CHOP) affiliated with the CHOP Epilepsy Neurogenetics Initiative (ENGIN) discovered a new gene associated with severe childhood epilepsy using a novel computational approach. The team systematically compared phenotypes, or clinical data, of patients with severe childhood epilepsies through a novel analysis strategy and looked for common genetic causes in patients who had similar clinical presentations.

This is the first time that such an analysis of clinical data has been used to identify novel genetic causes of neurological disorders, and this new computational method has the potential to help patients with a variety of complex and difficult-to-diagnose conditions. The findings were published today in the American Journal of Human Genetics.

"Genetic data are incredibly valuable, but when we do whole exome sequencing, this is really only half of the story," said Ingo Helbig, MD, a pediatric neurologist in the Division of Neurology at CHOP who directs the Genomics and Datascience Core of the CHOP Epilepsy Neurogenetics Initiative. "Genetic epilepsies can present with a wide range of symptoms, and what we really want to understand is which medications work and how we can improve outcome. Genetic testing alone does not give us this information. However, when we merge genetic information with large-scale clinical data, the combination can be very powerful."

Developmental and epileptic encephalopathies are severe heterogeneous brain disorders that often have a genetic cause. However, the genetic basis for these disorders remains unknown in a large portion of affected patients. These disorders can cause aggressive seizures, cognitive and neurological deficits and, in some cases, early death. Many patients do not respond to current treatment options, and identifying a causative gene is often the first step of improving treatment.

Over the last decade, technological advances have made it possible for genetic testing to be performed on a large scale, yielding large sets of genomic data that have enabled researchers to pinpoint a number of important genetic mutations in childhood epilepsies. However, the patient's phenotype - a set of observable characteristics such as type of seizures or developmental disabilities - has historically not been collected in the same standardized manner as genetic data. While new gene sequencing technologies can generate genomic data more thoroughly and quickly, clinical data must be entered by hand, which results in a "phenotypic bottleneck" where clinical data cannot be processed at the same level as genetic data.

To address this discrepancy, other researchers previously developed the Human Phenotype Ontology (HPO), a catalogue that provides a standardized format to characterize a patient's phenotypic features, including neurological findings, and allows for clinical data to be used at a similar level as genetic data.

Since many severe childhood epilepsies have very complex clinical findings, the study team believed that analyzing clinical data in the HPO data through computational methods would be an effective way to identify patients with similar symptoms that may not have been obvious. By combining this phenotypic information with a patient's whole exome sequencing data, researchers wanted to see if similarities in clinical features might reveal information about the genetic basis of the disorder that might otherwise go undetected.

"The main limitation in the past was the lack of large amounts of clinical information in a format that can be analyzed systematically through our informatics approaches," Helbig said. "In our study, we built the computational algorithms to leverage clinical data. We then used these tools to find the genetic cause for a patient's epilepsy."

Helbig and colleagues, including collaborators from the EuroEPINOMICS-RES Consortium and the U.S.-based Genomics Research and Innovation Network, analyzed whole exome sequencing data and clinical data transformed to HPO format for computational analysis in 314 patients with severe epilepsies. The team found a variant in the AP2M1 gene in two individuals with similar phenotypes in their study. Using this information, they looked for variants in AP2M1 in a second cohort of 2,310 individuals and found two additional patients with similar clinical features, including neurodevelopmental disorders and generalized epilepsy.

Upon further examination, the study team determined that this particular disorder caused a functional alteration of the AP-2 complex, which is involved in endocytosis, a process by which brain cells recycle small parts of their membrane to create so-called synaptic vesicles that are important in the communication between brain cells. The authors suggest that the key function of the AP2M1 protein is to regulate the balance between excitability and inhibition, a well-established mechanism in epilepsy.

"This is the first time that clinical patient information in a digital format was used to discover a disease gene," said Ethan Goldberg, MD, PhD, Assistant Professor of Neurology & Neuroscience and Director of the CHOP ENGIN, a recently launched program that integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies. "This study emphasizes how the large amount of clinical information that is collected in our patients can facilitate gene discovery and enhance our understanding of a gene's function. Increasingly, knowing how defects in a gene cause seizures allows us to better determine which medications might work and to develop new strategies to treat children with epilepsy. "


Helbig I, Lopez-Hernandez T, Shor O, Galer P, Ganesan S, Pendziwiat M, Rademacher A, Ellis CA, Hümpfer N, Schwarz N, Seiffert S, Peeden J, Shen J, Štěrbová K, Hammer TB, Møller RS, Shinde DN, Tang S, Smith L, Poduri A, Krause R, Benninger F, Helbig KL, Haucke V, Weber YG; EuroEPINOMICS-RES Consortium; GRIN Consortium. A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. Am J Hum Genet. 2019 May 2. pii: S0002-9297(19)30147-8. doi: 10.1016/j.ajhg.2019.04.001.
[Epub ahead of print]

Abstract
The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Comprehensive behavioral intervention for tics


To parents of teenagers, it often feels like their mere presence annoys their children. But for D'Ann Searls, it is a fact.

"It's kind of a joke, right? You say, 'I can't even breathe around them,'" the Naperville, Illinois, mom of two told TODAY Parents. "Well, for me, literally — I can't."

When Searls took her 13-year-old daughter Avery to the pediatric neurology clinic at Northwestern Medicine in Chicago 10 months ago, it was because Avery, who has Tourette syndrome, found it physically painful to be in the same room as her mom.

Even the way Searls breathed or talked made Avery's body tense and jerk involuntarily, leaving her in pain so severe she would miss school to recover.

Avery was diagnosed with Tourette syndrome at the age of 8…

A year and a half ago, Avery's tics — which included shoulder-rolling, back-arching, eye-blinking, and mimicking, among others — took an unusual turn: Some of them began to be triggered by the presence of her own mother.

It began with Avery's need for her mother to say exactly the words she expected her to say. "If I asked her something and I wanted her to say 'Yes,' and she said 'Sure' instead, I would do a tic with that," explained Avery.

Then, her mother's breathing began causing Avery to tic. "I'm very aware of my tics, and sometimes when my mom would breathe, I would yell at her to stop. I knew it was causing my tics," said Avery.

To an observer, it might appear that Avery and her mom had a troubled relationship, but Avery said that the fact that her mom caused her tics was in fact because she felt so close to Searls. "I don't have control over my body, so I want everything else to be controlled, and I am so close to my mom that included her," she said.

When Avery's tics were at their worst, she couldn't look at her mother or talk to her. It was challenging for her to even be in the same room with her. For her mom, it was "really hard, because I wanted to be there for her."

The Searls tried everything to help Avery: holistic doctors, medication, elimination diets, neurofeedback, acupuncture, supplements. Finally, they found the clinic at Northwestern Medicine where Mindy Meyer, a pediatric nurse practitioner, has treated hundreds of children with tics like Avery's using Comprehensive Behavioral Intervention for Tics (CBIT).

CBIT is a non-drug alternative treatment that uses behavioral therapy to teach children how to manage tics on their own.

"We work through one tic at a time, and the kids drive it," Meyer told TODAY Parents. "They pick the tic that bothers them the most and causes them the most problems."

"The first thing we have to do is get to know the tic extremely well, which is a challenge, because when someone is diagnosed with tics and they are not doing CBIT, they ignore the tics. That's what you do to cope," she explained.

Meyer helps the children think through and identify every aspect of the tic — when it happens the most, any emotions attached to the tic, and what the specific urge is that precedes it. "It's awareness training," Meyer said.

Once a child understands the tic's traits and can catch it before it happens, Meyer teaches them to use a "competing response" to stop the tic from being able to occur along with deep breathing techniques to help keep them calm.

If the tic is shoulder-rolling, for instance, she teaches the child to hold their arms with their elbows out in a way that prevents them from making that particular movement with their shoulders. If the tic is coughing, she teaches the child to identify when the urge to cough happens and to keep their mouth closed and breathe through their nose until the urge passes.

Meyer focuses solely on tics, but many of her patients also see therapists to address mental and emotional aspects of their condition concurrently with CBIT.

Though CBIT has helped hundreds of children in Meyers's clinic, the Tourette Association of America warns that the fact that tics can be managed with the help of behavioral therapy does not mean tics are easily controlled without medication.

"There is concern that families, co-workers, and teachers will read about CBIT and conclude that tics are willful and easily controlled," the association wrote on its website. "We have known for years that this conclusion is incorrect and harmful to people with tics. Expecting people to 'stop ticcing' or treating them as if tics are done 'on purpose' increases distress and triggers efforts to voluntarily suppress tics, which is ineffective and leads to greater impairment."

Meyer's success rate, she estimates, is 98%. Most of her patients are able to work through their tics in a matter of months, and with the CBIT training, they are able to help themselves when new tics arise. Tourette syndrome is incurable, but it is, Meyer stresses, manageable.

Though Avery's case has unique elements and is more complicated than most, she has been able to work through 20 of her 26 tics in the past 10 months — and after a lot of work, she and her mother can now go shopping together, have conversations, and enjoy each other without the pain that accompanied their interactions just a year ago.

Despite her struggles with Tourette syndrome, Avery has lived her life, said her mom. "She's a great volleyball player," she said.

"I used to be embarrassed. I wouldn't go places, I couldn't look at my brother or mother. It's gotten so much better," said Avery. "We can be in the same room. It's not like her breathing is awful to me anymore."

Despite the toll her condition has taken on her emotionally and physically, Avery has persisted. "She has lived her life. She has not let it stop her, even though it has been so hard. I am so proud of her for that," Searls said.

Avery wants others to know that although Tourette syndrome is a very difficult part of her life, it does not define her. "Everyone is different in their own way. Tourette syndrome is just a little part of me," she said. "I play volleyball, I have a lot of friends, I do a bunch of things.

"There is hope," she said. "I want everyone to know that. No matter who you are or what you have."

https://www.today.com/parents/teen-tourette-syndrome-tics-triggered-mom-uses-cbit-t154744 


White matter microstructural differences identified using multi-shell diffusion imaging in children born very preterm


Young JM, Vandewouw MM, Mossad SI, Morgan BR, Lee W, Smith ML, Sled JG, Taylor MJ. White matter microstructural differences identified using multi-shell diffusion imaging in six-year-old children born very preterm. Neuroimage Clin. 2019 May 4;23:101855. doi: 10.1016/j.nicl.2019.101855. [Epub ahead of print]

Abstract

INTRODUCTION:
The underlying microstructural properties of white matter differences in children born very preterm (<32 weeks gestational age) can be investigated in depth using multi-shell diffusion imaging. The present study compared white matter across the whole brain using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics in children born very preterm and full-term children at six years of age. We also investigated associations between white matter microstructure with early brain injury and developmental outcomes.

METHOD:
Multi-shell diffusion imaging, T1-weighted anatomical MR images and developmental assessments were acquired in 23 children born very preterm (16 males; mean scan age: 6.57 ± 0.34 years) and 24 full-term controls (10 males, mean scan age: 6.62 ± 0.37 years). DTI metrics were obtained and neurite orientation dispersion index (ODI) and density index (NDI) were estimated using the NODDI diffusion model. FSL's tract-based spatial statistics were performed on traditional DTI metrics and NODDI metrics. Voxel-wise comparisons were performed to test between-group differences and within-group associations with developmental outcomes (intelligence and visual motor abilities) as well as early white matter injury and germinal matrix/intraventricular haemorrhage (GMH/IVH).

RESULTS:
In comparison to term-born children, the children born very preterm exhibited lower fractional anisotropy (FA) across many white matter regions as well as higher mean diffusivity (MD), radial diffusivity (RD), and ODI. Within-group analyses of the children born very preterm revealed associations between higher FA and NDI with higher IQ and VMI. Lower ODI was found within the corona radiata in those with a history of white matter injury. Within the full-term group, associations were found between higher NDI and ODI with lower IQ.

CONCLUSION:
Children born very preterm exhibit lower FA and higher ODI than full-term children. NODDI metrics provide more biologically specific information beyond DTI metrics as well as additional information of the impact of prematurity and white matter microstructure on cognitive outcomes at six years of age.

https://www.mdlinx.com/journal-summaries/preterm-diffusion-tensor-imaging-white-matter/2019/05/06/7566113?spec=neurology

Utility of magnetic resonance imaging in children with strabismus


Yoon L, Kim HY, Kwak MJ, Park KH, Bae MH, Lee Y, Nam SO, Choi HY, Kim YM. Utility of Magnetic Resonance Imaging (MRI) in Children With Strabismus. J Child Neurol. 2019 May 21:883073819846807. doi: 10.1177/0883073819846807. [Epub ahead of print]

Abstract

PURPOSE:
Magnetic resonance imaging (MRI) of the brain can provide valuable information about structural abnormalities in strabismus. The aim of this study was to evaluate the utility of MRI in this regard and to identify risk factors for abnormal MRI results in children with strabismus.

METHODS:
A retrospective analysis of children <18 years of age presenting with strabismus, who underwent brain MRI at Pusan National University Hospital (Busan, Korea) between January 2012 and March 2017, was performed. Clinical characteristics, MRI results, and ophthalmologic findings were reviewed. Findings were classified as normal or abnormal according to MRI results. Additionally, patients were divided according to age to compare characteristics of infantile and childhood strabismus.

RESULTS:
A total of 90 patients (47 [52.2%] male, 43 [47.8%] female; mean age, 2.19 ± 0.53 years) were enrolled. Of those, 64 (71.1%) presented with normal and 26 (28.9%) with abnormal MRI results. The age at presentation was lower and abnormal findings on fundus examination were more common in the abnormal MRI group ( P = .002 and P = .008, respectively). Among the patients, 46 (51.1%) had infantile strabismus and 44 (48.9%) had childhood strabismus. Global developmental delays, speech delays, and MRI abnormalities were more common in patients with infantile than in those with childhood strabismus. Ptosis and headaches were more common in patients with childhood strabismus ( P = .025, P = .025, respectively).

CONCLUSION:
Brain MRI was helpful for accurate diagnosis and treatment of strabismus in younger children, those with abnormal findings on fundus examination, and infants with developmental, especially speech, delays.
___________________________________________________________________

From the manuscript

This study found that MRI produced abnormal results in 28% of patients with strabismus. Periventricular leukomalacia, the most frequently found in this study, is known to be a major cause of childhood strabismus.  In 2002, a study of patients with periventricular leukomalacia and vision impairment by Jacobson et al suggested that strabismus and nystagmus may be the only symptoms of periventricular leukomalacia. Studies involving premature infants with a gestation period <29 weeks also reported vision impairment in 6% of patients due to premature retinopathy and brain lesions; premature infants with retinopathy in early stages had a higher incidence of strabismus.  Periventricular leukomalacia is a major central nervous system complication in prematurity, and ischemic injury of the periventricular region interferes with the development of the visuomotor pathway, leading to ocular alignment abnormalities.  MRI is required to assess the periventricular region in prematurity, and in infants with a history of ischemic damage resulting in misalignment of the eyes.


In this study, developmental and speech delays were higher in patients with infantile than in those with childhood strabismus, with significant differences between the 2 groups (P = .014 and P = .030, respectively). We included patients who were referred to a pediatric neurology clinic by pediatric ophthalmologists because of the need to rule out underlying neurologic abnormalities. Strabismus may cause more damage during the critical period of brain development.  Early-onset strabismus not only affects visual function but also causes developmental delays.  Research investigating MRI abnormalities has been performed in a variety of ways and has also been used to examine patients with developmental and language delays. When comparing normal development and delayed speech, a high proportion of patients with delayed speech demonstrate abnormal MRI features.  Previous studies have consistently revealed a strong correlation between the appearance on MRI of impairment of the optic pathway to the visual cortex, reduced visual function, and decline of cognitive function.  Headache and ptosis were more common in patients with childhood strabismus. Ptosis affecting 5 patients in the childhood strabismus group was diagnosed before the age of 12 years, and their strabismus was noticed after 1 year of age. Headache may appear more common in patients with childhood strabismus because infants are unable to voice complaints.

Courtesy of:  https://www.mdlinx.com/journal-summaries/strabismus-magnetic-resonance-imaging-pediatrics/2019/05/23/7567640?spec=neurology

Saturday, May 25, 2019

Neurologic examination findings associated with small cerebellar volumes after prematurity


Tam EWY, Chau V, Lavoie R, Chakravarty MM, Guo T, Synnes A, Zwicker J, Grunau R, Miller SP. Neurologic Examination Findings Associated With Small Cerebellar Volumes After Prematurity. J Child Neurol. 2019 May 21:883073819847925. doi:10.1177/0883073819847925. [Epub ahead of print]

Abstract
To help clinicians understand what to expect from small cerebellar volumes after prematurity, this study aims to characterize the specific impacts of small cerebellar volumes on the infant neurologic examination. A prospective cohort of preterm newborns (<32 weeks' gestational age) had brain magnetic resonance imaging (MRI) studies at term-equivalent age. Cerebellar volumes were compared with neurologic examination findings in follow-up, adjusting for severity of intraventricular hemorrhage, white matter injury, and cerebellar hemorrhage. Deformation-based analyses delineated regional morphometric differences in the cerebellum associated with these findings. Of 119 infants with MRI scans, 109 (92%) had follow-up at 19.0±1.7 months corrected age. Smaller cerebellar volume at term was associated with increased odds of truncal hypotonia, postural instability on standing, and patellar hyperreflexia ( P < .03). Small cerebellar volume defined as <19 cm3 by 40 weeks was associated with 7.5-fold increased odds of truncal hypotonia ( P < .001), 8.9-fold odds postural instability ( P < .001), and 9.7-fold odds of patellar hyperreflexia ( P < .001). Voxel-based deformation-based morphometry showed postural instability associated with paravermian regions. Small cerebellar volume is associated with specific abnormalities on neurologic examination by 18 months of age, including truncal tone, reflexes, and postural stability.
Courtesy of:  https://www.mdlinx.com/journal-summaries/preterm-cerebellum-magnetic-resonance-imaging-mri/2019/05/24/7567639?spec=neurology

Friday, May 24, 2019

Meningitis B infection


“We thought it was the flu — we told her to rest and go to the student health center. She was more concerned with missing classes than how bad she felt,” Sara’s father, Greg Stelzer, 63, told Fox News.

But Sara then developed a blotchy, purple rash — what her parents would later learn was a sign of meningitis B.

Sara was in the emergency room by Tuesday morning, a friend of Sara’s informed Greg and his wife Laurie via text message. When they arrived at the hospital from the Los Angeles area later that afternoon, Sara was in an induced coma.

Though Sara’s doctors, after determining she contracted bacterial meningitis, started the teen on antibiotics, it was too late: the infection had spread to her brain and spinal cord, causing her to suffer a stroke. By the time her parents reached her, she was brain dead.

“In our minds, that was when she passed away,” said Greg.

In less than two days, their daughter was gone.

“We had no idea that these flu-like symptoms could develop and kill her within 36 hours,” Laurie, 51, told Yahoo Lifestyle.

Meningococcal disease is primarily caused by five types of meningococcal bacteria — A, C, W, Y and B. The Centers for Disease Control and Prevention (CDC) recommends children between ages 11 and 12 receive a meningococcal conjugate vaccine and receive a booster at 16 to prevent against serogroups A, C, W and Y. In addition, those age 16 to 23 can also receive a serogroup B meningococcal vaccine, the agency added.

Sara received the meningococcal conjugate vaccine, her father said — but not the serogroup B meningococcal vaccine.

One of the main meningococcal serogroup B vaccines — Trumenba — was first licensed in the U.S. in 2014, before another — Bexsero — became available in 2015, per the Immunization Action Coalition.

The CDC now recommends “permissive use of” meningococcal serogroup B vaccines, which essentially means the federal health agency doesn’t endorse all teens and young adults receive the vaccine at this time, unlike its universal recommendation for the meningococcal conjugate vaccine. Rather, a doctor determines the risk and assesses whether or not a patient should receive the shot, Greg explained.

“You don't realize how your body and mind is affected by a loss like that — the first year was a fog. My older daughter took a semester off [from college]. We grieved our way, went to support groups and counseling,” he said. But, when the fog lifted, “we felt that we needed to do something.”

In November 2014, just one month after their daughter died, Laurie was contacted by the National Meningitis Association and was urged to share Sara’s story with officials at the CDC in Atlanta. Greg claims it was after meeting with Laurie that the CDC set its “permissive use” guidelines regarding meningococcal serogroup B vaccines.

“We felt the need to get the word out about this terrible disease and started a campaign to speak at universities. Our story is simple: We tell our story then we present a PowerPoint presentation explaining what meningitis is, what the symptoms are and how at-risk students can protect themselves with the vaccine," Greg said.

The couple has already seen success at San Diego State University, where Sara attended before falling ill. They annually hold a roughly one-hour informative session with resident assistants (RAs), parents, students and more. Three students in the fall of 2018 were diagnosed with meningitis B but survived; an RA for one of the students told the couple their presentation helped her recognize the student likely had something more severe than the flu, Greg said.

https://www.foxnews.com/health/california-meningitis-b-infection-kills-teen

Tuesday, May 21, 2019

Transcranial magnetic stimulation for Tourette syndrome 2


Study Seeks Longer-Term Benefits From Tourette Treatment

Tourette syndrome (TS) is a neurodevelopmental condition that affects nearly 1 percent of children worldwide. While it can be treated with drugs and behavioral therapy, other modalities are being sought, especially in cases that are resistant to standard treatment. Keith Coffman, MD, Director of Tourette Syndrome Center of Excellence at Children’s Mercy Kansas City, is leading the way with a study designed to better understand the long-term effectiveness of multisite transcranial magnetic stimulation (mTMS)

TMS is already FDA-approved for treatment of depression and obsessive-compulsive disorder. It’s also used in various clinical studies to better understand its effectiveness in controlling Tourette syndrome symptoms. In these studies, magnetic stimulation is performed using a hand-held device that is bulky, delivers a high level of current that can cause unpleasant sensations, and can provide stimulation at only one cortical site at a time. Some studies using this device have shown promising results, but the benefits have worn off because patients were unable to keep a regular schedule of hospital visits for access to the device...

The Evolution of Technology

A new portable device has been developed and patented by Dr. Santosh Helekar of Houston Methodist Research Institute (HMRI) and Dr. Henning Voss of Weill-Cornell Medical College (WCMC). The only device of its kind in the U.S., it’s smaller and wearable and can deliver stimuli at multiple cortical sites simultaneously or sequentially.

It uses rapidly rotating, small, high-strength permanent magnets to induce currents in the brain. This device delivers lower levels of current during stimulation, eliminating the discomfort common in other TMS devices. Best of all, it can be used at home, making it more practical. This device is the cornerstone of Dr. Coffman’s study.

Setting Goals for the Study

Dr. Coffman’s study is testing the therapeutic effectiveness of bilateral mTMS of the supplementary motor areas (mTMS-SMA therapy) in TS patients presenting with tics uncontrolled by standard drug and behavioral treatment.

Two types of devices will be used: One is real and the other is a sham device. Only the manufacturer knows the difference. Patients are randomized at enrollment in a placebo-controlled fashion.
The specific aims of this study are:

To compare the immediate benefits experienced by TS patients subjected to stimulation to the TS patients receiving placebo treatment, in terms of reduction of the frequency of tics and alleviation (primary end points) of other comorbidities (ADHD and OCD, secondary end points) of TS.
To compare the long-term benefits over a two-month follow-up period in the same set of treated and placebo control TS patients.

Criteria for Participation

To be considered for the study, a patient must meet these criteria:

Meet a specific threshold on the Yale Global Tic Severity Scale (YGTSS) in order to show a drop in baseline level of symptoms.
Cannot have epilepsy, due to seizure risk from stimulation.
No implanted devices in body, such as vagal nerve stimulator, cochlear implants or intracranial hardware.

Study Design

The study period is 10 days, with five consecutive days of mTMS per week for two weeks.
Each session lasts one hour.
Symptom levels are assessed at enrollment and periodically during the treatment.
Patients are assessed again at follow-up visits two weeks and one month post-treatment.
Patients are also assessed for changes in levels of anxiety, ADHD symptoms and obsessive-compulsive symptoms.

Results

Dr. Coffman and his team are enrolling patients currently. Study details are listed on clinicaltrials.gov, where providers and patients’ families can find enrollment details. Once the entire cohort has been enrolled and treated, results will be available several months later.

Keeping glucose transporter type 1 deficiency syndrome in mind


Ros-Castelló V, Toledano R, Martínez-San-Millán JS, Alonso-Canovas A. Keeping Glucose Transporter Type 1 Deficiency Syndrome in Mind: A Late Diagnosis and Unusual Neuroimage Findings. Mov Disord Clin Pract. 2019 Mar 28;6(4):291-293.

A 52‐year‐old woman with previous diagnosis of CP and developmental delay, early‐onset epilepsy (generalized tonic‐clonic seizures and complex partial seizures), and episodic migraine without aura was referred to our Movement Disorders Clinic because of episodes of abnormal gait. Since childhood, she presented paroxysms of painful and disabling dystonic gait that were triggered by 10‐ to 20‐minute walks, with a frequency of four to five episodes per month. Dystonic position of the legs was mainly in adduction, flexion, and equinovarus. Symmetry, intensity, and latency were variable. These episodes improved after a few minutes of rest. They were unrelated with fasting or postpandrial state and unresponsive to levodopa (video at article).

Head circumference was normal. EEG recorded during an episode of dystonia was normal. Cranial MRI and CT scan findings were consistent with bilateral putaminal iron deposition. A lumbar puncture showed hypoglycorrhachia (34 mg/dL) with a blood glucose level of 90 mg/dL and a CSF/blood glucose ratio of 0.37. Heterozygous pathogenic p.Arg126Cys mutation in SLC2A1 gene was disclosed...


(A) Axial T2wTSE imaging at the level of the basal ganglia shows bilateral and symmetrical low signal in both pallidal and putaminal nuclei. (B) Axial GRE T2* weighted imaging at the same level shows exacerbated lower signal in both putaminal nuclei.

After 6 months on strict ketogenic diet (KD), no further disabling episodes of PEID occurred, and migraine and seizures were controlled. Moreover, symptoms recurred transiently after a short period of incomplete adherence to KD.

Discussion

Most SLC2A1 mutations are de novo. No phenotype‐genotype correlations have been clearly established, although some types of mutations have been related to specific clinical manifestations.2 Patients who carried the mutation of our patient (pArg126Cys) had been previously reported3-5 and presented symptoms that included intellectual impairment, different types of seizures, spastic paraplegia, paroxysmal choreoathetosis, PEID, gait ataxia, dysarthria, and microcephaly with a variable age at diagnosis.

Neuroimaging findings are usually noncontributory. To our knowledge, this is the first case of GLUT1‐DS with putaminal iron deposition. Although the present findings could be incidental, further reports could clarify the pathophysiological relevance of putaminal iron deposition in GLUT1‐DS.

The clinical spectrum of the disease is wide, and, as this case report illustrates, the delay on diagnosis is sometimes considerable. In patients with a chronic neurological disorder, paroxysmal manifestations such as PEID are an important clue to the diagnosis of GLUT1‐DS. Recognition of this syndrome is of critical importance given that treatment with KD may improve seizure control and movement disorders. Although degree of response clearly depends on the delay of diagnosis and severity of the manifestations, we have shown that this treatment could be worth trying in adult patients with long‐lasting disease when motor manifestations are disabling.

Monday, May 20, 2019

Variants of Guillain-Barré syndrome



E. Steve Roach, MD, Editorial Board Member, Pediatrics in Review

Most of us learned the basic clinical manifestations of Guillain-Barré syndrome in medical school and likely have encountered at least a few children with the condition during residency or in practice. Four January 2018 Pediatrics in Review articles focus on this immune-mediated peripheral neuropathy, emphasizing some of its less common clinical patterns that are apt to be less familiar to most physicians.

In their In Brief on the topic, Chung and Deimling summarize the classic manifestations of Guillain-Barré syndrome. This is an acute-onset, immunemediated peripheral neuropathy that likely is triggered by an infection or another immune stimulus. Guillain-Barré syndrome classically presents as an acute-onset, rapidly progressive, flaccid weakness starting in the legs, associated with diminished or absent tendon reflexes. The clinical severity of Guillain-Barré syndrome varies, but at its worst, it can lead to respiratory insufficiency and death. The cerebrospinal fluid (CSF) typically exhibits an elevated protein level but not an excess of white blood cells, although this pattern is not always present initially, and occasionally individuals have a mildly elevated white blood cell count.

In Index of Suspicion Case 3, Bassal and Lupo  present an 11-year-old boy with a 2-day history of gait unsteadiness and diplopia. His examination revealed initially diminished then absent tendon reflexes, dysmetria, and partial dysfunction of cranial nerves III and VI. His extremity muscles were not weak. Results of imaging and laboratory investigations were normal except for elevation of antiganglioside anti-GQ1b immunoglobulin G antibodies.

The differential diagnosis of acute ataxia is extensive.  This boy’s diagnosis is Miller Fisher syndrome. Generally considered to be a milder variant of Guillain-Barré syndrome, Miller Fisher syndrome features a triad of areflexia, ataxia, and cranial neuropathy.  Most individuals with Miller Fisher syndrome recover completely, with or without therapy. Nonetheless, prompt recognition of Miller Fisher syndrome may prevent unnecessary diagnostic tests, and occasionally patients progress to the riskier Guillain-Barré syndrome.

In Index of Suspicion Case 1, Shah et al describe a 5-year-old boy with right leg pain and difficulty walking for 5 days. His right leg was weak and tender to palpation. Tendon reflexes were absent in the right leg. Left leg strength was normal, but even on the left his reflexes were diminished. This presentation might suggest a localized joint problem, but hip magnetic resonance imaging (MRI) findings were normal. Weakness in 1 limb would once have suggested poliomyelitis, which often presents in this manner. More recently, asymmetrical flaccid paralysis due to acute myelitis has been described.

This boy too proved to have a variant of Guillain-Barré syndrome. His CSF revealed increased protein and immunoglobulin G levels. An MRI of the thoracic and lumbar spine documented asymmetrical contrast enhancement of ventral and dorsal nerve roots, and a nerve conduction velocity test confirmed axonal polyneuropathy in both legs. Back or leg pain is common in children with Guillain-Barré syndrome. The weakness of Guillain-Barré syndrome is typically symmetrical, but as this child illustrates, it isn’t always.

In Index of Suspicion Case 2, Bashir and Aarons describe a 2-year-old girl who refused to walk for 3 weeks. Based on the tests and treatments initially recommended, her symptoms at first were attributed to musculoskeletal disease. When examined, she had no tendon reflexes in the legs and could not dorsiflex the right foot. Movement of her legs seemed to elicit pain. Eventually an MRI demonstrated abnormal spinal nerve roots, and a lumbar puncture confirmed an elevated CSF protein level in the absence of inflammatory cells.

Persistent, painful dysfunction without complete paralysis has a broad differential diagnosis that includes several conditions that are far more common than Guillain-Barré syndrome. The symptoms of toxic synovitis usually improve with the use of nonsteroidal anti-inflammatory agents and heat. Septic arthritis, diskitis, and osteomyelitis were eliminated because of her lack of fever and normal laboratory test results. Postinfectious myositis could have explained her signs and symptoms. A spinal cord lesion, such as a tumor or epidural empyema, must be considered in this setting.

It is important to recognize not only classic Guillain-Barré syndrome but also its less obvious patterns. Children often improve spontaneously or in response to intravenous immunoglobulin therapy or plasmapheresis, and as is often the case, earlier treatment is generally more effective. There are potentially life-threatening complications of Guillain-Barré syndrome, including respiratory failure and autonomic dysfunction with systemic hypertension or cardiac arrhythmias. These 4 recent articles together provide an excellent overview of both the classic and the atypical manifestations of the syndrome.

Chung A, Deimling M. Guillain Barré syndrome. Pediatr Rev. 2018;39(1):53–54
Bassal F, Lupo P. Case 3: Ophthalmoplegia and Unsteady Gait in an 11-year-old
Boy. Pediatr Rev. 2018 Jan;39(1):39.
Shah S, Diaz-Medina G, Chen J. Unilateral leg pain and difficulty walking. Pediatr Rev. 2018;39(1):36–37
Bashir A, Aarons E. Refusal to walk in a 2-year-old girl. Pediatr Rev. 2018;39(1):38

Vagus nerve stimulation in refractory and super-refractory status epilepticus


Maxine Dibué-Adjeia, Francesco Brigo, Takamichi Yamamoto, Kristl Vonck, Eugen Trinka.  Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review.  Brain Stimulation.  In press.  DOI: https://doi.org/10.1016/j.brs.2019.05.011

Highlights

•A systematic literature review of vagus nerve stimulation used as a last-resort treatment for refractory and super-refractory status epilepticus is performed.
•Cessation of RSE/SRSE occurred in 28 of the 38 cases reported in the literature, however data quality is low and the risk for reporting bias is high.
•VNS was implanted on average 18 days after the start of the SE episode.
•Cessation of the SE episode occurred on average 8 days after VNS implantation.

Abstract

Rationale
Refractory status epilepticus (RSE) is the persistence of status epilepticus despite second-line treatment. Super-refractory SE (SRSE) is characterized by ongoing status despite 48 h of anaesthetic treatment. Due to the high case fatality in RSE of 16–39%, off label treatments without strong evidence of efficacy in RSE are often administered. In single case-reports and small case series totalling 28 patients, acute implantation of VNS in RSE was associated with 76% and 26% success rate in generalized and focal RSE respectively. We performed an updated systematic review of the literature on efficacy of VNS in RSE/SRSE by including all reported patients.

Methods
We systematically searched EMBASE, CENTRAL, Opengre.eu, and ClinicalTrials.gov, and PubMed databases to identify studies reporting the use of VNS for RSE and/or SRSE. We also searched conference abstracts from AES and ILAE meetings.

Results
45 patients were identified in total of which 38 were acute implantations of VNS in RSE/SRSE. Five cases had VNS implantation for epilepsia partialis continua, one for refractory electrical status epilepticus in sleep and one for acute encephalitis with refractory repetitive focal seizures. Acute VNS implantation was associated with cessation of RSE/SRSE in 74% (28/38) of acute cases. Cessation did not occur in 18% (7/38) of cases and four deaths were reported (11%); all of them due to the underlying disease and unlikely related to VNS implantation. Median duration of the RSE/SRSE episode pre and post VNS implantation was 18 days (range: 3–1680 days) and 8 days (range: 3–84 days) respectively. Positive outcomes occurred in 79% (31/38) of cases.

Conclusion
VNS can interrupt RSE and SRSE in 74% of patients; data originate from reported studies classified as level IV and the risk for reporting bias is high. Further prospective studies are warranted to investigate acute VNS in RSE and SRSE.

Courtesy of:  https://www.mdlinx.com/journal-summaries/status-epilepticus-vagus-nerve-stimulation-seizures/2019/05/16/7566945?spec=neurology

Friday, May 17, 2019

Fecal microbiota in ketogenic diet and epilepsy


Inspired by a patient.

We know that our intestines hold over 100 trillion microbes, including approximately 1,000 different species of bacteria. Our own DNA is overwhelmed in a way by the DNA of these bacteria living happily along with us! Probiotics, as well as bacteria in yogurts and other supplements, are very popular nowadays to improve “gut health.” But what does this mean for epilepsy in general and the ketogenic diet in specific?

What have studies found?

Two recent papers have raised awareness and excitement that maybe a part of the ketogenic diet’s mechanism of action may rest in changes in the population of several key bacteria in our intestines.

The first paper from UCLA was published in Cell in June. In mice, it appeared that two bacteria, Akkermansia and Parabacteroides, were important for protection from seizures. These mice did not have seizure control when on the ketogenic diet if they were treated with antibiotics (which would kill these bacteria) or were raised in a germ-free environment. Similarly, putting (transplanting) these bacteria into the intestines of other mice would protect them from seizures. The theory is that GABA (an inhibitory neurotransmitter) goes up when these bacteria are in the gut. These results were presented in a TEDx talk. Of note, a study from 2016 in Molecular Autism from Calgary found that Akkermansia decreased in mice treated with the ketogenic diet (the opposite finding).

In another study published in Epilepsy Research from Fudan University in China, researchers looked at the fecal samples of 20 children treated with the ketogenic diet. Again, there were changes in the gut microbiota, with increased Bacteroidetes and decreased Firmicutes, with perhaps hints of differences in those children who responded to the ketogenic diet. These findings were actually very different from published work from Italy in Clinical Nutrition ESPEN back in February 2017. These authors found NO changes in 6 children with Glut1 Deficiency on the ketogenic diet in amounts of Bacteroidetes and Firmicutes.

How do we interpret these often contradictory results?

Right now, we can say there is growing evidence that the ketogenic diet appears to affect the bacteria in your intestines. Yet, we are not certain if improving bacterial strains that affect seizures or possibly reducing those that could have a negative effect could make a difference. For now, it is too early to change probiotics or try to ingest any bacteria intentionally.

More Study Needed

Absolutely this line of research is fascinating and begs for more studies of children and adults on (and off) ketogenic diets. These studies could help us learn

If there are definite trends in larger numbers of people after many months
What these bacteria may be producing that could affect epilepsy
If changes correlate with seizure control (or may only just show a change based on the foods we eat that isn’t relevant for epilepsy)


Xie G, Zhou Q, Qiu CZ, Dai WK, Wang HP, Li YH, Liao JX, Lu XG, Lin SF, Ye JH, Ma ZY, Wang WJ. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol. 2017 Sep 7;23(33):6164-6171.

Abstract

AIM:
To investigate whether patients with refractory epilepsy and healthy infants differ in gut microbiota (GM), and how ketogenic diet (KD) alters GM.

METHODS:
A total of 14 epileptic and 30 healthy infants were recruited and seizure frequencies were recorded. Stool samples were collected for 16S rDNA sequencing using the Illumina Miseq platform. The composition of GM in each sample was analyzed with MOTHUR, and inter-group comparison was conducted by R software.

RESULTS:
After being on KD treatment for a week, 64% of epileptic infants showed an obvious improvement, with a 50% decrease in seizure frequency. GM structure in epileptic infants (P1 group) differed dramatically from that in healthy infants (Health group). Proteobacteria, which had accumulated significantly in the P1 group, decreased dramatically after KD treatment (P2 group). Cronobacter predominated in the P1 group and remained at a low level both in the Health and P2 groups. Bacteroides increased significantly in the P2 group, in which Prevotella and Bifidobacterium also grew in numbers and kept increasing.

CONCLUSION:
GM pattern in healthy infants differed dramatically from that of the epileptic group. KD could significantly modify symptoms of epilepsy and reshape the GM of epileptic infants.

Zhang Y, Zhou S, Zhou Y, Yu L, Zhang L, Wang Y. Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet. Epilepsy Res. 2018 Sep;145:163-168.

Abstract

OBJECTIVE:
The aim of this study was to investigate the characteristics and composition of intestinal microbiota in children with refractory epilepsy after ketogenic diet (KD) therapy and to explore the bacterial biomarkers related to clinical efficacy.

METHODS:
We prospectively analyzed 20 patients (14 males, 6 females) treated with KD. Clinical efficacy, electroencephalogram (EEG) changes, and laboratory tests were evaluated, and fecal specimens were obtained prior to and 6 months after therapy. The composition of gut microbiota was analyzed by 16S rDNA sequencing, and we screened the possible flora associated with efficacy of the KD.

RESULTS:
After 6 months of treatment, 2 patients were seizure free, 3 had ≥ 90% seizure reduction, 5 had a reduction of 50-89%, and 10 had < 50% reduction. All 10 responders showed an improvement in EEG. Compared with baseline, fecal microbial profiles showed lower alpha diversity after KD therapy and revealed significantly decreased abundance of Firmicutes and increased levels of Bacteroidetes. We also observed that Clostridiales, Ruminococcaceae, Rikenellaceae, Lachnospiraceae, and Alistipes were enriched in the non-responsive group.

CONCLUSIONS:
The results show that the KD can reduce the species richness and diversity of intestinal microbiota. The changes of gut microbiota may be associated with different efficacy after KD, and specific gut microbiota may serve as an efficacy biomarker and a potential therapeutic target in patients with refractory epilepsy.

Tagliabue A, Ferraris C, Uggeri F, Trentani C, Bertoli S, de Giorgis V, Veggiotti P, Elli M. Short-term impact of a classical ketogenic diet on gut microbiota in GLUT1 Deficiency Syndrome: A 3-month prospective observational study. Clin Nutr ESPEN. 2017 Feb;17:33-37.

Abstract

BACKGROUND&AIMS:
The classical ketogenic diet (KD) is a high-fat, very low-carbohydrate normocaloric diet used for drug-resistant epilepsy and Glucose Transporter 1 Deficiency Syndrome (GLUT1 DS). In animal models, high fat diet induces large alterations in microbiota producing deleterious effects on gut health. We carried out a pilot study on patients treated with KD comparing their microbiota composition before and after three months on the diet.

METHODS:
Six patients affected by GLUT1 DS were asked to collect fecal samples before and after three months on the diet. RT - PCR analysis was performed in order to quantify Firmicutes, Bacteroidetes, Bifidobacterium spp., Lactobacillus spp., Clostridium perfringens, Enterobacteriaceae, Clostridium cluster XIV, Desulfovibrio spp. and Faecalibacterium prausnitzii.

RESULTS:
Compared with baseline, there were no statistically significant differences at 3 months in Firmicutes and Bacteroidetes. However fecal microbial profiles revealed a statistically significant increase in Desulfovibrio spp. (p = 0.025), a bacterial group supposed to be involved in the exacerbation of the inflammatory condition of the gut mucosa associated to the consumption of fats of animal origin.

CONCLUSIONS:
A future prospective study on the changes in gut microbiota of all children with epilepsy started on a KD is warranted. In patients with dysbiosis demonstrated by fecal samples, it my be reasonable to consider an empiric trial of pre or probiotics to potentially restore the «ecological balance» of intestinal microbiota.

He Z, Cui BT, Zhang T, Li P, Long CY, Ji GZ, Zhang FM. Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: The first report. World J Gastroenterol. 2017 May 21;23(19):3565-3568.

Abstract

Fecal microbiota transplantation (FMT) is a promising strategy that involves reconstruction of gut microbiota. Recently, it has been considered as a treatment of Crohn's disease (CD) and certain neurological diseases. Here, to the best of our knowledge, we report the first case that used FMT to achieve remission of intestinal and neurological symptoms in a girl with CD and a 17-year history of epilepsy. During the 20 mo of follow-up, FMT has proved its efficacy in preventing relapse of seizures after withdrawing the antiepileptic drugs. Furthermore, this finding highlights the role of microbiota-gut-brain axis and inspires a novel treatment for epilepsy through remodeling gut microbiota.

Thursday, May 16, 2019

Fatigue, depression, and quality of life in children with multiple sclerosis


Florea A, Maurey H, Le Sauter M, Bellesme C, Sevin C, Deiva K. Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases. Dev Med Child Neurol. 2019 Apr 11. doi: 10.1111/dmcn.14242. [Epub ahead of print]

Abstract

AIM:
To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS).

METHOD:
Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation.

RESULTS:
Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007).

INTERPRETATION:
This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal.

WHAT THIS PAPER ADDS:
Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning.


Courtesy of:  https://www.mdlinx.com/journal-summaries/fatigue-depression-quality-of-life-children/2019/04/16/7564088?spec=neurology&rcid=81

Severe anemia associated with intracranial hemorrhage in an infant


Kin LL, Premkumar M. Severe anemia associated with intracranial hemorrhage in an infant [published online May 13, 2019]. Neurology Consultant.

A 5 ½-month-old girl was referred to the pediatric emergency department (ED) by her primary care provider (PCP) for a temperature of 39.2°C. The infant’s mother had taken her to the PCP for evaluation of fever and constipation. The mother said that the infant had felt warm for the past 2 days and had had cough, congestion, and rhinorrhea. The infant had bowel movements once every 2 to 3 days and had been feeding and urinating well.

History. The girl had been born via elective cesarean delivery at 29 weeks of gestation due to decreased fetal movement. Apgar scores were 6 at 1 minute and 8 at 5 minutes. Severe intrauterine growth restriction was noted at birth due to poor placental perfusion and placental calcifications.

She had been admitted to the neonatal intensive care unit (NICU) for 2 months for respiratory distress, during which time multiple sepsis workups were performed and antibiotics administered, but all blood culture results had been negative for bacteria. She also had received 3 transfusions of packed red blood cells (PRBC), epoetin alfa for anemia of prematurity, phototherapy for jaundice, and ursodiol for cholestasis.

Ultrasonography of the head done while in the NICU had shown an intraparenchymal bleed of 1.5 cm in the right occipitoparietal area, with no ventriculomegaly or midline shift. Follow-up head sonograms and magnetic resonance imaging without contrast of the brain after discharge from the NICU had shown resolution of the bleed. She also had had a left inguinal hernia repair at 3 months of age with no complications or bleeding problems.

Physical examination. At the current presentation, her temperature was 39.1°C, heart rate was 166 beats/min, respiratory rate was 48 breaths/min, and oxygen saturation was 95%. General physical examination revealed a very pale infant who was awake and not in acute distress. Her anterior fontanel was open, and sutures splayed. S1 and S2 heart sounds were present but with no murmur; capillary refill was less than 2 seconds. She had normal tone and equal power in all limbs, and no cranial nerve deficits were noted.

Diagnostic tests. Results of a complete blood cell count showed that the hemoglobin level was only 5.6 g/dL (reference range, 12-16 g/dL) and the platelet count was 341 × 103/µL. The white blood cell count was normal. Subsequent repeated hemoglobin levels were 5 g/dL and then 4.6 g/dL. After consultation with a pediatric hematologist, the patient was admitted to the pediatric unit for observation and for repeated hemoglobin tests, a parvovirus panel, and monitoring of epoetin alfa levels. Blood type and cross-match testing was done, and PRBC transfusion was initiated. Blood and urine culture results were negative for bacteria.

Because of the significant fever and anemia and the patient’s history of an intracranial bleed at birth, head ultrasonography was done, which showed a large, right-sided, extra-axial hematoma overlying the temporal, parietal, and likely occipital lobes. The hematoma appeared lentiform on coronal images, although the distribution on sagittal images suggested blood in the subdural space rather than the epidural space. Intraventricular hemorrhage was noted in the right lateral ventricle with a 3-mm midline shift from right to left at the foramen of Monro

Computed tomography (CT) of the head without contrast showed a large, right-sided epidural hematoma overlying the frontal, temporal, and parietal lobes with mass effect and midline shift from right to left.

Upon further questioning, the mother reported retrospectively that the girl had a history of a fall 5 days prior to presentation. There had been no loss of consciousness, vomiting, or abnormal movements. The mother said that she had called and informed the PCP, who advised her to observe the infant and to take her to the ED if there were any changes in mental status, vomiting, or seizures.

The patient was intubated to protect the airway and was transported to the neurosurgical unit at the tertiary hospital, where she underwent evacuation of the hematoma, which was subdural according to the operative report. She was discharged home in stable condition.

The presence of fever and anemia are common in patients with intracranial hemorrhage. Anemia is present in up to 25% of cases at admission and is associated with larger hematoma volumes. PRBC transfusion in these patients has been found to be associated with improved survival, although the ideal target hemoglobin level has not been determined...

Our patient, who had multiple medical problems including anemia of prematurity, was admitted for evaluation of a fever and severe anemia. A severe drop in the hemoglobin level, as in this patient’s case, should prompt clinicians to look for serious potential causes. Moreover, not all lentiform intracranial hemorrhages are epidural hemorrhages. Our patient had an acute subdural bleed and was clinically stable initially, but she had a progressive drop in hemoglobin due to a massive subdural hemorrhage causing midline shift.

Cannabinoids and autism


Yamasue H, Aran A, Berry-Kravis E. Emerging pharmacological therapies in fragile X syndrome and autism. Curr Opin Neurol. 2019 Apr 30. doi:10.1097/WCO.0000000000000703. [Epub ahead of print]

Abstract

PURPOSE OF REVIEW:
Research on the pathophysiology of syndromic autism spectrum disorder (ASD) has contributed to the uncovering of mechanisms in nonsyndromic ASD. The current review aims to compare recent progress in therapeutics development for ASD with those for fragile X syndrome (FXS), the most frequent monogenic form of ASD.

RECENT FINDINGS:
Although candidates such as oxytocin, vasopressin, and cannabinoids are being tested as novel therapeutics, it remains difficult to focus on a specific molecular target of drug development for ASD core symptoms. As the pathophysiology of FXS has been well described as having a causal gene, fragile X mental retardation-1, development of therapeutic agents for FXS is focused on specific molecular targets, such as metabotropic glutamate receptor 5 and GABAB receptor.

SUMMARY:
There is a large unmet medical need in ASD, a heterogeneous and clinically defined behavioral syndrome, owing to its high prevalence in the general population, lifelong cognitive and behavioral deficits, and no established treatment of ASD core symptoms, such as deficits in social communication and restrictive repetitive behaviors. The molecular pathogenesis of nonsyndromic ASD is largely undefined. Lessons from initial attempts at targeted treatment development in FXS, and new designs resulting from these lessons, will inform trials in nonsyndromic ASD for development of therapeutics for its core symptoms.

Aran A, Eylon M, Harel M, Polianski L, Nemirovski A, Tepper S, Schnapp A, Cassuto H, Wattad N, Tam J. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Mol Autism. 2019 Jan 30;10:2.

Abstract

BACKGROUND:
The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet.

METHODS:
Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2).

RESULTS:
Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons.

CONCLUSIONS:
We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid "tone" in the brain, as found in animal models of ASD.

Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2019 Mar;49(3):1284-1288.

Abstract

Anecdotal evidence of successful cannabis treatment in autism spectrum disorder (ASD) are accumulating but clinical studies are lacking. This retrospective study assessed tolerability and efficacy of cannabidiol-rich cannabis, in 60 children with ASD and severe behavioral problems (age = 11.8 ± 3.5, range 5.0-17.5; 77% low functioning; 83% boys). Efficacy was assessed using the Caregiver Global Impression of Change scale. Adverse events included sleep disturbances (14%) irritability (9%) and loss of appetite (9%). One girl who used higher tetrahydrocannabinol had a transient serious psychotic event which required treatment with an antipsychotic. Following the cannabis treatment, behavioral outbreaks were much improved or very much improved in 61% of patients. This preliminary study supports feasibility of CBD-based cannabis trials in children with ASD.