Towards a neurophysiological signature for fibromyalgia

López-Solà M, Woo CW, Pujol J, Deus J, Harrison BJ, Monfort J, Wager TD. Towards a neurophysiological signature for fibromyalgia. Pain. 2017 Jan;158(1):34-47.

Abstract

Patients with fibromyalgia (FM) show characteristically enhanced unpleasantness to painful and nonpainful sensations accompanied by altered neural responses. The diagnostic potential of such neural alterations, including their sensitivity and specificity to FM (vs healthy controls) is unknown. We identify a brain signature that characterizes FM central pathophysiology at the neural systems level. We included 37 patients with FM and 35 matched healthy controls, and analyzed functional magnetic resonance imaging responses to (1) painful pressure and (2) nonpainful multisensory (visual-auditory-tactile) stimulation. We used machine-learning techniques to identify a brain-based FM signature. When exposed to the same painful stimuli, patients with FM showed greater neurologic pain signature (NPS; Wager et al., 2013. An fMRI-based neurologic signature of physical pain. N Engl J Med 2013;368:1388-97) responses. In addition, a new pain-related classifier ("FM-pain") revealed augmented responses in sensory integration (insula/operculum) and self-referential (eg, medial prefrontal) regions in FM and reduced responses in the lateral frontal cortex. A "multisensory" classifier trained on nonpainful sensory stimulation revealed augmented responses in the insula/operculum, posterior cingulate, and medial prefrontal regions and reduced responses in the primary/secondary sensory cortices, basal ganglia, and cerebellum. Combined activity in the NPS, FM pain, and multisensory patterns classified patients vs controls with 92% sensitivity and 94% specificity in out-of-sample individuals. Enhanced NPS responses partly mediated mechanical hypersensitivity and correlated with depression and disability (Puncorrected < 0.05); FM-pain and multisensory responses correlated with clinical pain (Puncorrected < 0.05). The study provides initial characterization of individual patients with FM based on pathophysiological, symptom-related brain features. If replicated, these brain features may constitute objective neural targets for therapeutic interventions. The results establish a framework for assessing therapeutic mechanisms and predicting treatment response at the individual level.

Underdosing of lorazepam in children is associated with increased seizure duration

The first dose of lorazepam, when administered as a first-line antiepileptic drug (AED) for pediatric refractory status epilepticus, frequently is underdosed, and doses lower than 0.1 mg/kg are associated with increased seizure duration, according to research presented at the 70th Annual Meeting of the American Epilepsy Society (AES).

The results emphasize the importance of following AES status epilepticus guidelines, which call for lorazepam dosing of 0.1 mg/kg, said Dmitry Tchapyjnikov, MD, of Duke University School of Medicine in Durham, North Carolina, and colleagues.

“There is high variability in lorazepam dosing when used in the treatment of status epilepticus, but little is known about how this dosing variability affects seizure duration,” the researchers said. The investigators analyzed data from a multicenter prospective observational cohort of pediatric patients admitted with refractory status epilepticus (ie, status epilepticus did not resolve after two or more AEDs) between 2011 and 2016. The data were compiled by the Pediatric Status Epilepticus Research Group.

Researchers grouped patients by those who received a lower dose ( < 0.05 mg/kg), medium dose (0.05 mg/kg to < 0.1 mg/kg), and higher dose ( ≥ 0.1 mg/kg) of lorazepam. They used Cox proportional hazards models to assess the association between lorazepam dose and time to seizure resolution, adjusting for age, sex, presumed seizure cause, seizure duration prior to lorazepam administration, home AED use, prior neurologic conditions, and study site.

A total of 103 patients were included in the analysis. Patients had a median age of 4.5, and 48% were female. Lorazepam was administered at a median of 20 minutes after seizure onset. Twenty-eight percent of patients received a lower dose, 43% a medium dose, and 29% a higher dose. Individuals in the higher dose group were significantly more likely to experience seizure resolution sooner than patients in the medium and lower dose groups, with hazard ratios of 1.62 and 2.49, respectively. Median time to total seizure resolution following lorazepam administration was 93 minutes in the higher dose group, 160 minutes in the medium dose group, and 350 minutes in the lower dose group.

Among patients who had convulsive seizures, those in the higher dose group were more likely to experience convulsive seizure resolution sooner than those in the lower dose group (hazard ratio, 1.89). Median time to convulsive seizure resolution was 67 minutes in the higher dose group and 120 minutes in the lower dose group.

http://www.mdedge.com/neurologyreviews/article/130405/epilepsy-seizures/underdosing-lorazepam-children-associated

Spinocerebellar ataxia type 13

Pulst SM. Spinocerebellar Ataxia Type 13. 2006 Nov 9 [updated 2012 Mar 1]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

Excerpt

CLINICAL CHARACTERISTICS:

In the families described to date, the phenotype of spinocerebellar ataxia type 13 (SCA13) has ranged from slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria and often accompanied by mild intellectual disability and occasional seizures to adult-onset progressive ataxia. Life span is not shortened and many persons live beyond age 70 years, but assistance with gait may be required as the disease progresses.

DIAGNOSIS/TESTING:

Diagnosis is based on clinical findings and molecular genetic testing of KCNC3 (also known as Kv3.3), the only gene known to be associated with SCA13.

MANAGEMENT:

Treatment of manifestations: Antiepileptic drugs for seizures; canes, walkers and other adaptive devices to help prevent falls; speech therapy and communication devices; feeding assessment if dysphagia is present. Prevention of secondary complications: Weight control. Surveillance: Evaluation by a neurologist at least annually, and more often in the event of acute exacerbation. Agents/circumstances to avoid: Alcohol and sedating drugs because they can exacerbate ataxia.

GENETIC COUNSELING:

SCA13 is inherited in an autosomal dominant manner. Too little data are available to estimate the proportion of cases resulting from a new pathogenic variant. Each child of an individual with SCA13 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for SCA13 is possible if the pathogenic variant in the family is known.

Gallego-Iradi C, Bickford JS, Khare S, Hall A, Nick JA, Salmasinia D, Wawrowsky K, Bannykh S, Huynh DP, Rincon-Limas DE, Pulst SM, Nick HS, Fernandez-Funez P, Waters MF. KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. Neurobiol Dis. 2014 Nov;71:270-9.

Abstract

Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.

Waters MF, Pulst SM. Sca13. Cerebellum. 2008;7(2):165-9.

Abstract

Spinocerebellar ataxia 13 (SCA13), initially described in a four-generation French family, has now also been characterized in a large Filipino pedigree. Ongoing investigations continue to identify additional SCA13 families and individuals. Recently, studies have shown that mutations in the voltage-gated potassium channel KCNC3 are causative for SCA13. Sequence analysis of KCNC3 revealed mutations 1554G-->A (R420H) in the Filipino and 1639C-->A (F448L) in the French pedigrees. Both mutations alter KCNC3 function in a Xenopus laevis oocyte expression system. KCNC3(R420H), located in the voltage sensor of the channel, has no detectable channel activity when expressed alone, and strong dominant negative effects when coexpressed with wild-type KCNC3. KCNC3(F448L) shifts the activation curve in the negative direction and causes an approximately sevenfold slowing of channel closure. These mutations are expected to change the output characteristics of fast-spiking cerebellar neurons, where KCNC channels confer capacity for high-frequency repetitive firing.

Herman-Bert A, Stevanin G, Netter JC, Rascol O, Brassat D, Calvas P, Camuzat

A, Yuan Q, Schalling M, Dürr A, Brice A. Mapping of spinocerebellar ataxia 13 to

chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia

and mental retardation. Am J Hum Genet. 2000 Jul;67(1):229-35.

Abstract

We examined a large French family with autosomal dominant cerebellar ataxia (ADCA) that was excluded from all previously identified spinocerebellar ataxia genes and loci. The patients-seven women and a 4-year-old boy-exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ 62-76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some cases. This unique association of clinical features clearly distinguishes this new entity from other previously described ADCA. Cerebral magnetic-resonance imaging showed moderate cerebellar and pontine atrophy in two patients. We performed a genomewide search and found significant evidence for linkage to chromosome 19q13.3-q13.4, in an approximately 8-cM interval between markers D19S219 and D19S553.

See:  http://childnervoussystem.blogspot.com/2016/08/genetic-teasers.html#comment-form 

A cannabidiol potpourri

Cannabidiol (CBD) interacts significantly with clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine, researchers said at the 70th Annual Meeting of the American Epilepsy Society. The study results underscore the importance of monitoring levels of antiepileptic drugs (AEDs) during treatment with CBD. “In the future, these data will need to be correlated with reported side effects or laboratory abnormalities to determine whether they are clinically significant,” said Jerzy P. Szaflarski, MD, PhD, Director of the University of Alabama at Birmingham Epilepsy Center.

Dr. Szaflarski and colleagues monitored serum AED levels during active titration of pharmaceutical grade CBD in patients with refractory epilepsy who were enrolled in an open-label safety study. The study was intended to investigate CBD as a potential adjunctive therapy. As part of the study protocol, researchers checked serum AED levels frequently to identify interactions between CBD and AEDs. Based on previous data and anecdotal observations, Dr. Szaflarski and colleagues hypothesized that they would find interactions between CBD and clobazam and valproate.

Participants received an initial CBD dose of 5 mg/kg/day. The dose was increased by 5 mg/kg/day every two weeks, provided that tolerability was maintained, to a maximum of 50 mg/kg/day. Baseline AED levels were drawn, and AEDs were required to have been at a stable dose for one month before enrollment. The researchers obtained AED levels at almost all study visits during dose titration and maintenance. AED doses were adjusted at the investigators’ discretion if an adverse effect, laboratory abnormality, or drug level change was considered related to a potential interaction between CBD and the AED. The researchers frequently adjusted doses of clobazam and valproate because of complaints of sedation and alteration in liver function tests, respectively. At the time of Dr. Szaflarski’s analysis, 81 participants were enrolled in the study (39 adults and 42 children). There were sufficient data to analyze potential interactions between CBD and 19 AEDs.

The researchers found increases in serum levels of topiramate, rufinamide, and desmethylclobazam (an active metabolite of clobazam), and a decrease in levels of clobazam, with increasing CBD dose in the pediatric and adult arms. In addition, they noted significant increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose in the adult arm. Dr. Szaflarski and colleagues observed no significant interactions between CBD and the other AEDs investigated, which included valproate, levetiracetam, lacosamide, and perampanel.

http://www.mdedge.com/neurologyreviews/article/128497/epilepsy-seizures/how-does-cannabidiol-interact-antiepileptic-drugs

Pharmaceutical-grade cannabidiol (CBD) may reduce seizure severity in adults and children with medically refractory epilepsy, according to an open-label trial described at the 70th Annual Meeting of the American Epilepsy Society. A controlled trial to confirm the drug’s effect may be warranted.

Jennifer L. DeWolfe, DO, Associate Professor of Neurology at the University of Alabama at Birmingham, and colleagues conducted a state-sponsored compassionate-use study of CBD in patients with refractory epilepsy. Patients received Epidiolex (a CBD formulation developed by GW Pharmaceuticals) in addition to their antiepileptic drugs. Eligible participants were adults and children with epilepsy confirmed by video EEG. Participants were required to have failed four antiepileptic drugs and had to have had four countable seizures per month. Exclusion criteria included psychogenic nonepileptic seizures confirmed by video EEG and prior CBD use.

The investigators measured participants’ seizure frequency and used the Chalfont Seizure Severity Scale to measure seizure severity. The scale solicits information about various factors, such as whether the patient lost awareness, dropped an object, fell, or was injured. The total possible score on the scale is 178, and the score increases with seizure severity. Changes of 10 or more points were considered significant. The researchers particularly focused on participants’ most frequent seizure type, which the Chalfont Seizure Severity Scale names the Type 1 seizure.

Dr. DeWolfe and colleagues measured patients’ total seizure severity scores and severity scores for Type 1 seizures at baseline, three months, and six months. To compare the scores, the researchers calculated time-weighted average values. They also examined percent change in seizures; seizure severity in adults, children, and all patients; and severity in responders and nonresponders. Responders were defined as patients who had a reduction in seizure frequency of more than 50%. The analysis included 81 participants, approximately half of whom were children. At the time of the analysis, 57 patients had undergone evaluation at three months, and 47 patients had undergone evaluation at six months. At baseline, the majority of patients had at least two types of seizures.

The total change in Chalfont Seizure Severity Scale score at three months was significant for adults, children, and all patients. The change remained significant at six months. The difference in the percent change in seizure severity between responders and nonresponders was significant at three months, but not at six months.

The change in severity of Type 1 seizures was significant for adults, children, and all patients at three months and at six months. The difference between responders and nonresponders in change in severity of Type 1 seizures was significant at three months, but not at six months.

At three months, the majority of adults, the majority of all patients, the majority of responders, and the majority of nonresponders had a reduction in seizure severity of at least 10 points. Approximately one-third of children had a reduction in seizure severity of at least 10 points at three months. At six months, the majority of adults, children, all patients, responders, and nonresponders had a decrease in seizure severity of at least 10 points. Patients’ average seizure severity tended to increase at six months, compared with the three-month point, but was still significantly lower than at baseline.

“One of the things I find most exciting is [that] … even if you were considered a nonresponder, you still had improvement in seizure severity,” said Dr. DeWolfe. She and her colleagues plan to examine the data by seizure type (eg, absence or tonic-clonic), to identify which factors measured by the Chalfont Seizure Severity Scale contributed most to the reductions in seizure severity, and to examine whether the effect of CBD on levels of antiepileptic drugs contributed to the change in seizure severity. The findings of this open-label trial suggest that CBD may improve seizure severity in people with medically refractory epilepsy. Randomized placebo-controlled studies are needed to further evaluate the effects of CBD on seizure severity.

http://www.mdedge.com/neurologyreviews/article/130151/epilepsy-seizures/does-cannabidiol-affect-seizure-severity 

Iron-sulfur cluster assembly gene potpourri

Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, Almass R, Al-Harazi OS, Al-Hindi H, Malibari OI, Almutari FB, Tulbah S, Alhadeq F, Al-Sheddi T, Alamro R, AlAsmari A, Almuntashri M, Alshaalan H, Al-Mohanna FA, Colak D, Kaya N. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet. 2015 Mar;52(3):186-94.

Abstract

BACKGROUND:

There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families.

METHODS:

Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients.

RESULTS:

We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres.

CONCLUSIONS:

Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

_________________________________________________________________________

Debray FG, Stümpfig C, Vanlander AV, Dideberg V, Josse C, Caberg JH, Boemer F, Bours V, Stevens R, Seneca S, Smet J, Lill R, van Coster R. Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. J Inherit Metab Dis. 2015 Nov;38(6):1147-53.

Abstract

Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters.

Ajit Bolar N, Vanlander AV, Wilbrecht C, Van der Aa N, Smet J, De Paepe B, Vandeweyer G, Kooy F, Eyskens F, De Latter E, Delanghe G, Govaert P, Leroy JG, Loeys B, Lill R, Van Laer L, Van Coster R. Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. Hum Mol Genet. 2013 Jul 1;22(13):2590-602.
_______________________________________________________________________

Abstract

Two siblings from consanguineous parents died perinatally with a condition characterized by generalized hypotonia, respiratory insufficiency, arthrogryposis, microcephaly, congenital brain malformations and hyperglycinemia. Catalytic activities of the mitochondrial respiratory complexes I and II were deficient in skeletal muscle, a finding suggestive of an inborn error in mitochondrial biogenesis. Homozygosity mapping identified IBA57 located in the largest homozygous region on chromosome 1 as a culprit candidate gene. IBA57 is known to be involved in the biosynthesis of mitochondrial [4Fe-4S] proteins. Sequence analysis of IBA57 revealed the homozygous mutation c.941A > C, p.Gln314Pro. Severely decreased amounts of IBA57 protein were observed in skeletal muscle and cultured skin fibroblasts from the affected subjects. HeLa cells depleted of IBA57 showed biochemical defects resembling the ones found in patient-derived cells, including a decrease in various mitochondrial [4Fe-4S] proteins and in proteins covalently linked to lipoic acid (LA), a cofactor produced by the [4Fe-4S] protein LA synthase. The defects could be complemented by wild-type IBA57 and partially by mutant IBA57. As a result of the mutation, IBA57 protein was excessively degraded, an effect ameliorated by protease inhibitors. Hence, we propose that the mutation leads to partial functional impairment of IBA57, yet the major pathogenic impact is due to its proteolytic degradation below physiologically critical levels. In conclusion, the ensuing lethal complex biochemical phenotype of a novel metabolic syndrome results from multiple Fe/S protein defects caused by a deficiency in the Fe/S cluster assembly protein IBA57.

Dopey, a seizure response dog

It’s before the crack of dawn. The grass is crunchy with frost and the small brick house is the only one with its porch lights on, casting an eerie glow on the sidewalk.

Britton Voss, a skinny 12-year-old with a shuffle in his step, boards the bus.

A wavy-haired golden retriever boards with him. He is Dopey — Britton’s seizure response dog.

Britton, an energetic boy who loves hugs and Star Wars, has a rare form of epilepsy that causes seizures and developmental delays. As a service dog, Dopey is trained to help Britton by comforting him, fetching medicine or even calling 911 while he’s seizing.

But Dopey also has another ability — one that has baffled scientists and brought the staff at Britton’s school to tears.

Dopey appears to be able to predict Britton’s seizures, often hours before they actually happen.

“You hear about man’s best friend, but there’s something beyond special about the bond between a service animal and who they’re loving and providing for," said Sunset Junior High special education teacher Melissa Lovell.

“Dopey is an extension of (Britton),” she added. “That’s his whole world. That’s his life source.”

At home or at school, at day or at night, as soon as the vest is on, boy and dog are one. 

Lovell was stunned the first time Dopey gave her an “alert.”

A quiet soul with velvety ears and “chocolate chips for eyes,” in the words of one of Lovell’s students, Dopey spends the vast majority of his days laying quietly at Britton’s side.

One day about two months ago, however, he began panting, licking and nudging Lovell’s pregnant belly, more agitated than she had ever seen him.

About an hour later, Britton began seizing.

"I looked at (my lead aide), and we just both looked at each other like … 'That is unbelievable,’” Lovell said.

They have a process for seizure alerts now. Lovell clears the other students from the room, places Britton in a safe position on his beanbag and make sure she has the medication she needs in case she needs to intervene.

For the most part, there’s little they can do besides allow the seizure to happen and make sure Britton is safe.

Once Britton starts seizing, Dopey will lick his face until he "comes out" of the seizure, Lovell says. Afterward, Dopey usually cuddles Britton as he naps.

"When you actually witness and see the whole thing from alert to the end of the seizure, it's almost difficult to describe," Lovell said. "You don't want to use the term beautiful for something like that, but to see an animal actually communicate with you and then take a kid out of a seizure ...”

"It was unbelievable," she continued. "You wouldn't even believe it if you didn't see the whole thing from beginning to end."

But that wasn’t the first time Dopey detected a seizure in class.

Months before he ever detected one of Britton’s, Dopey started picking up on another student in Lovell’s class — one who has even more frequent seizures than Britton.

Dopey has predicted seizures in that student more than 10 times, according to Lovell.

Britton's mom, Dawn Voss, said Dopey has never given a false positive, either at home or at school.

"He's their little guardian angel, I guess you could say," Voss said. "They're his boys to watch over."  

Sunset Junior High Assistant Principal Matt Christensen said administrators were initially "apprehensive" about having a service dog in a classroom.

Although not unheard of, service dogs for students as young as Britton are not common.

"Once we saw how effective Dopey is at helping not only Britton but the other student, there's no question the dog has been a huge help," Christensen said.

Dopey has been an asset for the entire class, which is a functional skills class for students with moderate to severe disabilities.

"If somebody's having an issue or behavior ... I will say, 'Just look at the dog. Everything's OK,'” Lovell said. “His presence in the room is enough to bring some of our students down — and that is a fact."

Lovell, who is 36 weeks pregnant, jokes that Dopey will alert her that she’s going into labor before she feels the first contraction.

But there’s no doubt that Dopey's No. 1 mission is Britton. Dopey, the gentle guardian and constant companion, rarely takes his eyes off of the boy.

If Britton goes to the bathroom, Dopey goes too.

If Dopey needs to go potty, there goes Britton.

They are together from the moment they board the bus until school ends around 2:55 p.m., and they are together at night, sleeping together in a bedroom filled with Star Wars posters.

"Thank God for Dopey," Lovell said. "It really truly is like having another member of the team."

Voss said she used to worry about Britton getting bullied.

Because children with Dravet's syndrome have a significantly higher risk of Sudden Unexplained Death in Epilepsy (SUDEP) — which often happens at night — she also worried every time she tucked him in for bed.

Now, knowing that Dopey is by Britton’s side “gives me a sense of comfort, especially at night when he’s sleeping,” Voss said. “Now, it doesn’t bother me."

There’s no objective evidence that dogs can reliably predict seizures.

The organization that trained Dopey, Noelle's Dogs Four Hope in Colorado Springs, emphasizes that research does not support claims that dogs can be trained to detect oncoming seizures.

The ability appears to be innate to some dogs, especially those that have a strong bond with their owners or handlers, said president Christopher Smith.

Some people theorize that dogs may be able to smell chemical changes in people or detect slight behavioral changes invisible to human eye.

Smith says trainers pick puppies based on their temperament and personality. After eight months of basic obedience training, they begin teaching them how to help their handlers during seizures. Dopey, for example, is trained to block Britton from wandering out of doorways or down stairs while he’s disoriented, so he doesn’t hurt himself.

A lover of data, Lovell has looked into the science of seizure alert dogs herself. But she couldn’t find any scientific proof that dogs can alert to seizures.

The only explanation she has, Lovell says, is “faith.”

"He’s beyond a companion. He's beyond a friend. He's beyond a lifesaver. He's an angel.”

http://www.deseretnews.com/article/865669915/Boys-best-friend-Dog-is-guardian-angel-for-Sunset-classroom.html?clear_cache=1

Also:  http://www.foxnews.com/health/2017/01/30/boys-golden-retriever-can-detect-his-seizures-hours-in-advance.html

Adolescent cannabis use, change in neurocognitive function, and high-school graduation

Castellanos-Ryan N, Pingault JB, Parent S, Vitaro F, Tremblay RE, Séguin JR. Adolescent cannabis use, change in neurocognitive function, and high-school graduation: A longitudinal study from early adolescence to young adulthood. Dev Psychopathol. 2016 Dec 29:1-14.

Abstract

The main objective of this prospective longitudinal study was to investigate bidirectional associations between adolescent cannabis use (CU) and neurocognitive performance in a community sample of 294 young men from ages 13 to 20 years. The results showed that in early adolescence, and prior to initiation to CU, poor short-term and working memory, but high verbal IQ, were associated with earlier age of onset of CU. In turn, age of CU onset and CU frequency across adolescence were associated with (a) specific neurocognitive decline in verbal IQ and executive function tasks tapping trial and error learning and reward processing by early adulthood and (b) lower rates of high-school graduation. The association between CU onset and change in neurocognitive function, however, was found to be accounted for by CU frequency. Whereas the link between CU frequency across adolescence and change in verbal IQ was explained (mediated) by high school graduation, the link between CU frequency and tasks tapping trial and error learning were independent from high school graduation, concurrent cannabis and other substance use, adolescent alcohol use, and externalizing behaviors. Findings support prevention efforts aimed at delaying onset and reducing frequency of CU.

___________________________________________________________________________

Using a community sample of young men ages 13 to 20, the researchers looked a variety of cognitive measurements to undercover potential differences between those who used marijuana and those who did not.

From 1991 and 1998, the participants completed cognitive tests at ages 13, 14, and 20. They also answered questionnaires at ages 13, 14, 16, 17, and 20. Of the 294 participants, 43% had used pot at some point during the study period—most reported that it was only a few times a year. Results showed that 51% of participants had used marijuana by age 20.

The young men who started using marijuana early typically already had poor short-term memory and working memory, such as remembering a phone number after it was given. They were more likely to drop out of high school than non-smokers. However, these early pot users typically had good verbal skills and vocabulary. Lead author, Natalie Castellanos-Ryan, PhD, hypothesized that these results could have developed as the students found ways to get possession of drugs.

Smoking at the age of 17 or older appeared to have less risk. “We found that adolescents who started using cannabis at 17 or older performed equally well as adolescents who did not use cannabis,” explained Castellanos-Ryan, an assistant professor at UdeM’s [Université de Montréal]School of Psychoeducation.

Difficulties in both verbal and cognitive abilities emerged later in life for those who smoked during adolescence. These problems occurred sooner in those who started smoking pot earlier, as described in the journal article in Development and Psychopathology. 

“The results of this study suggest that the effects of cannabis use on verbal intelligence are explained not by neurotoxic effects on the brain, but rather by a possible social mechanism: Adolescents who use cannabis are less likely to attend school and graduate, which may then have an impact on the opportunities to further develop verbal intelligence,” Castellanos-Ryan continued. 

Marijuana can hurt teenagers cognitively, and is linked to increased dropout rates; so what’s the solution? 

Castellanos-Ryan said that when talking to adolescents about pot, it’s important to avoid exaggerating negative effects. Instead, she says to encourage a delay in smoking. “We can’t tell children, ‘If you smoke cannabis you’re going to damage your brain massively and ruin your life,’” Castellanos-Ryan explained. “We have to be realistic and say, ‘We are finding evidence that there are some negative effects related to cannabis use, especially if you start early, and so, if you can hold off as long as you can – at least until you’re 17 – then it’s less likely there’ll be an impact on your brain.” 

Next up in this research is seeing if the results are replicated in other population samples. Castellanos-Ryan also wants to examine cannabis’ influence on drug abuse and other issues later in life. 

The study, “Adolescent cannabis use, change in neurocognitive function, and high-school graduation: A longitudinal study from early adolescence to young adulthood,” was published in Development and Psychopathology. The news release was provided by UdeM.

- See more at: http://www.mdmag.com/medical-news/hold-off-on-pot-before-age-17-study-says/P-2#sthash.NQQBAtkd.dpuf

NeuroGum

NeuroGum is a sugar-free, nootropic energy gum. Nootropics are a class of compounds that improve one or more aspects of mental function such as working memory, motivation, and attention. NeuroGum uses ingredients shown to give your brain the boost it needs to function at its best. The first gum to utilize the effectiveness of nootropics along with natural ingredients scientifically proven to enhance cognition, NeuroGum helps unlock your potential by delivering ingredients that improve concentration, alertness, memory and overall cognition. All of this in a tasty gum that's aspartame free.

NeuroGum was introduced on the Dr. Oz show earlier this year. Rumor has it that a close friend let Dr. Oz try NeuroGum when OZ complained of being tired. The doctor has been hooked ever since. Dr. Oz has been known to film four episodes in one day! The doctor has been heard crediting his ability to deal with his long and strenuous production schedule to chewing NeuroGum regularly. It's no surprise that NeuroGum was featured on the Dr. Oz show. NeuroGum gives the doctor just the right amount of energy without the crash to take on the toughest of days…

The synergy of NeuroGum’s primary ingredients , caffeine, L-theanine, vitamin B6, and vitamin B12 have been studied extensively through a number of clinical experiments to show positive results in the treatment of post-stroke aphasia, epilepsy, cognitive decline following heart and brain surgery, depression, dementia, and a list of other cognitive concerns.

The key to this gums amazing results is the interaction between L-theanine and caffeine. L-theanine, a natural constituent in green tea, has been used for treating anxiety, high blood pressure, possibly preventing Alzheimer’s disease, and making cancer drugs more effective. It has a chemical structure very similar to glutamate, a naturally occurring amino acid in the body that helps transmit nerve impulses in the brain. The combination of this amazing formula is what gives users that “conquer the world” feeling” says Dr. Steven Green, a neurologist.”This gum is truly unique in what it offers in terms of unlocking our untapped human potential.” Says Dr. Green “This winning combination sends your senses into over drive and gives you the focus and alertness you need to take on your days biggest challenges.”…

You might be a little skeptical about the results of NeuroGum, like I was. The results are very real: thousands of people have tried NeuroGum and countless published clinical studies report the beneficial effects of Nootropics as well as the main active ingredients in NeuroGum. I’m going to continue to chew NeuroGum to help me get through my day. It's helped me cut back on coffee drinking and the focus I now have is unreal , this gum really works. You can simply pop a gum in the morning and superman your way through the day, that’s nuts! If you add in the fact that it help you in the gym and with appetite suppression, don't be surprised if you lose a couple pounds even if your not trying to. I encourage you to try NeuroGum whether you need more energy or just want an extra edge, you will experience instant results.  

Good luck with your own brain hack!

http://livefitforless.com/neurogum/?pubid=100755&subid=&clickid=108201523380&cid=14299

See:  http://childnervoussystem.blogspot.com/2015/10/off-to-see-wizard-2.html
http://childnervoussystem.blogspot.com/2015/04/off-to-see-wizard.html

Transcranial direct current stimulation for children with perinatal stroke and hemiparesis

Kirton A, Ciechanski P, Zewdie E, Andersen J, Nettel-Aguirre A, Carlson H, Carsolio L, Herrero M, Quigley J, Mineyko A, Hodge J, Hill M. Transcranial direct current stimulation for children with perinatal stroke and hemiparesis. Neurology. 2017 Jan 17;88(3):259-267.

Abstract

OBJECTIVE:

To determine whether the addition of transcranial direct current stimulation (tDCS) to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy.

METHODS:

This was a randomized, controlled, double-blind clinical trial. Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, age of 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention to treat.

RESULTS:

Twenty-four participants were randomized (median age 11.8 ± 2.7 years, range 6.7-17.8). COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001). COPM scores increased more with tDCS compared to sham control (p = 0.004). AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well tolerated with no decrease in either arm function or serious adverse events.

CONCLUSION:

tDCS trials appear feasible and safe in hemiparetic children. Lack of change in objective motor function may reflect underdosing of therapy. Marked gains in subjective function with tDCS warrant further study.

CLINICALTRIALSGOV IDENTIFIER:  NCT02170285.

CLASSIFICATION OF EVIDENCE:

This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.

Neonatal vitamin D and multiple sclerosis risk

Nielsen NM, Munger KL, Koch-Henriksen N, Hougaard DM, Magyari M, Jørgensen KT, Lundqvist M, Simonsen J, Jess T, Cohen A, Stenager E, Ascherio A. Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology. 2017 Jan 3;88(1):44-51.

Abstract

OBJECTIVE:

As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.

METHODS:

We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1-2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.

RESULTS:

We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36-0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57-0.84).

CONCLUSION:

Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.

Editorial:  Marrie RA, Daumer M. A gestational dose of vitamin D per day keeps the MS doctor away. Neurology. 2017 Jan 3;88(1):13-14.

Endovascular therapy in pediatric stroke

Jenny L. Wilson, Carl O. Eriksson,  Cydni N. Williams.  Endovascular therapy in pediatric stroke: utilization, patient characteristics, and outcomes.  Pediatric Neurology.  In press.

Abstract

Background and Purpose

Despite strong evidence for endovascular therapy in adults with acute arterial ischemic stroke, limited data exists in children. We aimed to describe endovascular therapy utilization and explore outcomes in a national sample of pediatric arterial ischemic stroke.

Methods

We queried the 2012 Kids’ Inpatient Database for children aged >28 days to 20 years with ICD-9-CM codes for arterial ischemic stroke and evaluated groups based on procedure code for endovascular therapy. Poor outcome was defined as need for tracheostomy or gastrostomy, discharge to rehabilitation facility, or death. Logistic regression evaluated the association between endovascular therapy and poor outcome, adjusted for age, disease severity (hemiplegia, critical care interventions, neurosurgical interventions), and comorbidities.

Results

We identified 3184 pediatric discharges with a diagnosis code for arterial ischemic stroke. Thirty-eight (1%) had an endovascular therapy procedure code. Endovascular therapy patients were older (10.2 versus 4.5 years, p<.001), and more likely to have hemiplegia/paresis (RR 3.8, 95% CI 2.0-7.4), aphasia (RR 5.3, 95% CI 2.8-10.1), and facial droop (RR 4.0, 95% CI 1.9-8.7). Endovascular therapy was not associated with critical care and neurosurgical interventions or intracranial hemorrhage. Length of hospitalization, mortality, and discharge disposition were similar between groups. In a multivariable model, endovascular therapy was not associated with poor outcome (aOR 1.7, 95% CI 0.7-4.1).

Conclusions

In a national sample of children with a diagnosis of arterial ischemic stroke, endovascular therapy was infrequently utilized. Patients with a procedure code for endovascular therapy had significant stroke-related deficits, but outcomes were similar to children who did not receive endovascular therapy. Our data in conjunction with evidence of benefit in adults support consideration of endovascular therapy for select children with acute stroke.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/01/27/pediatric-stroke-endovascular-treatment-ischemic-stroke/7033795/?category=latest&page_id=1

A favorite

For those who may have come to the blog recently, I wanted to cite from the archives a favorite of mine:

http://childnervoussystem.blogspot.com/2015/10/where-was-child-protection.html

Mirabile dictu 4

An American basketball player's eye popped out of its socket after he was poked in the face while going for a rebound during a game in New Zealand.

Akil Mitchell, a 24-year-old former University of Virginia forward, was playing for the New Zealand Breakers in a game against Cairns on Thursday when the accident happened.

The game was stopped for 15 minutes while Mitchell was treated by medical officials, with his teammates left visibly upset by the incident. Cairns won the National Basketball League game 94-81.

On Friday, Mitchell said he had no vision impairment, but won't be watching any videos of the incident.

"(Teammate) Paul (Carter) really wanted me to see it and I was like, 'I can't do it,'" Mitchell told the New Zealand Herald on Friday. "It kind of makes my eye throb a little just thinking about it, so I don't know if I'll ever be able to watch it."

Mitchell told the Herald he could still see from the eye after it had popped out of his socket, saying the sensation was akin to "a chameleon, how they can see different directions."

http://www.foxnews.com/health/2017/01/27/basketball-players-eyeball-pops-out-during-game.html

Video at http://www.sportingnews.com/nba/news/akil-mitchell-eye-injury-video-update-nbl/jsmj8psrumw113mdrawrb0ags

Infant colic is actually baby fibromyalgia

MINNEAPOLIS, MN – Researchers at the Center for Research in the Young (CRY) finally unlocked the mystery of infantile colic, discovering the condition is actually the baby presentation of fibromyalgia.

Colic is defined by infant crying at least three hours per day, at least three days per week, for at least three weeks.  If the babies can survive this period, without being shaken to death, they typically outgrow their symptoms by four months of age.

Rheumatologist Dr. Amanda Ache led this groundbreaking research in the baby fibromyalgia project.  She noted similarities between her fibromyalgia patients and her own colicky baby.  “My precious infant seemed to have a heightened sensitivity to touch and noise, wanted to sleep throughout the day, and was in a complete ‘fibro fog.’  We tried massages, physical therapy, stretching exercises, and dietary changes, none of which made any improvement in her symptoms.  But I really knew I was onto something when I realized spending more than 10 minutes with her piercing cry made me want to grab a kitchen knife and jam in into my ears… That’s exactly the way I feel when I’m with my some of my patients!”

Until now, treatment for infant colic included supportive management aimed at helping parents cope with the child’s symptoms.  But with this groundbreaking discovery of baby fibromyalgia, numerous additional therapies can now be found ineffective as well.

Parents everywhere expressed relief with this new diagnosis.  “When I tell people that my infant has ‘colic’ I always get the same eye roll.  It feels so good to finally have a legitimate diagnosis: baby fibromyalgia.”

http://gomerblog.com/2016/04/baby-fibromyalgia/

Courtesy of a colleague

MRI contrast boosts gadolinium levels in Korean rivers

By Brian Casey, AuntMinnie.com staff writer  January 26, 2017 -- 

South Korean researchers have found levels of gadolinium in the Han River near Seoul that are almost 300 times normal levels at some locations. They attribute the levels to the use of MRI contrast -- echoing previous research on the persistence of gadolinium in the environment.

The level and distribution of gadolinium in the waters of the Han River and its tributaries roughly correlated with the number of MRI scanners in particular areas around Seoul, according to a research group from Chungnam National University in Daejeon and the Korea Basic Science Institute, Chungbuk.

"This result indicates a positive correlation between population and number of MRI instruments, and positive [gadolinium levels]," the authors wrote in a paper published December 29 in Chemosphere…

Gadolinium serves as a key raw material for most MRI contrast agents. While extremely useful for MRI scans, the rare earth element has developed a checkered reputation in recent years. It was linked to the development of nephrogenic systemic fibrosis in patients starting in 2006, and more recently, residual gadolinium has been found in humans years after they received MRI scans.

Gadolinium also makes its way into wastewater as patients excrete it from their bodies following MRI scans. Gadolinium's persistence in the environment has even spawned a new field of environmental research, such as a 2016 study of the element in San Francisco Bay. Researchers found high levels of gadolinium in the body of water, and these levels corresponded with the number of MRI scanners installed in the region.

In the current study, the researchers postulated that the Seoul metropolitan area could be a good region to investigate for environmental gadolinium, due to its large population (around 25 million people) and relatively high concentration of MRI scanners (21.3 units per 1 million population). The scanner concentration is much higher than the average for countries in the Organization for Economic Co-operation and Development (OECD).

The researchers collected 20 water samples from the Han River and its tributaries in August 2013. Some samples were collected at pristine spots in upper tributary streams before they flow into the Seoul metropolitan area, while other samples were collected from more populated locations, such as the effluent from wastewater treatment plants (unlike other rare earth elements, gadolinium is not removed from water in the wastewater treatment process).

The researchers measured the chemical composition of the water samples and performed a process designed to isolate rare earth elements such as gadolinium, lanthanum, and samarium. Concentrations were rendered as picometers (pM), and prevalence was compared with normal levels as found in a type of Australian shale that in geology is considered to be a standard for the presence of rare earth elements.

Gadolinium concentrations rose when water samples were acquired near populated areas -- areas that had higher concentrations of MRI scanners, the group found. The levels ranged from 1.2 times the normal levels of gadolinium in the environment to as high as 297 times the normal levels.

For example, at the upper end of the Han River, near the Paldang Dam above Seoul, gadolinium levels dropped from 44.0 pM at the first measuring station near the dam to 17.7 pM and 17.2 pM at the next two stations, as tributary streams fed the river. But downstream from Seoul, gadolinium concentrations rose sharply to as high as 181 pM at the first sample station downstream of the city.

Meanwhile, gadolinium levels were far lower in upstream tributaries of the Han River, with one tributary seeing levels ranging from 2.29 pM to 41.0 pM. On the other hand, some downstream tributaries had extremely high levels: A station located next to a tributary that drained an area with a high concentration of MRI scanners had a gadolinium level of 425 pM.

Levels skyrocketed when measured at sources near wastewater treatment plans. One station near the inflow of such a plant recorded a gadolinium level of 3,710 pM, or 297 times the normal gadolinium concentration in the environment, while other stations recorded levels of 781 pM and 756 pM…

"The results indicate that the [Han River] is significantly contaminated by anthropogenic [gadolinium] sources, which are contrast agents from MRI," the authors wrote.

They reported that gadolinium levels correlated with population levels (and therefore the number of MRI scanners) in the upstream samples, but this relationship was not found in the downstream samples, indicating that wastewater treatment plants may disrupt the association.

Ultimately, the researchers found that the anthropogenic gadolinium most likely follows the Han River into the Yellow Sea, where it could disturb the rare earth distribution in the water and potentially "pose harmful effects on aquatic ecosystems."

http://www.auntminnie.com/index.aspx?sec=ser&sub=def&pag=dis&ItemID=116397

Courtesy of a colleague

Hyeongseok Song, Woo-Jin Shin, Jong-Sik Ryu, Kwang-Sik Lee.  Anthropogenic rare earth elements and their spatial distributions in the Han River, South Korea.  Chemosphere 172 · December 2016 DOI: 10.1016/j.chemosphere.2016.12.13

Abstract

Rare earth elements (REE) consist of lanthanides (from La to Lu), together with yttrium and scandium, in which anthropogenic REE, such as gadolinium (Gd), lanthanum (La), and samarium (Sm), has emerged as micro-contaminants in natural waters in highly developed countries. Here, we collected water samples in the Han River (HR) and its tributaries flowing through Seoul Capital Area, the world's second largest metropolitan area in order to examine how and to what extent anthropogenic REE anomalies may occur. Water samples show higher light REE concentrations than heavy REE concentrations, while wastewater treatment plant (WWTP) samples display much higher heavy REE concentrations due to high Gd concentration. The PAAS-normalized REE patterns indicate that WWTP samples display the pronounced positive Gd anomalies, in which anthropogenic Gd from magnetic resonance imaging (MRI) diagnostic system occurs as a form of Gd complexation with either Cl⁻ or SO4²⁻. Due to the WWTP, both the HR and tributaries show also positive Gd anomalies and the anthropogenic Gd concentrations increase as a function of the distance from the Paldang dam. This result indicates a positive correlation between populaton, number of MRI instruments, and positive Gd anomaly. Similarly, positive La and Sm anomalies exist in the HR, indicating that the HR is also affected by their point sources. Based on the discharge rate and anthropogenic REE concentrations, their fluxes are estimated to be 952 ± 319 kg/yr, suggesting that this amount of fluxes could disturb REE distribution in the Yellow Sea, and pose harmful effects on aquatic ecosystems.

Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis

Scheibe F, Prüss H, Mengel AM, Kohler S, Nümann A, Köhnlein M, Ruprecht K, Alexander T, Hiepe F, Meisel A. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017 Jan 24;88(4):366-370.

Abstract

OBJECTIVE:

We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti-NMDA receptor (anti-NMDAR) encephalitis.

METHODS:

Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1-6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored.

RESULTS:

Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile.

CONCLUSIONS:

Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis.

CLASSIFICATION OF EVIDENCE:

This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis.

____________________________________________________________________________

JANUARY 26, 2017

New treatment for a rare form of encephalitis

Charité - Universitätsmedizin Berlin News

Researchers from Charité report success in treating anti–NMDA receptor encephalitis.

Anti–NMDA receptor encephalitis is an inflammatory disease that affects the central nervous system. It is a rare autoimmune disease that results in the body producing antibodies against the NMDA receptor, a protein that plays an important role in signal transduction in the brain. Using a new treatment regimen, researchers from Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have recorded significant progress in treating the disease, including in patients who did not previously respond to treatment.

Results from this study were published in the journal Neurology.

In a study led by Dr. Franziska Scheibe and Prof. Dr. Andreas Meisel from the Department of Neurology and the NeuroCure Cluster of Excellence, Charité–based researchers recorded outcomes obtained using a new treatment regimen. In addition to standard treatment, patients received bortezomib, a drug known as proteasome inhibitor that has proven successful in treating patients with plasmacytoma, a specific type of blood cancer. Proteasomes play an important role in the degradation of proteins that regulate the cell cycle, thereby regulating cell growth. Given their high rates of protein synthesis, antibody–producing plasma cells display particularly high levels of metabolic activity. This renders them as sensitive to the effects of the drug as cancer cells, and results in their death.

In their study of five patients, the researchers were able to show for the first time that bortezomib treatment quickly resulted in clinical improvements in patients with severe forms of the disease. Treatment was also associated with a decline in the antibodies responsible for the disease. 

“'Bortezomib is capable of treating the causes of the disease by eliminating plasma cells. This makes it a valuable new treatment option in cases of anti–NMDA receptor encephalitis that have so far proven resistant to treatment,” explains Franziska Scheibe, the study's first author.

Future studies will focus on developing biomarkers capable of making early predictions on whether patients will develop a severe form of the disease. This should then allow physicians to initiate specific treatments early. “As is the case with all other treatments currently used in patients with this disease, our results need to be confirmed by randomized trials” notes Prof. Andreas Meisel.

https://www.mdlinx.com/neurology/top-medical-news/article/2017/01/26/8

Network over-connectivity in autism

Conti E, Mitra J, Calderoni S, Pannek K, Shen KK, Pagnozzi A, Rose S, Mazzotti S, Scelfo D, Tosetti M, Muratori F, Cioni G, Guzzetta A. Network over-connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study. Hum Brain Mapp. 2017 Jan 17. doi: 10.1002/hbm.23520. [Epub ahead of print]

Abstract

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P < 0.05. No contra-comparison results were found. The over-connectivity pattern in ASD occurred in networks primarily involving the fronto-temporal nodes, known to be crucial for social-skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network-based diffusion study comparing toddlers with ASD and those with other-DD. Results indicate the detection of different connectivity patterns in ASD and other-DD at an age when clinical differential diagnosis is often challenging.

Courtesy of Doximity

Stigma

I grew up proud to be a polio survivor, blissfully unaware of the stigma many people attach to paralysis and deformity. I grew up proud to be a Jew, blissfully unaware of the stigma many people attach to my faith. I grew up proud to be a girl, blissfully unaware of the stigma many people attach to my gender.

It was only later, on the cusp of adulthood, that – on all three fronts – I was rudely awakened. Against my will, I became a warrior. And nowhere did the battle rage more fiercely than at the intersection where all three identities converged: the dating front.

I had battled exclusion before. I always won. The movie theater, the restaurant, the concert hall, the university, the world of work: they had dispensed my basic training. This time the barricades wouldn’t budge. When it came to marriage, so central to my Orthodox Jewish upbringing, I seemed destined to remain on the sidelines forever.

With every passing year, I searched more and more frantically for someone, anyone, who believed – as I did – that I would marry. It’s not that my parents didn’t believe it. When I asked, they assured me that they did. But I didn’t want to ask. I wanted their words to reach me unbidden. I wanted to hear unshakable conviction, even righteous indignation, in their voices. I didn’t.

One day, I heard a lilting song about Vincent van Gogh on the radio. It became a life preserver.

Now I understand

What you tried to say to me,

And how you suffered for your sanity,

And how you tried to set them free.

They would not listen, they did not know how.

Perhaps they’ll listen now.

Surely I couldn’t be the only sane one in my world. And if I were, I refused to believe that the world expected me to embrace its insanity. I often found myself humming a strident, long-forgotten folksong I had known since childhood, I Don’t Want to Get Adjusted to This World. If being well adjusted meant adjusting to society’s maladjusted view of life with a disability, I’d stay maladjusted, thank you very much.

Happily, a paperback book on my friend’s living room shelf enabled me to do just that.

It almost escaped my notice, that’s how slender it was. But like candy, its spine’s graphic design – pink and orange against a black background – caught my eye and whetted my appetite. Equally diminutive was its title: Stigma. But its author, sociologist Erving Goffman, was an intellectual giant.

Stigma: a little word whose meaning I did not know. Goffman wasted no time enlightening me: Stigma is an “attribute that is deeply discrediting” and that reduces the bearer “from a whole and usual person to a tainted, discounted one.”

Goffman postulated that a stigmatized individual may consider himself “normal,” a human being like everyone else. At the same time, he may detect – and not without reason – that others do not accept him. And the kicker: As a product of the same society whose members stigmatize him, the stigmatized person subscribes to many of its attitudes, making him “intimately alive to what others see as his failing, inevitably causing him, if only for moments, to agree that he does indeed fall short of what he really ought to be.”

Time and again, I saw myself in Stigma’s pages, never more cathartically than in Goffman’s excerpts from The Little Locksmith, the 1943 memoir by Katherine Butler Hathaway, with whose scoliosis I thoroughly identified.

When I got up at last… and had learned to walk again, one day I took a hand glass and went to a long mirror to look at myself… That person in the mirror couldn’t be me. I felt inside like a healthy, ordinary, lucky person – oh, not like the one back in the mirror!

The discrepancy between Hathaway’s body image and her mirror’s reflection reminded me of the time my cousin Avrumi took me to a New York Knicks game at Madison Square Garden. After the game, we were waiting outside the Garden for my taxi to arrive. Traffic was horrendous and at least fifteen minutes went by – and still, no cab. Then, all of a sudden, I saw Avrumi lifting a wheelchair into the trunk of a yellow taxi.

“No!” I called out to him in alarm. “The car we’re expecting is dark blue!”

Bewildered, Avrumi turned toward me, the wheelchair in midair. “But this is not your wheelchair.”

Equally bewildered, I looked down. Avrumi couldn’t have been lifting my chair; I was still sitting in it.

Reading Stigma at age 20 clarified why, unless society holds its “mirror” up to my face, I often have no idea that I am sitting in a wheelchair. It’s almost as if the chair is so much a part of me that I don’t even know it’s there. That night waiting outside Madison Square Garden, I actually thought I was standing.

Nourished by Goffman, determined to fight stigma tooth and nail rather than internalize it, it was disheartening that with every passing year, my chances for love seemed to dwindle. When I was 28 years old, my tender Tante Miriam helped me get dressed for the very first time. Several hours later, cheeks blushing, eyes luminous, she confided, “I never realized how attractive you are. I told Uncle Moshe that I can envision a man wanting to marry you.” My confidence boost was short-lived. What did it matter what Tante Miriam could envision, what I could envision, if a man could not?

Two years later, in 1982, Steven Spielberg’s E.T.: The Extra-Terrestrial was released. The theater lights dimmed and soon I saw two elongated, reptilian fingers rising ominously. They pulled down a branch, juxtaposed against a globe of light glowing in the night sky. Those fingers terrified me. They disgusted me. And based on the audience’s collective gasp, I knew I wasn’t alone. Then, magic. Gradually, the fingers became far more than tolerable. They were lovable. Loving. Life-giving. It occurred to me that mine were too.

Within the year, I met and married my husband.

http://www.aish.com/sp/so/Stigma.html

The author of this is also the author of http://childnervoussystem.blogspot.com/2017/01/love-beyond-words.html 

Love beyond words

Something about Manhattan breeds detachment. Pedestrians cram the sidewalks. Their elbows practically touch. Yet eye contact is a rarity. A Manhattanite for many years, I confess that I too subscribed to anonymity on the sidewalks of New York. But that all changed on a sunlit spring afternoon in 1994.

A bank errand completed, I was heading home. I rounded the corner at Broadway and 72nd Street, my motorized wheelchair cruising me along at an impressive 7 mph. Amid the blur of people, someone halfway up the block was coming into focus. I tried not to notice her. She was impossible to ignore.

Approaching me was a slender young woman, with straight brown hair framing her pale face. She had a tentative smile and a four-footed aluminum cane. She sliced the distance one laborious step at a time.

As we neared each other, her smile broadened. I stopped and reluctantly waited. Supper, and my two children, needed attending to.

"Hi," I said tentatively.

She appeared to have a problem speaking.

"Sister," she replied.

"Do you know my sister?"

She shook her head. "Sister."

"Um, do I know your sister?"

She nodded. My brow furrowed. This wasn't making sense.

Suddenly, a scene penetrated the fog. A recent morning in my friend's spacious dining room. Some two dozen women seated around a long table. Cookies, coffee and the hum of conversation.

"See that woman over there?" my friend had asked, her chin angling to her right. "Her younger sister had a stroke last month, just 10 weeks after getting married. She and her husband live right around the corner from you."

I had said I would pay her a visit. Two months had passed. I had done nothing. And here she was, beaming at me.

"Oh! I met your sister, right?"

She nodded enthusiastically. I extended my hand. Her right hand remained limply at her side.

Attempting to mask my embarrassment, I effusively invited her and her husband for Shabbat dinner. She looked puzzled and glanced to her left. That's when I noticed her attendant. She must have been standing there all along.

"Since her stroke,” the attendant explained, “Bluma can't process things like days of the week and numbers." She retrieved a tiny memo pad from her pocket and recorded the pertinent information, including my address and phone number. "Her husband will get back to you," she said.

The attendant turned to her right. "Ready to go?" she asked. Bluma shook her head emphatically. Then her eyes locked with mine.

"Baby," she said.

I smiled. "Yes, thank God, I have two babies."

"Baby," she repeated insistently.

"Do… Would you like to have a baby?"

Her eyes were wistful, her voice tremulous. "Baby."

Steve, Bluma’s husband, phoned that night. I expected his voice to exude anguish or at least anxiety. Equanimity met my ears instead.

That Friday night, Steve and Bluma arrived at seven on the dot, looking like your average yuppie couple. We introduced them to our children.

"Nice," Bluma said. "Nice. Beautiful."

We took our seats. Minutes later, my husband and I were stunned when Bluma joined in on Shalom Aleichem, the song with which Jews welcome the Sabbath angels into their home. I shot a bewildered look in Steve’s direction. He explained that some people with aphasia, the loss or reduction of speech following a stroke, are better at singing than speaking.

We spent the rest of the evening trading songs – Broadway, folk, Jewish, the works. We became fast friends, and Bluma and Steve came over for many more Shabbat meals, replete with lots of singing.

By the time Bluma traded her old four-footed cane for a sleek, slender one, she had become one of the most popular people on the Upper West Side. Everyone knew her. Everyone loved her. At the A & P, Denise, the most hostile cashier on the planet, lit up whenever Bluma approached. So did I.

I remember stopping impulsively at a clothing store one winter afternoon. There was Bluma, rifling through the sale rack. She was just as surprised to see me as I was to see her.

"Unbelievable. Unbelievable!"

"Hey, what brings you here?" I asked.

Bluma hummed the opening bars of Maoz Tzur, a popular Chanukah song.

"Who are you buying a present for?"

With a mischievous wink, she thumped her chest.

"Good answer!"

"You?"

"Well, what with Chanukah coming up, I thought I’d pick up something for my daughter."

In a flash, she grabbed my forearm. She looked at me intently.

"I."

"No, that's okay."

Her palm left my arm and flew to her chest. Her eyes widened.

"I!" Her expression made it clear that I wasn't getting away with anything. We compromised. We each bought my daughter a sweater.

On a Sunday the following autumn, Steve phoned. "Can we stop by?"

About an hour later, our doorbell rang. Bluma, her face glowing, had barely crossed our threshold when she began to hum Rock a Bye Baby.

Seven months later, their son was born. Two years later, their daughter arrived on the scene.

Soon after, our family picked up stakes and headed for suburbia. Encounters with Bluma and Steve dwindled from infrequent to never. But nine years later, wedged between the inevitable catalogs and bills, a large cream-colored envelope – graced with fluid, delicate calligraphy – arrived in the mail. A bar mitzvah invitation.

Every bar mitzvah is a celebration. This one was a lovefest. The hall hummed with a palpable joy, yet fell reverentially silent when Bluma and Steve’s son gave his speech. He reflected on the Talmudic sage Elisha, who spurned his faith after seeing a boy climb a ladder at his father's behest to shoo away a mother bird before taking her eggs – fulfilling two biblical commandments guaranteeing a long life – only to lose his footing and die.

"Elisha decided that if this kind of thing could happen, then there was no God," the bar mitzvah boy asserted. "But the Talmud saw things differently: The tragedy wasn't caused by a flaw in God. It was caused by a shaky ladder."

He paused for a moment. "Now anyone who knows our family knows that we, too, started out with a shaky ladder. When my mother had a stroke shortly after my parents were married, it wasn’t at all clear that they'd be able to thrive, or to have me or my sister. However, my family had one definite advantage. Yes, we had a shaky ladder. But we also had a lot of people holding onto our ladder so it wouldn’t fall. And of course, that includes many of you who are here today.”

As I heard these words, I found myself thinking, Yes, and now Bluma and Steve are holding onto their beautiful children’s ladder.

I glanced at Bluma. She was beaming, her daughter leaning on her arm. Everyone in the hall was gazing at a radiant woman in festive attire. Not me. I saw a pale, casually dressed figure limping toward me on 72nd Street. Everyone in the hall was hearing a bar mitzvah boy's insightful speech. But I detected a faint echo superimposed over his voice:

Sister.

Baby.

Reliving our first encounter on the sidewalks of New York, I relived the battle we both fought and won: to become mothers when some may have considered it an elusive, unattainable dream. As I marveled at the economy of Bluma's words, her simultaneously tremulous and unwavering voice, I realized for the first time: Not only had she gotten her baby. I had gotten a sister.

http://www.aish.com/f/hotm/Love-Beyond-Words.html

GRIN and bear it

von Stülpnagel C, Ensslen M, Møller RS, Pal DK, Masnada S, Veggiotti P, Piazza E, Dreesmann M, Hartlieb T, Herberhold T, Hughes E, Koch M, Kutzer C, Hoertnagel K, Nitanda J, Pohl M, Rostásy K, Haack TB, Stöhr K, Kluger G, Borggraefe I. Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. Eur J Paediatr Neurol. 2017 Jan 14. pii: S1090-3798(17)30004-1. doi: 10.1016/j.ejpn.2017.01.001. [Epub

ahead of print]

Abstract

OBJECTIVE:

To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment.

METHODS:

Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire.

RESULTS:

7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion).

CONCLUSIONS:

Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2017/01/25/grin2a-epilepsy-epileptic-encephalopathy-specialized-therapy/7011736/?category=latest&page_id=1

See:  http://childnervoussystem.blogspot.com/2016/06/grin1-phenotypic-spectrum.html
http://childnervoussystem.blogspot.com/2015/11/grin1-mutation.html