Monday, May 20, 2019

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.

Tuesday, May 14, 2019

KCNMA1 Channelopathy International Advocacy Foundation

If any other KCNMA1 patient is taking verapamil or another type of calcium channel inhibitor, I strongly urge you to ask your neurologist to provide information on the dosage and efficacy to the website: https://www.kciaf.org/. Knowing how patients respond to verapamil could be an important development in our understanding of this channelopathy, and I would like to see the neurologists share that information which may end up helping others in the group. (Facebook)

KCNMA1 Channelopathy International Advocacy Foundation https://www.kciaf.org/

OUR MISSION
We are a new and small organization with simple but ambitious goals:

Educate patients, families, the public and the scientific community about KCNMA1-associated conditions

Encourage and promote efforts to find effective treatments for the wide range of symptoms which can be caused by KCNMA1 mutations

Provide opportunities for patients and families to meet, whether in-person or otherwise, and share their experiences

Golden age of migraine therapy


The recent Food and Drug Administration (FDA) approval of 3 calcitonin gene-related peptide (CGRP) monoclonal antibody therapies has cast a spotlight on the field. Several millions and perhaps billions of dollars have been spent advertising these 3 medications—galcanezumab, fremanezumab, and erenumab—attracting more people with migraine to pursue medical care for the condition than ever before.

Other antibody and small-molecule CGRP antagonists are also in development, and new targets are being considered. Just as CGRP was targeted after it was shown that infusing CGRP in individuals with migraine induced attacks, similar studies are being conducted with pituitary adenylate cyclase-activating polypeptide (PACAP). This exciting target has been identified for the acute and preventive treatment of migraine and with a second migraine-specific therapeutic target, we are perhaps moving into a golden age of migraine therapy. We have more treatment options to offer individuals with migraine than ever before requiring thoughtful and informed care from neurologists, primary care physicians, pain physicians, and other specialists.


Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide is among the most potent vasodilatory neuropeptides in humans and has been shown to induce trigeminovascular inflammation with subsequent peripheral and central pain sensitization that is pertinent to migraine pathogenesis. Receptors for CGRP are found on trigeminal Aδ fibers, endothelial cells, and others leading to neurogenic inflammation and activation of the trigeminovascular system.  Although CGRP cannot cross the blood-brain barrier, it modulates nociceptive pathways involving the brainstem, thalamus, and cingulate cortex. CGRP levels are elevated during migraine attacks, and CGRP infusions trigger delayed migraine attacks in susceptible individuals. For these reasons, CGRP antagonists have been explored as a novel therapeutic class in migraine.

Calcitonin Gene-Related Peptide Antagonists

Monoclonal Antibodies

Eptinezumab, which binds to CGRP, is the only MAb CGRP antagonist delivered intravenously. In clinical trials.Eptinezumab has demonstrated superiority over placebo for migraine prevention, and the drug is under review by the FDA at the time this article is being written. The Table lists a summary of 2 trials of eptinezumab for individuals with episodic or chronic migraine. Participants with episodic migraine (≤ 14 headache days/month, ≥ 4 migraine days) who had single-dose infusions of 100 mg or 300 mg of eptinezumab had significantly reduced mean monthly migraine days (MMD) in 12 weeks (baseline 8.5 MMD, 100 mg −0.7 placebo-adjusted days, 300 mg -1.1 placebo adjusted days). A year after the fourth infusion, those treated with 300 mg of eptinezumab had a reduction of 5.2 MMD compared with 4.0 MMD reduction for those given placebo (nonsignificant); 31% of participants in the treatment group achieved headache freedom vs 21% of participants who received placebo. For individuals with chronic migraine (15-26 headache days/month, ≥ 8 migraine days), treatment with 100 mg or 300 mg of eptinezumab reduced MMD in 12 weeks (baseline 16.1 MMD, 100 mg −2.1 placebo-adjusted days, 300 mg −2.6 placebo-adjusted days).

In both studies, the percentage of participants treated with eptinezumab who achieved at least 50% and 75% reductions in MMD was significantly higher than in those who received placebo. For participants with chronic migraine treated with eptinezumab, the number of participants achieving 100% freedom from headache was statistically significant compared with those who received placebo (Table). In both studies, those receiving eptinezumab were also headache-free 1 day after treatment about twice as often. The most commonly reported adverse events (> 2%) were upper respiratory tract infection, nasopharyngitis (common cold), fatigue, urinary tract infection, diarrhea, and oropharyngeal (mouth) pain. The former 2 events are reported 1% to 2% more in the treatment groups than in the placebo group.

-Gepants

The -gepants are small molecule CGRP receptor antagonists. They have been studied for more than a decade for acute and preventive migraine treatment. Early trials demonstrated superior clinical efficacy to placebo with no cardiovascular side effects, making -gepants potentially a favorable option for people with contraindications to triptans and ergots. Although initial clinical development was hampered by potential hepatotoxicity, the next generation -gepants seem to have similar clinical properties without significant hepatic side effects.

Both rimegepant and atogepant are under investigation for migraine prevention.10-12 In a phase 2b/3 trial,a after 12 weeks of daily atogepant use (10 mg to 120 mg), there was a significant reduction in MMDs/probable migraine days (3.55-4.23 absolute days and 0.7-1.38 placebo-adjusted days). The most common adverse events were nausea, fatigue, constipation, nasopharyngitis, and urinary tract infection. The liver safety profile was similar to placebo. Data from a clinical trialb of rimegepant for migraine prevention are expected in 2020.

Pituitary Adenylate Cyclase Activating Peptide Antagonists

Pituitary adenylate cyclase-activating peptide (PACAP) is a 38 amino acid peptide that shares 68% homology with vasoactive intestinal peptide (VIP) and is a widely distributed neuropeptide. Involved in inflammatory regulation, hypothalamo-pituitary-gonadal axis modulation, energy homeostasis, and pain transmission, PACAP and VIP bind to VPAC1 and VPAC2 receptors with equal affinity. However, PACAP is 100 times more selective than VIP for the PAC1 receptor, which has multiple isoforms with similar responses to adenylate cyclase stimulation but variable responses to phospholipase C. Pertinent to migraine, PACAP-containing fibers and PAC1 receptors are found in the periventricular nucleus of hypothalamus, periaqueductal gray, locus coeruleus, solitary nucleus, trigeminal nucleus caudalis, and trigeminal ganglion, which are all involved in migraine. Levels of PACAP increase during migraine attacks and decrease after successful treatment with sumatriptan. Infusion of PACAP also induces immediate headache followed by a migraine-like attack after a mean of 6 hours, along with dilation of middle cerebral artery and superficial temporal artery. These phenomena were observed less than 20% of the time after VIP infusion. PACAP levels were increased after infusion of PACAP38 only in those participants who later reported migraine-like attacks. Such a correlation presents an interesting opportunity for PACAP blockade in migraine prevention. At this moment, biologics seem a better option than small molecules in blocking the PACAP/PAC1 pathway. A PAC1 receptor blocking antibody, AMG301, has been studied in a recently-completed phase 2a trialc for migraine prevention, but results are not yet available. Clinical trials are planned but not yet underway for a potent PACAP neutralizing antibody with picomolar affinity, ALD1910.17 The effect of long-term blockade of PACAP/PAC1 pathway on endocrine systems, energy metabolism, and inflammatory regulation remains to be investigated.

https://practicalneurology.com/articles/2019-may/migraine-preventive-therapies-in-development

Movement disorders in mitochondrial disease


Flønes IH, Tzoulis C. Movement disorders in mitochondrial disease: a clinicopathological correlation. Curr Opin Neurol. 2018 Aug;31(4):472-483.

Purpose of review The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on recently discovered clinicopathological correlations.

Recent findings Movement disorders are common clinical manifestations of mitochondrial diseases, in part because of the high vulnerability of neurons controlling motor circuits to mitochondrial respiratory dysfunction and energy failure. Intriguingly, the clinicopathological correlations of movement disorders in mitochondrial disease do not always conform to established neurophysiological knowledge. In particular, nearly complete substantia nigra degeneration and nigrostriatal denervation can occur without being accompanied by any of the clinical signs traditionally associated with parkinsonism. This apparent paradox, may be because of compensation by concomitant impairment of other motor circuits involving the cerebellum and thalamus.

Summary Movement disorders commonly accompany mitochondrial disease and may show paradoxical clinical−anatomical correlations. Further research is warranted in order to elucidate the mechanisms underlying the phenotypic expression of movement disorders in mitochondrial disease. This knowledge will advance our understanding of the pathogenesis of movement disorders in a broader broader clinical and pathophysiological context.
__________________________________________________________________

From the article

Ataxia is among the most common and debilitating movement disorders in patients with mitochondrial disease, of either mtDNA or nuclear cause, because of the high prevalence of cerebellar degeneration...

Dystonia is the most common movement disorder in children with mitochondrial disease [35]. Although the population-based prevalence of dystonia in mitochondrial disease is not known, Leigh syndrome is probably the most common cause of dystonia among patients with mitochondrial disorders. Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a genetically and phenotypically heterogeneous disorder of mostly infantile onset, which is commonly characterized by severe OXPHOS impairment. Leigh syndrome is caused by mutations in the mtDNA or a variety of nuclear genes encoding MRC subunits, complex assembly proteins, components of the Krebs cycle and other factors involved in mitochondrial bioenergetics...

In line with the profound mitochondrial vulnerability of the SNc, nigrostriatal degeneration is a common phenomenon in mitochondrial disease and shows a strong predilection for defects of mtDNA maintenance in which accumulation of somatic mtDNA damage occurs, including mutations of POLG, TWNK and OPA1. Paradoxically, in spite of the high prevalence of SNc degeneration, considered to be the principal cause of the parkinsonistic syndrome, parkinsonism is a relatively uncommon manifestation of mitochondrial disease. Parkinsonism has been described with mutations in mtDNA  and nuclear-encoded mitochondrial genes . Furthermore, parkinsonism has been described in a small number of cases with multiple mtDNA deletions, suggesting nuclear-encoded disorders of mtDNA maintenance, but with unknown genetic cause...

Although the SNc was affected in all reported cases of mitochondrial parkinsonism, severe SNc degeneration and nigrostriatal denervation can occur in patients with mitochondrial disease without any of the clinical correlates of parkinsonism. In fact, recent studies suggested that SNc degeneration is a common, possibly universal phenomenon in disease caused by POLG or TWNK mutations, yet clinical parkinsonism is an uncommon manifestation...

Movement disorders are common manifestations of mitochondrial disease because of a pathological predilection for energy-sensitive neurons controlling motor circuits. Although the clinicopathological correlations mostly conform to established neurophysiological knowledge, this is not always the case. Nearly complete nigrostriatal degeneration may occur in POLG-associated disease without being accompanied by any of the clinical signs traditionally associated with parkinsonism. Elucidating the mechanisms underlying this apparent lack of clinicopathological correlation in these cases will advance our understanding of the pathogenesis of movement disorders, not only with respect to mitochondrial disease but also in a broader clinical and pathophysiological context.

Sunday, May 12, 2019

Generics


America needs generic drugs. They make up 90 percent of the American drug supply. Without them, every large-scale government health program — the Affordable Care Act, Medicare Part D, the Veterans Health Administration, charitable programs for the developing world — would be unaffordable.

But what Mr. Baker uncovered in six years of doing foreign inspections exposed the dangerous compromises behind the production of generic drugs, and the F.D.A.’s limits as a global regulatory agency.

Six months into his stint, Mr. Baker visited a plant in Aurangabad run by the Indian company Wockhardt, which made about 110 generic-drug products for the American market. He had one week at the plant to ensure that it complied with the F.D.A. regulations known as “current good manufacturing practices.” Generating and preserving data at each manufacturing step is crucial to those regulations.

On his second day at the Wockhardt plant, Mr. Baker and a colleague caught an employee trying to smuggle out a garbage bag of documents. The documents led Mr. Baker to discover that the plant had knowingly released into Indian and other foreign markets vials of insulin containing metallic fragments. These had apparently come from a defective sterilizing machine. He learned that the company had been using the same defective equipment to make a sterile injectable cardiac drug for the American market. The willful deception there and at other plants so shocked him that he overhauled his inspection methods, with significant results.

Two months after Mr. Baker’s Wockhardt inspection, the F.D.A. banned the import of drugs from that plant into the United States, a potential $100 million loss in sales for the company. Company officials declined to comment on the fallout from the inspection.

Mr. Baker kept digging. Over the next five years, first in India and then in China, he uncovered fraud or deceptive practices in almost four-fifths of the drug plants he inspected. Some of the plants used hidden laboratories, secretly repeated tests and altered results to produce fake data that fundamentally misrepresented drug quality, then submitted that data to regulators.

In some instances, deceptions and other practices have contributed to generic drugs with toxic impurities, unapproved ingredients and dangerous particulates reaching American patients. Some doctors have struggled to stabilize patients who became sicker after they were switched from a brand-name to a generic, or between generic versions. A low-cost drug is not a bargain if it doesn’t work…
The F.D.A. declares that “Americans can be confident in the quality of the products the F.D.A. approves.” Because of that reassurance, even savvy consumers — the sorts of people who are well versed in the quality distinctions between Velveeta and artisanal Cheddar — don’t think about how and where their drugs are made when they head to a pharmacy. Their only question usually is: Can they afford, or will their insurance cover, the drug being dispensed?

The F.D.A., which approved more than 1,000 new generic drug products last year, faces a vast challenge in safeguarding these medications. Nearly forty percent of all our generic drugs are made in India. Eighty percent of active ingredients for both our brand and generic drugs come from abroad, the majority from India and China. America makes almost none of its own antibiotics anymore…
In the United States, F.D.A. investigators typically show up unannounced to inspect plants. But overseas, the F.D.A. has opted to announce the vast majority of its foreign inspections in advance. Overseas plants even “invite” the F.D.A. to inspect; the investigators then become the company’s guests and agree on an inspection date in advance. Plant officials have served as hosts and helped to arrange local travel.

The F.D.A. has defended this system as the best way to ease the complex logistics of getting visas and ensuring access to the plants. But the resulting inspections are largely “staged,” say a number of F.D.A. staff members. With advance notice and low-cost labor, the plants can make anything look like anything. “You give them a weekend, they’ll put up a building,” as one F.D.A. investigator put it.

Mr. Baker, the young inspector, pulled back the curtain on these staged visits. He rejected guided tours. Instead, he would arrive at a plant and head to the quality control laboratory, where employees typically audit test results coming in from the factory floor. There, he would get into the computer system and sift through the data himself.

As Mr. Baker followed clues, he unearthed devious practices at what seemed like transparently run plants. Technicians used initial hidden tests to get preliminary results, which then guided them as they tinkered with the test settings. Then they retested in the plant’s official system to get the desired results showing that the drugs fell within specifications. Those drugs with altered test results could then be released to patients.

During his 27 months in India, of the 38 drug plants he inspected, Mr. Baker found fraudulent or deceptive data in 29 of them. As he worked, other investigators learned from his techniques. The difference was stunning, one F.D.A. employee recalled. “Like you walk into a dark room and suddenly someone just turns on the light,” the employee said. “It was shocking.”

And there was an additional negative consequence to the F.D.A.’s system of advanced notice. With the companies serving as travel agents, F.D.A. investigators spoke of inappropriate perks: hotel upgrades, for which the investigators would never see a bill; golf outings, massages, and trips to the Taj Mahal. The result was what some F.D.A. employees referred to as “regulatory tourism.” The F.D.A. said in response that “any allegations of improper conduct by F.D.A. personnel are investigated.”…

A new head of the F.D.A.’s India office, Altaf Lal, arrived in mid-2013. To tame the twin problems of company fraud and compromised investigators, Mr. Lal made a novel pitch to agency officials. He proposed a pilot program to make all inspections in India either on short notice or unannounced. By December 2013, he had a green light. The results were instantaneous.

In January 2014, the F.D.A. was planning an unannounced inspection at a plant in northern India on a Monday. Fearing that plant officials had heard they were coming, Mr. Baker and his colleague went a day early, unannounced. They proceeded to the quality control laboratory, expecting it to be quiet on Sunday morning. Instead, they were stunned to see a hive of activity. Dozens of workers hunched over documents, backdating them. On one desk, Mr. Baker found a notebook listing the documents the workers needed to fabricate in anticipation of the inspectors’ arrival. There were Post-it notes stuck to some surfaces, noting what data to change.

In large swaths of India’s generic drug industry, the pilot program uncovered a long-running machinery dedicated not to producing perfect drugs but to producing perfect data. At one plant, Mr. Baker went straight to the microbiology laboratory and found the paperwork for testing the sterility of the plant in perfect order: microbial limits testing, biological indicators, all the samples with perfect results. Yet most of the samples didn’t exist. The plant was testing almost nothing. The laboratory was a fake.

At the vast majority of the unannounced inspections, the investigators found things the plants no longer had time to fix: Infestations of birds and insects. A pile of critical manufacturing records, tossed in a trash bin. An employee bathroom near a sterile manufacturing area in one plant lacked drainage piping, so urine puddled directly onto the floor.

Under the pilot program, the rate of inspections resulting in the F.D.A.’s most serious finding, “official action indicated,” increased by almost 60 percent, according to my own analysis of F.D.A. records. Before long, drugs from numerous plants in India had been banned from the United States market. Given these results, it seemed logical for the F.D.A. to make unannounced inspections or short notice the norm around the world. But in July 2015, F.D.A. officials decided to terminate the program and return to largely pre-announced inspections in India. When asked why, the agency declined to explain its reasoning and stated that “after evaluation of the pilot a decision was made to discontinue the pilot.”

Most Americans agree that our drug supply is in crisis. But the crisis they point to is that of cost: brand-name drugs that are unaffordable, because of corporate greed, and a labyrinth of deals between drug makers, drugstore chains and insurance companies. One response has been to push for more, cheaper generics made available as quickly as possible. But that solution has come with a quality crisis that has been largely invisible to American consumers.

Our drug supply needs one system of regulation that prioritizes both low cost and high quality: an unannounced inspection at every plant that makes drugs for the United States market. Companies or countries that refuse to comply should not be allowed to sell to American consumers. Those consumers deserve to know where their medicines are made, information they get on their cereal boxes and shirt labels. “Made in America” on a pill bottle label could have a strong market effect, helping to draw drug manufacturing back to the United States, where it can be more effectively policed.

In February 2015, Peter Baker moved to China, where he found similar data fraud and deception in 38 of the 48 drug plants he inspected. He left the agency this March. Shaken by what he uncovered in his work for the F.D.A., he told a colleague that if people knew how some of those drugs were manufactured overseas “then no one would take them.”

https://www.nytimes.com/2019/05/11/opinion/sunday/generic-drugs-safety.html?smid=nytcore-ios-share

Courtesy of a colleague

Saturday, May 11, 2019

Gene therapy for myotubular myopathy

A new gene therapy treatment has had striking results in nine boys born with myotubular myopathy (MTM), a rare disease that causes extreme muscle weakness often from birth. All of the boys have better neuromuscular function, most can sit on their own, and four are now breathing without ventilators. As videos of their improvements were shown here on 1 May at the annual meeting of the American Society of Gene & Cell Therapy (ASGCT), the audience broke out in applause. The results, the first of their kind for this rare disease, cap a year of early signs of success in using gene therapy for inherited muscle diseases.

As far as muscle function is concerned, the boys “have gone from nothing to something,” says principal investigator Perry Shieh, a neurologist at the University of California, Los Angeles. “Time will tell how much that something will be.”

The patients in the new study have X-linked MTM, caused by a defect in a gene called MTM1 that encodes an enzyme, myotubularin. Skeletal muscles need the enzyme to develop and function. Boys with the disease have low muscle tone and, in many cases, can barely breathe or move on their own; most require a ventilator and feeding tube. Half of patients die by 18 months, and few live past age 10.

In the trial, sponsored by Audentes Therapeutics, a gene therapy company in San Francisco, California, nine boys between 8 months and 6 years old with X-linked MTM received an intravenous (IV) infusion of many trillions of particles of a harmless virus, called an adeno-associated virus. The viruses were designed to carry a good copy of the MTM1 gene into the boys’ muscle cells. The gene, a free-floating piece of DNA, could then trigger the cell’s proteinmaking machinery to produce myotubularin. Three patients had serious side effects that may have been related to the therapy, such as heart inflammation, but all were treatable.

Biopsies showed that 48 weeks after the first six boys received treatment, their leg muscle cells that previously had virtually no myotubularin were making, on average, 85% of the normal amount, Shieh reported yesterday. The boys’ abnormally small muscle fibers had grown larger. Four can now sit up without help, and three are taking steps with assistance; although still receiving nutrition through a feeding tube, several have started to eat food. And some can vocalize sounds for the first time, Shieh says.

In one set of before-and-after videos, a 1-year-old boy lay passively on an examining table; 48 weeks after his treatment, he could stand and take steps with help. In another, a child who wobbled and needed help to sit up later sat alone and reached out to grab a toy. Three children treated with a higher dose are showing similar motor function gains after 6 months, along with faster changes in their muscle cells and up to double the amount of myotubularin that a healthy child’s cells make, Shieh reported.

“They’re getting great results,” says gene therapy researcher and ASGCT president Michele Calos of Stanford University in Palo Alto, California, who chaired a symposium of the meeting’s top abstracts, where Shieh presented. And in theory, those results could last: Because muscle cells don’t normally divide, the extra myotubularin could keep the boys’ muscles working for years to come. Dogs with a milder form of MTM that received the same therapy and gained the ability to run are still doing fine years later, Shieh notes.

The treatment will be tested in more children before Audentes seeks approval from the U.S. Food and Drug Administration (FDA). Meanwhile, another IV gene therapy, for a rare genetic disease called spinal muscular atrophy that led to dramatic improvements in 15 children is expected to soon become the second FDA-approved gene therapy for an inherited disorder. (The first was gene therapy for an inherited form of blindness in late 2017.)


Courtesy of Doximity

652 - ASPIRO Phase 1/2 Gene Therapy Trial In XLinked Myotubular Myopathy (XLMTM): Update on Preliminary Safety and Efficacy Findings

Author Block: Perry B. Shieh1, Nancy Kuntz, Barbara Smith, Carsten G. Bönnemann, James J. Dowling, Michael W. Lawlor, Wolfgang Müller-Felber, Mo Noursalehi, Salvador Rico, Laurent Servais, Suyash Prasad Neurology, UCLA Medical Center, Los Angeles, CA, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL,University of Florida, Gainesville, FL, NIH Porter Neuroscience Research Center, Bethesda, MD,Hospital for Sick Children, Toronto, ON, Canada,Medical College of Wisconsin, Milwaukee, WI,Klinikum der Universität München, Munich, Germany,Audentes Therapeutics, San Francisco, CA,Hôpital Armand Trousseau, Paris, France

Background: XLMTM is a rare monogenic disease caused by mutations in the MTM1 gene, which encodes myotubularin, a protein required for normal development and function of skeletal muscle. XLMTM is characterized by extreme muscle weakness, respiratory failure and early death. Methods: ASPIRO is an ongoing Phase 1/2 open-label, randomized, ascending dose study to evaluate the safety and efficacy of an investigational gene therapy product (AT132) in patients with XLMTM. AT132 (rAAV8- Des-hMTM1) is designed to deliver functional copies of the MTM1 gene to skeletal muscle cells. ASPIRO was designed for XLMTM pts <=5 years, randomized onto drug or delayed control, and enrolled into ascending dose cohorts to receive a single AT132 infusion.

Results: At the time of 26Sep18 data cut, safety and efficacy data from 4-48 weeks of follow-up were reported for 8 patients, including 7 patients in Cohort 1 (1x1014 vector genomes per kilogram (vg/kg); 6 treated and 1 untreated control) and the sentinel patient in Cohort 2 (3x1014 vg/kg), as well as Week 24 muscle biopsy data for the first 4 treated patients. All treated patients showed meaningful improvements in neuromuscular and respiratory function; with increased limb and trunk strength; improved velocity, coordination, and movement accuracy; and improved ability to communicate (increased loudness during vocalization and crying). In addition, there have been improvements in airway clearance, secretions management and swallowing capability, to the extent that patients are now beginning to tolerate oral food. Efficacy assessments have shown clinically meaningful improvements in both the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale and maximal inspiratory pressure (MIP) (Table). Notably, patients achieved scores close to the maximum CHOP INTEND score of 64, a level of functional performance typically achieved in a healthy child by 3-6 months of age. All patients had attained the ability to sit without support, one patient was crawling, and two patients were standing with support and making stepping movements. At 24 weeks, all patients assessed showed significant reductions in ventilator use, with three patients reaching ventilator independence. All of these improvements are clinically meaningful and inconsistent with the natural course of this disease. Muscle biopsy results were consistent with marked functional improvements, demonstrating robust tissue transduction and myotubularin expression, and considerably improved muscle fiber morphology. The safety profile of AT132 has been manageable: a total of seven serious AEs occurred, five in Patient 3 of which four were possibly or probably related to treatment. Subsequent to the data cutoff date, the remainder of Cohort 2 has been enrolled. Updated safety and efficacy data will be presented at the 2019 ASGCT Annual Congress.

http://50.23.255.131/clients/schedule_pdfs/1866/mediaid_337.pdf

Friday, May 10, 2019

Trametinib for progressive pediatric low-grade gliomas



Kondyli M, Larouche V, Saint-Martin C, Ellezam B, Pouliot L, Sinnett D, Legault G, Crevier L, Weil A, Farmer JP, Jabado N, Perreault S. Trametinib for progressive pediatric low-grade gliomas. J Neurooncol. 2018 Nov;140(2):435-444.

Abstract
INTRODUCTION:
Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors.

METHODS:
Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed.

RESULTS:
The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life.

CONCLUSION:
Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.


Thursday, May 9, 2019

Epidemiology of brain death in pediatric intensive care units


Kirschen MP, Francoeur C, Murphy M, Traynor D, Zhang B, Mensinger JL, Ichord R, Topjian A, Berg RA, Nishisaki A, Morrison W. Epidemiology of Brain Death in Pediatric Intensive Care Units in the United States. JAMA Pediatr. 2019 Mar 18. doi: 10.1001/jamapediatrics.2019.0249. [Epub ahead of print]

Abstract

IMPORTANCE:
Guidelines for declaration of brain death in children were revised in 2011 by the Society of Critical Care Medicine, American Academy of Pediatrics, and Child Neurology Society. Despite widespread medical, legal, and ethical acceptance, ongoing controversies exist with regard to the concept of brain death and the procedures for its determination.

OBJECTIVES:
To determine the epidemiology and clinical characteristics of pediatric patients declared brain dead in the United States.

DESIGN, SETTING, AND PARTICIPANTS:
This study involved the abstraction of all patient deaths from the Virtual Pediatric Systems national multicenter database between January 1, 2012, and June 30, 2017. All patients who died in pediatric intensive care units (PICUs) were included.

MAIN OUTCOMES AND MEASURES:
Patient demographics, preillness developmental status, severity of illness, cause of death, PICU medical and physical length of stay, and organ donation status, as well as comparison between patients who were declared brain dead vs those who sustained cardiovascular or cardiopulmonary death.

RESULTS:
Of the 15 344 patients who died, 3170 (20.7%) were declared brain dead; 1861 of these patients (58.7%) were male, and 1401 (44.2%) were between 2 and 12 years of age. There was a linear association between PICU size and number of patients declared brain dead per year, with an increase of 4.27 patients (95% CI, 3.46-5.08) per 1000-patient increase in discharges (P < .001). The median (interquartile range) of patients declared brain dead per year ranged from 1 (0-3) in smaller PICUs (defined as those with <500 discharges per year) to 10 (7-15) for larger PICUs (those with 2000-4000 discharges per year). The most common causative mechanisms of brain death were hypoxic-ischemic injury owing to cardiac arrest (1672 of 3170 [52.7%]), shock and/or respiratory arrest without cardiac arrest (399 of 3170 [12.6%]), and traumatic brain injury (634 of 3170 [20.0%]). Most patients declared brain dead (681 of 807 [84.4%]) did not have preexisting neurological dysfunction. Patients who were organ donors (1568 of 3144 [49.9%]) remained in the PICU longer after declaration of brain death compared with those who were not donors (median [interquartile range], 29 [6-41] hours vs 4 [1-8] hours; P < .001).

CONCLUSIONS AND RELEVANCE:
Brain death occurred in one-fifth of PICU deaths. Most children declared brain dead had no preexisting neurological dysfunction and had an acute hypoxic-ischemic or traumatic brain injury. Brain death determinations are infrequent, even in large PICUs, emphasizing the importance of ongoing education for medical professionals and standardization of protocols to ensure diagnostic accuracy and consistency.

Courtesy of:  https://www.mdlinx.com/journal-summaries/epidemiology-pediatric-brain-death-pediatric-intensive/2019/04/15/7563852?spec=neurology

The sydrome of the trephined


Khan NAJ, Ullah S, Alkilani W, Zeb H, Tahir H, Suri J. Sinking Skin Flap Syndrome: Phenomenon of Neurological Deterioration after Decompressive Craniectomy. Case Rep Med. 2018 Oct 23;2018:9805395.

Abstract
Sinking skin flap syndrome is rare phenomenon that occurs in patients with large craniectomies. Alteration in normal anatomy and pathophysiology can result in wide variety of symptoms including altered mental status, hemodynamic instability, and dysautonomias. Management is largely conservative. We here present a case of a patient with large craniectomy who was admitted to our hospital with pneumonia. Later on, he developed worsening mental status and CT head revealed sinking skin flap with significant midline shift. This is a very rare case of neurological deterioration after craniectomies, commonly known as sinking skin flap syndrome. To our knowledge, only few cases have been reported so far.
_______________________________________________________________________

From the article 

An 18-year-old male, nursing home resident, presented to the hospital with labored breathing and acute respiratory failure. The patient at baseline was nonverbal with a Glasgow coma scale (GCS) of 10/15. Approximately a year prior to presentation, the patient had suffered from traumatic brain injury after a fall. He underwent large left-sided craniectomy with a bone flap and placement of VP shunt at an outside hospital at the time. At initial presentation to our hospital, the patient was started on broad-spectrum intravenous antibiotics to cover for pneumonia. On day 3, the patient was noted to have sinus bradycardia with heart rate in the 40 s and low blood pressure at 90/60. On examination, the patient had a GCS of 8/15 with unequal pupils. Emergent CT head revealed sinking skin flap syndrome with paradoxical brain herniation and 19.9 mm midline shift (Figure 1). The patient was placed in Trendelenburg position and transferred to the intensive care unit for close monitoring. An urgent neurosurgery consult was also obtained, and cranioplasty was advised but the family deferred. The patient’s VP shunt was adjusted to increase the intracranial pressure. A repeat CT scan after 5 days revealed stable midline shift with no interval changes and improvement in mental status (Figure 2).


The syndrome of trephined is an uncommon postoperative complication that usually occurs after months of surgery in patients who undergo large craniectomy for various reasons like traumatic brain injury, malignant middle cerebral artery infarction, contusions, and subdural hematomas. The first case of sinking skin flap syndrome was reported by Yamamura et al. back in 1977. After that, sinking skin flap syndrome has been reported fairly in the literature. In a study of 108 patients performed back in 2008 who underwent decompressive crainectomy, syndrome of trephined was reported in 13% of patients between 28 and 188 days after the surgery.

Patients often present with symptoms of neurologic deterioration including new onset headache, dizziness, mood changes, fatigability, or seizures. Some patients present with delayed dysautonomic symptoms like postural hypotension and urinary and bowel dysfunction. Physical examination often reveals a large skull defect with an overlying depressed skin flap. The ubiquitous CT findings include paradoxical herniation, sunken skin flap sign, and deviation of the midline structures. The CT head without contrast of our patient revealed small slit-like ventricles and left-sided craniectomy defect with a sunken brain/skin flap. In addition, it was noted that the adjacent brain had an outwardly concave appearance with an associated midline shift to the right by 19.9 mm (Figure 1).

The pathophysiology of this syndrome is not clear. Some authors suggest that large craniectomies convert the cranium from a closed box to an open cavity which alters the brain pathophysiology. The atmospheric pressure and gravity overwhelms the intracranial pressure which leads to paradoxical herniation and sunken skin flap syndrome. Langfitt TW theorized that atmospheric pressure is directly transmitted to the intracranial cavity, which increases inward shifting of the scalp over the surgery site.

The treatment options in this catastrophic syndrome are limited and not clearly defined. The primary goal of treatment in syndrome of trephined is the restoration of external pressure that is exerted by the depression of the craniectomy site. The data supporting conservative management in patients with neurological deterioration are lacking. However, trendelenberg position largely reverses the paradoxical herniation in this syndrome. In some cases, intrathecal saline infusion was found to be effective in reversing the impending herniation.

The principal treatment option available currently is cranioplasty. It corrects the abnormal CSF dynamics by lowering the local intracranial pressure, thus improving postural blood flow and cerebral glucose metabolism.

Park HY, Kim S, Kim JS, Lim SH, Kim YI, Lee DH, Hong BY. Sinking Skin Flap Syndrome or Syndrome of the Trephined: A Report of Two Cases. Ann Rehabil Med.2019 Feb;43(1):111-114.

Abstract
Decompressive craniectomy (DC) is commonly performed in patients with intracranial hypertension or brain edema due to traumatic brain injury. Infrequently, neurologic deteriorations accompanied by sunken scalp may occur after DC. We report two patients with traumatic subdural hemorrhage who had neurologic deteriorations accompanied by sunken scalp after DC. Neurologic function improved dramatically in both patients after cranioplasty. Monitoring for neurologic deterioration after craniectomy is advised. For patients showing neurologic deficit with a sunken scalp, early cranioplasty should be considered.

Dillen WL, Pittman TA, Grupke SL. Novel Temporary Treatment for a Severe Case of Syndrome of Trephined. World Neurosurg. 2018 Dec;120:200-204.

Abstract
BACKGROUND:
Syndrome of the trephined is a unique neurosurgical condition that is seen in patients that have undergone craniectomy. While the symptoms of the condition range from mild to severe, the only definitive treatment for the condition is replacement of the bone flap. This article presents a novel, temporary treatment for syndrome of the trephined in a patient with severe symptoms who was unable to undergo immediate cranioplasty due to infection.

CASE DESCRIPTION:
A 25-year-old gentleman with a history of trauma resulting in hydrocephalus, craniectomy, and eventually ventriculoperitoneal shunt placement presented with a cranial wound infection requiring removal of his bone flap. While being treated with antibiotics, with his bone flap removed, he developed severe syndrome of the trephined. An emergency bedside procedure was developed and executed to treat his condition.

CONCLUSIONS:
Treating syndrome of the trephined with an external suction device proved useful and lifesaving fort the patient presented. Such a device can be made with common supplies found within any hospital. The technique used to treat the patient is novel and may be useful for others to consider if ever faced with a similar situation.

Nasal encephalocele


A family in Pakistan is desperate for surgeons to save their infant son whose brain is growing out of his nose. The boy, named Daeima, was born with nasal encephaloceles, a rare birth defect which causes a lack of bone fusion, leading to gaps in the skull in which portions of the brain can stick out.

Surgical intervention is typically necessary for children with encephalocele, and it’s usually performed between birth and 4 months of age depending on the size, location and associated complications as well as whether a layer of skin covers the encephalocele, according to the National Organization for Rare Disorders (NORD). But for 8-month-old Daeima, it wasn’t until his parents blew through their life savings and were turned away from numerous hospitals that he landed at Jinnah Postgraduate Medical Center in Karachi, Caters News reported.

“The infant was brought to us four days ago,” Dr. Raza Haroon, head of the hospital’s neurology department, told the news outlet. “It is a case of nasal encephalocele. We are waiting for more tests and MRI, but in such cases, surgery is the only treatment. If left untreated, a life-threatening infection called meningitis could develop.”

Haroon said his team will only proceed with the surgery if all tests are positive for the condition and has recommended changes to the boy’s diet plan to improve his overall health in the meantime.

https://www.foxnews.com/health/infant-born-with-brain-sticking-out-nose






Wednesday, May 8, 2019

Foreseeability


In a case that could have wide-reaching implications for medical practice in Minnesota, the Minnesota Supreme Court issued a ruling on April 17 in the case of Warren v. Dinter holding that the existence of a physician-patient relationship is not a prerequisite for a medical malpractice action. Rather, a person may sue a physician for malpractice – even if that person was not a patient of the physician – if the harm suffered by the person was a “reasonably foreseeable consequence” of the physician’s actions.

The MMA partnered with the AMA and the Minnesota Hospital Association to participate in the case as amici curiae, forcefully arguing that expanding physician liability outside of the physician-patient relationship would damage physician collaboration and informal consultation and ultimately harm patients. Despite this counsel, the Court issued a ruling that may hinder a physicians’ ability to collaborate with care partners.

“The overall expansive language in the Court’s opinion does raise concerns,” said Mark Fogg, COPIC’s General Counsel. Colorado-based COPIC is the MMA’s endorsed medical professional liability insurance (MPLI) provider for its members. “We respectfully believe that it is important that a physician-patient relationship be established before any liability may occur for alleged medical malpractice.”

The Warren v. Dinter case arises out of the care provided to a woman (Susan Warren), who complained of abdominal pain, fever, chills, and other symptoms to a nurse practitioner at Essentia Health Clinic in Hibbing. After testing showed that Warren had an elevated white blood cell count, the nurse practitioner suspected infection and sought hospitalization for her at Fairview Range Medical Center. The nurse practitioner’s call was randomly assigned to a hospitalist at Fairview to discuss admission.

After a brief conversation, during which the physician was unable to view the patient’s medical record, the physician and the nurse practitioner discussed hospitalization and whether the elevated white-cell count and blood sugar could be the result of diabetes. The physician did not recommend hospitalization during the conversation and the nurse practitioner did not seek hospitalization for the patient following the conversation. The patient subsequently died from sepsis caused by an untreated staph infection. Warren’s family sued both the nurse practitioner and the physician for medical malpractice.

Before its ruling April 17, Minnesota law has generally required the existence of a physician-patient relationship to sustain a malpractice action against a physician. The Court’s decision to rely on a broader legal theory of “foreseeability” represents a troubling change that puts Minnesota in the minority of states that do not require the existence of a physician-patient relationship for a malpractice action. This change may expose physicians and other health professionals to malpractice risk in a variety of actions that were previously protected, including unbilled consultations. Although the ruling puts Minnesota physicians in uncertain legal territory, it does not change the underlying duty that physicians have to their patients and, more generally, to maintain a professional and ethical medical practice.

The MMA is developing resources for physicians to better understand their legal risks following the Warren v. Dinter decision and is exploring policy options to ensure that physicians can continue to collaborate with their peers and provide the best care possible to their patients.

https://www.mnmed.org/news-and-publications/News/MN-Supreme-Court-Rules-Physician-Patient-Relations?utm_source=Informz+Email&utm_medium=Informz&utm_campaign=Informz+Emails&_zs=7CPLX&_zl=kE8b1

The FDA has approved the first treatment for children with Lambert-Eaton myasthenic syndrome


The US Food and Drug Administration (FDA) has approved the first treatment for children with Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disorder.

Amifampridine (Ruzurgi, Jacobus Pharmacuetical) is an oral potassium channel blocker indicated for children and adolescents aged 6 years to less than 17 years who have LEMS.

The FDA first approved amifampridine tablets (Firdapse, Catalyst Pharmaceuticals) for adults with LEMS in November 2018, as reported by Medscape Medical News.

"We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children," Billy Dunn, MD, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, said in a news release. "This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities," said Dunn.
  
LEMS affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. LEMS may be associated with other autoimmune diseases but more commonly occurs in patients with small–cell lung cancer. In these patients, its onset precedes or coincides with the diagnosis of cancer.

The prevalence of LEMS in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per 1 million individuals worldwide, according to the FDA.

The agency says use of Ruzurgi in patients aged 6 years to less than 17 years is supported by evidence from studies conducted in adults with LEMS as well as pharmacokinetic modeling and simulation to identify the appropriate dosing regimen for children and to determine safety data for children.

The effectiveness of amifampridine for the treatment of LEMS was established in a randomized, double-blind, placebo-controlled withdrawal study of 32 adults who took amifampridine for at least 3 months prior to entering the study. Effectiveness was measured by the degree of change in scores on the Timed Up and Go Test. Patients who continued to take amifampridine instead of switching to placebo experienced less impairment than those who took placebo.

Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients who switched to placebo.

The most common side effects experienced by pediatric and adult patients taking amifampridine were paresthesia, abdominal pain, indigestion, dizziness, and nausea. Side effects reported in children were similar to those seen in adult patients. Seizures have been observed in patients who do not have a history of seizures.

The drug received breakthrough and orphan drug designation and priority review.

https://www.medscape.com/viewarticle/912722

The treatment landscape for spinal muscular atrophy,


SPINAL MUSCULAR ATROPHY

The treatment landscape for spinal muscular atrophy, or SMA, a rare and potentially lethal genetic disease, is about to change. Until the 2016 approval of nusinersen (Spinraza) from Biogen (NASDAQ: BIIB), there were no approved medicines to help slow the progressive weakness that characterizes the disease. Infused into the spine a few times a year, for life, Spinraza has shown it works for people with multiple forms of SMA. It is now the standard of care for the disease and generated $1.7 billion for Biogen last year.

But other treatments are coming, which, as Xconomy reported last week, will present doctors and payers with tough logistical and economic questions. The two treatments under the microscope at AAN are Zolgensma, from Novartis (NASDAQ: NVS), and risdiplam, from Roche and partner PTC Therapeutics (NASDAQ: PTCT).

ZOLGENSMA

The gene therapy ideally would provide the same benefits as Spinraza, but through a single long-lasting infusion. The FDA could approve Zolgensma this month.

Prior to AAN, Zolgensma has shown promise in Type 1 SMA, the deadliest form of the disease, diagnosed within six months of birth. On Sunday, the Basel, Switzerland-based pharma offered more Type 1 data from the STR1VE study. But it also offered the first glimpse of studies meant to show that, like Spinraza, Zolgensma can help others with the disease as well. The STRONG study is testing Zolgensma in Type 2 patients who could sit, but not stand or walk, at the start of the study. Pre-symptomatic patients got Zolgensma in a study known as SPR1NT.

Both trials compare Zolgensma’s effects to historical data, not a placebo. Those effects are measured via tests (CHOP-INTEND, HFMSE, and Bayley-III Gross Motor Milestones) that assess physical abilities and developmental milestones. One key milestone is whether patients are alive and not using a ventilator at the age of 14 months.

Patients in STRONG were followed a median of 6.5 months after treatment, in SPR1NT, 5.4 months. At this point, neither study has lasted long enough to assess Zolgensma’s promise of a long-lasting treatment, let alone a cure. The data are being closely watched, despite not including results from the highest dose in the study. Here’s a snapshot.

STRONG: Novartis put Type 2 patients in two groups: babies six to 24 months of age, and young children two to five years old. For babies, the study’s main goal is to help them stand or walk without support for more than three seconds. For young children, the goal was a positive change on the HFMSE.

Two of the 16 babies evaluated thus far can stand without help. One of them can walk. One of the 12 young children can walk with assistance. All the patients, at minimum, maintained their abilities from the study’s start, like rolling over, controlling their head, and more. Seven of the babies and three of the young children gained an ability. All the patients are still alive, and those who have gone through HFSME evaluations have seen their scores increase.

The only serious side effects were a temporary spike in liver enzymes, a common occurrence in gene therapy trials.

SPR1NT: Novartis enrolled 18 newborn patients who had yet to show symptoms and had either two or three copies of the SMN2 gene, a predictor of disease severity. The more SMN2 genes a person has, the more mild their disease will be. (SMN stands for spinal motor neuron.)

Thus far, all 18 patients are alive. Four of eight patients with two SMN2 copies could sit independently following treatment, and one could walk. Historical data suggest these patients would never hit those goals otherwise. They also saw their CHOP-INTEND scores increase, a sign of improvement that wouldn’t be expected without treatment. No serious side effects seen were attributed to the gene therapy.

Alex Fay, a pediatric neurologist at UCSF Benioff Children’s Hospital in San Francisco, CA, cautions that it will probably take more time to “see the full range of benefit” of Zolgensma in Type 2 and 3 patients. He also notes that older patients appear more likely to have an immune defense against the treatment, which could be a problem. Still, “I think the take-home points are that gene therapy seems to be effective and safe across subtypes of early-onset SMA, efficacy appears comparable to Spinraza’s, and that there will likely be a continued role for Spinraza in treating patients with SMA,” he said after looking over the data.

Using Spinraza and Zolgensma together, particularly in pre-symptomatic patients, could be more beneficial, he adds. But combination therapy hasn’t been tested and the costs would be significant.

RISDIPLAM

Like Spinraza and Zolgensma, risdiplam is meant to boost the production of the SMN protein that SMA patients lack. (Without it, motor neurons in the spinal cord waste away.)

The oral risdiplam could be more convenient. Susan Begelman, the head of medical affairs for neuroscience for Roche’s Genentech unit, notes that patients could take risdiplam on their own, and not have to go to a doctor’s office. Some SMA patients have scoliosis or spinal fusions and may not be eligible for therapy infused into the spine; some might have trouble tolerating the painful spinal taps three times a year. “This is another advantage of an oral medicine,” Begelman says.

Roche isn’t just testing risdiplam in infants, but in teenagers and adults as well. The data backing Spinraza and Zolgensma has come from younger patients.

It’s hard to compare results across trials, but until there are head-to-head studies, Spinraza and Zolgensma have set a high bar for safety and efficacy. And Roche still has a ways to go. This week’s AAN data are only from dose-finding studies, which aren’t designed to show whether the drug can change the disease. That work is now underway, with data expected later this year and in early 2020.

Here are the results from the Roche studies FIREFISH and SUNFISH.

FIREFISH: This is a study in babies one to seven months old with Type 1 SMA. Roche said, a median of 14.8 months after beginning treatment, seven of the 17 babies who got the risdiplam dose being carried forward could sit independently for at least five seconds—the main goal of the “confirmatory” portion of the trial. Additionally, 11 could sit with or without support; nine had head control; and one could stand.

Fifteen of the 17 getting the key risdiplam dose are alive. Their CHOP-INTEND scores have improved. And none have lost the ability to swallow or needed a ventilator or a tube inserted into their windpipe to help them breathe.

“It’s really encouraging how much improvement we’ve noticed in these children,” says Giovanni Baranello, a Pediatric Neurologist at the Carlo Besta Neurological Institute in Milan, Italy, and the lead investigator of the FIREFISH study.

Despite side effects including fever, respiratory tract infections, vomiting, diarrhea, and pneumonia, no patient stopped treatment, Begelman says.

SUNFISH: This study tests risdiplam in patients from two to 25 years old and have either Type 2 or 3 SMA. Some might be unable to sit, while others can walk. To judge their progress, Roche is using a neuromuscular disease test called Motor Function Measure-32.

In the dose-finding portion of its study, Roche found that 25 of 43 patients (58 percent) evaluated for at least 12 months saw their MFM-32 scores rise at least three points. (In a disease where function steadily decreases, any increase in functional score is notable.)

The benefits were less pronounced for older patients, 12 to 25 years old, which appears to jive with what’s become known about SMA; the earlier the treatment, the better the benefit. “We’ll learn as we collect more data,” Begelman says.

So will patients. Roche enrolled 180 of them in the confirmatory part of the study. Baranello is keeping an eye on what patients say about their experience—particularly the teenagers and young adults. “Ultimately they are the ones responsible for making the decision to be treated,” he says.