Sunday, June 30, 2019

Mirabile dictu 5

An expectant mother in Chicago said she would do whatever it took to bring her girls safely into the world after she learned that a mass was growing on one of her unborn babies' necks, putting both her and her twin sister’s health in potential jeopardy.

Although the mass was determined to be a teratoma tumor, which is not cancerous, it was restricting baby Jenessa’s airway and causing fluid buildup in the womb, while also putting potential stress on their shared placenta.

But doctors at The Chicago Institute for Fetal Health at Ann & Robert H. Lurie Children’s Hospital of Chicago miraculously were able to partially deliver Jenessa through an ex utero intrapartum treatment (EXIT) at 29 weeks gestation to place a breathing tube in her airway and IV in her hand, all while her twin sister, Genesis, remained unaffected in her mother’s womb, according to the hospital’s blog.

“We brought the upper torso, the neck and the arms out to be able to get access to the airway, the windpipe, as well as to the hands, and to be able to put an IV in and to monitor the baby’s oxygenation and heart rate,” Dr. Aimen Shaaban, who led the 40-person team, told WGN9.

Throughout the procedure, Janessa’s umbilical cord remained attached, until the pre-surgical prep was complete and doctors delivered her completely.

She was then immediately whisked from the delivery room to the operating room where they removed the mass, which had grown to nearly the same size as her head. Genesis, who was being monitored carefully while surgeons worked on her sister, was born immediately after Jenessa’s birth. Both girls spent several months separated in the NICU, with Genesis first getting released in March, and mom Theodora Flores finally able to pack up Jenessa’s room this past Thursday.

“I’m so happy for her,” Shaaban, said, according to the hospital’s blog. “She told us the most important thing is that she takes home the babies that God gave her. And she has.”

While Jenessa headed home with a tracheostomy tube and gastronomy tube, her medical team believes she will one day be strong enough to get rid of both, according to the hospital’s blog.

Saturday, June 29, 2019

Tocilizumab in autoimmune encephalitis

Randell RL, Adams AV, Van Mater H. Tocilizumab in Refractory Autoimmune Encephalitis: A Series of Pediatric Cases. Pediatr Neurol. 2018 Sep;86:66-68.


Autoimmune encephalitis can result in significant neurological and psychiatric morbidity and mortality in patients of all ages and often does not respond to standard therapies. Recent reports suggest efficacy of tocilizumab, a monoclonal antibody against interleukin 6, in refractory autoimmune encephalitis.

We describe three children with refractory autoimmune encephalitis who experienced a robust, immediate clinical response following treatment with tocilizumab.

These findings support the efficacy and short-term safety of tocilizumab as a third-line treatment for refractory autoimmune encephalitis in children.

Breu M, Glatter S, Höftberger R, Freilinger M, Kircher K, Kasprian G, Seidl R, Kornek B. Two Cases of Pediatric AQP4-Antibody Positive Neuromyelitis Optica Spectrum Disorder Successfully Treated with Tocilizumab. Neuropediatrics. 2019 Jun;50(3):193-196.


B cell depletion with the anti-CD20-antibody rituximab is widely considered treatment of choice for long-term immunotherapy in aquaporin-4 (AQP4)-antibody positive neuromyelitis optica spectrum disorder (NMOSD). However, up to 30% of patients suffer from relapses despite complete B cell depletion. In these cases, the IL6 (interleukin-6)-receptor blocking antibody tocilizumab has been suggested as an alternative. We report two female adolescents with AQP4-antibody positive NMOSD who relapsed under rituximab treatment and clinically stabilized after switching to monthly administrations of tocilizumab. Our data suggest that early escalation of therapy with tocilizumab may lead to stabilization of disease activity in pediatric NMOSD patients who relapse under B cell depletion.

Friday, June 28, 2019

Medical mayhem 11

[a $250,000 fine for more than $13 million in insurance claims]

A federal jury in Pittsburgh deliberated just 2 hours before finding cardiologist Samirkumar J. Shah, MD, guilty on two counts of fraud related to more than $13 million in insurance claims for external counterpulsation (ECP) therapy, the US Department of Justice has announced.

ECP treatment uses inflatable cuffs wrapped around the lower extremities to increase venous return and augment diastolic blood pressure. Enhanced ECP gained US approval in 1995 for the treatment of patients with CAD and refractory angina.

Evidence during the 8-day trial showed that Shah, 56, of Fox Chapel, Pennsylvania, advertised ECP as the "Fountain of Youth," claimed it made patients "younger and smarter," and offered treatment for conditions other than disabling angina, including obesity, hypertension, hypotension, diabetes, and erectile dysfunction.

Insurers, however, only reimbursed for ECP for patients with disabling angina and only when a physician supervised treatment.

"After signing up new patients, including many patients who never experienced chest pain, Shah instructed his employees to indicate that every patient had disabling angina on billing sheets that were used to support false insurance claims. In certain instances, Shah never met patients for whom he billed for ECP treatments," says the June 14 news release.

Shah owned 25 beds and offered ECP to patients at more than 18 locations in Western Pennsylvania, Ohio, New York, and Florida. These treatments "routinely occurred" while neither Shah nor other physicians were present and, in one such instance, a patient experienced an adverse event requiring transport to hospital, according to the release.

Witness testimony also established that Shaw required patients to undergo diagnostic ultrasounds prior to ECP, in part to rule out blood clots, but did not review any of the images prior to approving new patients for ECP.

Contraindications to enhanced ECP include decompensated heart failure, severe peripheral artery disease, and severe aortic regurgitation, according to a 2014 multisociety focused update on stable ischemic heart disease (SIHD). It states that enhanced ECP "may be considered" for relief of refractory angina in patients with SIHD (class IIb evidence).

Shah double-billed insurers using a bundled ECP code, "routinely submitted fabricated patient files," and "made false statements concerning his practice, his patient population, his record keeping, and his compliance with applicable coverage guidelines," the release says.

Between 2008 and 2013, Shah submitted ECP-related claims to Medicare, Medicaid, Highmark Blue Cross Blue Shield, UPMC Health Plan, and Gateway Health Plan beneficiaries totaling more than $13 million, for which he received payments in excess of $3.5 million.

"Doctors and medical professionals like Dr Shah who issue false diagnoses, order unnecessary testing and fraudulently bill Medicare and Medicaid in effect steal from the most vulnerable in our community," United States Attorney Scott W. Brady said in the release. "Today's jury verdict sends a clear message to those who would do the same: if you commit health care fraud, you will be prosecuted to the fullest extent of the law."

Shah is to be sentenced November 6 and faces a maximum of 10 years in prison, a fine of $250,000, or both.

CLN7-NCL treated with an antisense oligonucleotide

A custom-crafted antisense oligonucleotide therapy (ASO) has brought hope, and perhaps effective treatment, to a young girl with a rare form of Batten disease—so rare, in fact, that she is likely the only person in the world whose disease is caused by this particular mutation. Her treatment is also unique to her. And as the ultimate example of “personalized medicine,” it illustrates the potential of the genomic revolution in medicine, even as it raises questions about how such uniquely crafted therapies can be offered to other patients with other diseases.

“This drug is only applicable to our patient, not to others with Batten disease,” said lead researcher Timothy W. Yu, MD, PhD, assistant professor in pediatrics at Harvard Medical School and attending physician in the division of genetics and genomics at Boston Children's Hospital. “But we do think it has potentially broad implications.”...

The patient, a young girl, developed normally until 2016, when, at the age of 4, she began to exhibit vision loss and gait impairment. By age 6, her gait had worsened, her speech became slurred, her behavior regressed, and her vision declined significantly. She was admitted to the hospital, where tests showed retinal degeneration, cerebellar atrophy, and subclinical seizures. Clinical genetic testing led to a diagnosis of Batten disease, or neuronal ceroid lipofuscinosis, specifically CLN7-NCL, so rare that only about 70 patients have been described in the literature.

“This is a terrible, terrible, diagnosis,” Dr. Yu said, with invariable and rapid progression, leading to death at about 11 years of age. “But in this case, there was a wrinkle, because she only had half a diagnosis.”

The genetic testing had turned up only one mutation in the CLN7 gene, but all other known cases were autosomal recessive, with two mutations. “So where was the second mutation?”

The family's geneticist told them they would need whole genome sequencing to understand the full genetic picture. In late 2016, there were relatively few labs in the country that could perform such sequencing with very rapid turnaround, but a friend of the girl's family used social media to plead for help. “That's where my lab came in,” Dr. Yu said, who became aware of the case when his wife shared the social media post with him.

Members of his lab began sequencing, and by early 2017, they had their answer: “Instead of finding a point mutation in the CLN7 gene, we found a retrotransposon,” Dr. Yu said. Commonly known as “jumping genes,” retrotransposons, which litter the genome, are mostly inactive, but occasionally become transcribed into RNA, converted back into DNA, and then randomly inserted back into the genome. “And if you are unlucky enough, it can land in a critical neurogenetic disease gene, where it can disrupt that gene and cause a disease. We discovered this is exactly what had happened in our patient,” Dr. Yu said.

The retrotransposon had been inserted into the CLN7 gene deep within an intron between exons 6 and 7—clinical testing did not detect the mutation because the tests only look for exonic or near-exonic variants. The insertion had created a new splice site, which in turn created a new exon, but one that carried a stop codon, preventing protein production.

“So then we asked the question, could we fix this using an antisense oligonucleotide to block the abnormal splicing?” Dr. Yu said. He was “only emboldened to even think about this approach” because in December 2016, the ASO nusinersen (Spinraza), which alters splicing, was approved for spinal muscular atrophy, an autosomal recessive neurodegenerative disease.

“We decided to try to design an ‘N-of-one’ customized therapy,” he said. [An “N-of-one is a study in which a single patient is the entire clinical trial.] To do so, they combined a gene-specific screen in patient fibroblasts, bioinformatics to predict the exact splice site regulatory elements, design and synthesis of candidate ASOs, and cellular assays to determine if the ASO improved cellular function. After discussions with the family, they approached the US Food and Drug Administration (FDA) in August of 2017 to discuss their plans to move ahead if the preclinical results were promising.

By October 2017, they had shown that one candidate ASO partially corrected expression of the normal transcript, and cell assays indicated it reduced storage material, shrank lysosomal mass, and corrected lysosomal enzyme trafficking. “By every measure we looked at, our oligonucleotide was improving lysosomal function,” Dr. Yu said. He named the ASO “milasen,” in honor of his patient, Mila (her parents gave permission for her name and details of the story to become public).

At the same time, though, Mila was declining, with many prolonged seizures every day—“Time is running out,” her family said during that summer. Dr. Yu's team began to create a plan to accelerate the rest of the drug development process, including manufacturing, formulation, and animal toxicity tests, and to design the elements of their N-of-one trial.

Through cooperation and tight coordination among the lab, contract research and manufacturing organizations, and the FDA, all of that was completed within four months. On January 31, 2018, Mila received her first dose of the ASO, delivered intrathecally. Administration at escalating doses continued every two weeks for 14 weeks, followed by maintenance dosing about every three months.

“We are now a little over one year into our trial,” Dr. Yu said. “The treatment is well tolerated, and there are no adverse effects attributable to the drug.” As for outcomes, he stressed, “this is a single patient,” with no control group, “but the family has reported substantial stabilization compared with the steep decline she was exhibiting before treatment.”

Supporting that observation are results from seizure diaries. “At the beginning, there were up to 30 seizures per day, with almost all of them lasting more than one minute. What we saw over the course of the dose escalation is the frequency went down, and the intensity lessened, so that almost none of them were over one minute.” That improvement has been maintained, Dr. Yu said, over the first year. “We think of this as a very promising early sign.”...

But in order to proceed with treatment, Dr. Bennett [Frank Bennett, PhD, senior vice president of research and franchise leader for neurological programs at Ionis Pharmaceuticals, which discovered and developed nusinersen] stressed, “you need to demonstrate that the ASO leads to a recovery of function,” or a slowing of decline, which, as in Dr. Yu's case, required significant lab resources in addition to the genomic and bioinformatic investments. It is likely impossible to calculate the full cost of the development of milasen, since much of the work was donated and done by volunteers, but a similar effort done at market rates might approach one million dollars, he said.

“I don't see a way we can do this commercially with a viable business model, but I do see ways, either through charities, or foundations, or the NIH, that we can broaden the applicability of this to treat more patients,” Dr. Bennett said. “Tim has opened a brave new frontier for us.”

Thursday, June 27, 2019

Spastic paraplegia and psychomotor retardation with or without seizures and HACE1 deficiency

Vanja Nagy, Ronja Hollstein, Tsung-Pin Pai, Michel K. Herde, Pisanu Buphamalai, Paul Moeseneder, Ewelina Lenartowicz, Anoop Kavirayani, Georg Christoph Korenke, Ivona Kozieradzki, Roberto Nitsch, Ana Cicvaric, Francisco J. Monje Quiroga, Matthew A. Deardorff, Emma C. Bedoukian, Yun Li, Gökhan Yigit, Jörg Menche, E. Ferda Perçin, Bernd Wollnik, Christian Henneberger, Frank J. Kaiser, Josef M. Penninger.  HACE1 deficiency leads to structural and functional neurodevelopmental defects.  Neurol Genet Jun 2019, 5 (3) e330; DOI: 10.1212/NXG.0000000000000330


Objective We aim to characterize the causality and molecular and functional underpinnings of HACE1 deficiency in a mouse model of a recessive neurodevelopmental syndrome called spastic paraplegia and psychomotor retardation with or without seizures (SPPRS).

Methods By exome sequencing, we identified 2 novel homozygous truncating mutations in HACE1 in 3 patients from 2 families, p.Q209* and p.R332*. Furthermore, we performed detailed molecular and phenotypic analyses of Hace1 knock-out (KO) mice and SPPRS patient fibroblasts.

Results We show that Hace1 KO mice display many clinical features of SPPRS including enlarged ventricles, hypoplastic corpus callosum, as well as locomotion and learning deficiencies. Mechanistically, loss of HACE1 results in altered levels and activity of the small guanosine triphosphate (GTP)ase, RAC1. In addition, HACE1 deficiency results in reduction in synaptic puncta number and long-term potentiation in the hippocampus. Similarly, in SPPRS patient–derived fibroblasts, carrying a disruptive HACE1 mutation resembling loss of HACE1 in KO mice, we observed marked upregulation of the total and active, GTP-bound, form of RAC1, along with an induction of RAC1-regulated downstream pathways.

Conclusions Our results provide a first animal model to dissect this complex human disease syndrome, establishing the first causal proof that a HACE1 deficiency results in decreased synapse number and structural and behavioral neuropathologic features that resemble SPPRS patients.

Han-Xiang Deng   HACE1, RAC1, and what else in the pathogenesis of SPPRS?  Neurol Genet Jun 2019, 5 (3) e326; DOI: 10.1212/NXG.0000000000000326

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is a complex neurodevelopmental disorder with an autosomal recessive inheritance. SPPRS typically shows an infantile onset, starting with hypotonia either at birth or by age 3–4 months, followed by severely impaired global development and delayed early motor milestones.  All patients with SPPRS develop slowly progressive bilateral lower limb spasticity, leaving them wheelchair bound and bed bound by their 20s. In some cases, patients may never walk. Most patients develop seizures in childhood and have a speech delay. Other variable features include ocular abnormalities, sensorineural hearing loss, skeletal abnormalities, obesity, and double incontinence. Some male patients have hypoplastic genitalia. Brain imaging may show generalized cerebral atrophy, ventricular dilatation, hypoplasia of the corpus callosum, and decreased white matter.

By using family-based and unbiased genotype-driven whole-exome sequencing approaches, Hollstein et al. and Akawi et al. identified mutations of HACE1 in several patients with SPPRS.1,2 HACE1 encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase (HACE1), which is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. Most HACE1 mutations in patients with SPPRS lead to a premature stop codon, suggesting that loss of HACE1 function causes SPPRS. However, the pathogenic mechanism remains largely unknown.

In this issue, Nagy et al. provide important information for understanding the pathogenic mechanism underlying SPPRS.  They identified 2 novel homozygous truncating mutations in HACE1 in 3 patients from 2 families. More importantly, they performed detailed molecular and phenotypic analyses of Hace1 knockout mice and SPPRS patient fibroblasts. They showed several clinical features in the Hace1 knockout mice, which are similar to those observed in patients with SPPRS, including deficiencies in locomotion and learning/memory, enlarged ventricles, and hypoplastic corpus callosum. Pathologic and neurophysiologic studies demonstrated a reduced number of synaptic puncta and altered hippocampal synaptic transmission. The authors observed increased levels of active Rac1 in the Hace1 knockout mouse brain and SPPRS patient–derived fibroblasts. RAC1 is a small GTPase with diverse roles in signaling, and HACE1 targets RAC1 to the ubiquitin/proteasome system for degradation.  Therefore, the authors hypothesize that upregulation of the RAC1 pathway may underlie the pathogenesis of SPPRS because of defective degradation of RAC1 by HACE1 deficiency. This is the first in vivo study to show a molecular pathway underlying SPPRS.

A total of 11 mutations in 17 SPPRS cases have been reported to date.  Except for a single amino acid deletion (p.Leu832del), all the others are truncation mutations. Although these truncation mutations presumably have almost identical functional consequences, great variations of clinical symptoms and disease severity were observed in these patients with SPPRS, suggesting that other genetic and environmental modifiers influence phenotype expression. It is known that the ankyrin repeats of HACE1 are responsible for substrate recognition, whereas the HECT domain is essential for ubiquitinylation. The p.Leu832del mutation is located in the HECT domain, suggesting that the loss of ubiquitinylation activity, rather than the loss of the entire HACE1 protein, is critical for development of SPPRS.

Loss of HACE1 was initially noted in human malignancies, and Hace1 knockout mice were shown to develop spontaneous, late-onset multiple tumors after age 1 year.  The tumor incidence was almost tenfold higher in the Hace1 knockout homozygotes than the heterozygotes in 2-year-old mice (12% vs 1.3%). Loss of Hace1 also rendered mice susceptible to second environmental and genetic hits for the development of multiple cancers. This led to the hypothesis that HACE1 is a tumor suppressor gene, which prevents tumorigenesis by suppressing cyclin D levels and reactive oxygen species generation. However, the neurodevelopmental phenotype and pathology in the Hace1 knockout mice have not been comprehensively investigated until the present study.

The hypothesis that upregulation of the RAC1 pathway underlies the pathogenesis of SPPRS is compatible with the previous data. It is well known that RAC1 plays an essential role in development and structural plasticity of dendrites and dendritic spines Transgenic mice overexpressing constitutively active RAC1 in Purkinje neurons lead to ataxia and reduced Purkinje neuron axon terminals and smaller but increased number of dendritic spines. Recently, heterozygous missense mutations in RAC1 were identified in developmental disorders with diverse phenotypes. Among 7 RAC1 mutations, p.Tyr64Asp appears to be constitutively active. The patient with this mutation showed some clinical features overlapping with those in SPPRS, including severely impaired global development and delayed early motor milestones, hypoplastic corpus callosum and genitalia, ocular abnormalities, and sensorineural hearing loss. However, marked differences were also observed. Notably, the patient with p.Tyr64Asp showed hypotonia soon after birth, but he did not seem to develop progressive spasticity, a specific feature in SPPRS, even by age 12 years.  This may suggest that upregulation of RAC1 is one of the multiple pathways affected by the HACE1 deficiency in SPPRS.

Upregulation of RAC1 in SPPRS suggests a potential therapeutic approach by using specific pharmacologic inhibition of RAC1.  However, caution should be taken because the development and function of the brain requires RAC1 to be finely tuned, as shown by the observations that either loss (or dominant-negative effect) or gain of RAC1 function led to developmental disorders in humans, and both depletion and overexpression of Rac1 resulted in abnormal phenotypes in Xenopus laevis.

Upregulation of RAC1 may explain a part of the clinical symptoms in SPPRS, but it does not cover the full spectrum. This suggest that HACE1 may have other substrates. Indeed, HACE1 also regulates other small GTPases, including RAB11a, RAB6a, and RAB8a. It has also been reported that Hace1 promotes the stability of Nrf2 and plays an important role in antioxidant response, and loss of hace1 in a mouse model of Huntington disease accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes.

The molecular mechanism by which increased RAC1 leads to the abnormal structure and function of synapses and the pathogenic roles of other HACE1 regulated proteins in the pathogenesis of SPPRS are still not understood. These issues remain to be addressed in future studies.

Vanja Nagy, Ronja Hollstein, Tsung-Pin Pai,  Michel K. Herde, Pisanu Buphamalai, Paul Moeseneder, Ewelina Lenartowicz, Anoop Kavirayani, Georg Christoph Korenke, Ivona Kozieradzki, Roberto Nitsch, Ana Cicvaric, Francisco J. Monje Quiroga, Matthew A. Deardorff, Emma C. Bedoukian, Yun Li, Gökhan Yigit,  View ORCID ProfileJörg Menche, E. Ferda Perçin, Bernd Wollnik.  HACE1 deficiency leads to structural and functional neurodevelopmental defects.  Neurol Genet Jun 2019, 5 (3) e330; DOI: 10.1212/NXG.0000000000000330


Objective We aim to characterize the causality and molecular and functional underpinnings of HACE1 deficiency in a mouse model of a recessive neurodevelopmental syndrome called spastic paraplegia and psychomotor retardation with or without seizures (SPPRS).

Methods By exome sequencing, we identified 2 novel homozygous truncating mutations in HACE1 in 3 patients from 2 families, p.Q209* and p.R332*. Furthermore, we performed detailed molecular and phenotypic analyses of Hace1 knock-out (KO) mice and SPPRS patient fibroblasts.

Results We show that Hace1 KO mice display many clinical features of SPPRS including enlarged ventricles, hypoplastic corpus callosum, as well as locomotion and learning deficiencies. Mechanistically, loss of HACE1 results in altered levels and activity of the small guanosine triphosphate (GTP)ase, RAC1. In addition, HACE1 deficiency results in reduction in synaptic puncta number and long-term potentiation in the hippocampus. Similarly, in SPPRS patient–derived fibroblasts, carrying a disruptive HACE1 mutation resembling loss of HACE1 in KO mice, we observed marked upregulation of the total and active, GTP-bound, form of RAC1, along with an induction of RAC1-regulated downstream pathways.

Conclusions Our results provide a first animal model to dissect this complex human disease syndrome, establishing the first causal proof that a HACE1 deficiency results in decreased synapse number and structural and behavioral neuropathologic features that resemble SPPRS patients.

Wednesday, June 26, 2019

Supratherapeutic clobazam

Gedela S, Gedela S, Glynn P, Salvator A, Patel AD. Safety and Efficacy of Supratherapeutic Doses of Clobazam. J Child Neurol. 2019 Jun 19:883073819856834. doi: 10.1177/0883073819856834. [Epub ahead of print]

Clobazam is a commonly used long-acting benzodiazepine approved by the US Food and Drug Administration (FDA) to treat seizures associated with Lennox Gastaut syndrome. The FDA approved maximum dosage of clobazam is 1 mg/kg/d or a total of 40 mg a day. Many providers exceed this dosage but there is limited data on the safety, tolerability, and efficacy of supratherapeutic doses. We reviewed retrospective data at our institution and compared patients on supratherapeutic doses to patients on therapeutic doses. A total of 133 patients met inclusion criteria (65 supratherapeutic, 67 therapeutic). There was no statistically significant difference in terms of seizure control, health care utilization, or side effects between patients on supratherapeutic doses and those on therapeutic doses. This study lends further support to the safety and tolerability of supratherapuetic doses of clobazam.

From the article:

Clobazam dose was calculated into milligrams per kilogram body weight for each patient using the weight from the same visit that dose was obtained. Patients were then classified as supratherapeutic dosing (SUPRA, defined as using a dose of >1 mg/kg/d or 40 mg/d) or therapeutic dosing for patients with doses less than the FDA-approved maximum dose of 1 mg/kg/d or 40 mg/d (THERA)…

Overall, patients with supratherapeutic doses of clobazam were younger and more likely to have generalized onset seizures. Patients given therapeutic doses were more likely to have focal onset seizures. In addition, these higher doses were well tolerated, and there was no statistical difference in adverse events for the 2 groups. Importantly, no differences in seizure frequency or health care utilization were noted between the 2 groups…

In summary, supratherapeutic doses of clobazam were well tolerated, without an increased reporting of side effects compared to patients receiving doses that are in the normal therapeutic range as recommended by the FDA. Therefore, patients who do require higher doses can be counseled that the likelihood of side effects may not increase with elevated dosing. Interestingly, patients in our study receiving higher doses of clobazam did not appear to have greater benefit in seizure reduction when compared to normal dose ranges of clobazam. However, it is unclear if this correlation is accurate based on the difficulty of seizure frequency reporting in our chart review. Further work with a uniform and accurate method of detailing seizure frequency would be needed to determine truly if differences in seizure reduction exist between higher doses compared to lower doses of clobazam. In addition, the patients receiving higher doses of clobazam may have had more difficult to treat seizures, thus necessitating increased doses in a treatment-resistant population. Finally, the patients receiving supratherapeutic doses of clobazam were younger and more likely to have generalized onset seizure types, which may have reflected a population with a higher likelihood of treatment failure or not having a reduction in seizure frequency.18 Further randomized controlled prospective studies are needed to fully understand the differences between dosing strategies in epilepsy patients treated with clobazam.

Tuesday, June 25, 2019

Forced abortion of young disabled woman halted

On Monday, after a public outcry ensued when a British judge ordered a young disabled woman to have an abortion, the English Court of Appeal reportedly overturned the decision.

As the Catholic News Agency reports, Lord Justice McCombe, Lady Justice King and Lord Justice Peter Jackson overruled the June 21 decision by Justice Nathalie Lieven of the Court of Protection, who had ruled that a forced abortion was “in the best interests” of the pregnant woman.

The decision triggered over 75,000 people to sign a petition that Right to Life UK posted on June 22 that asked U.K. Health and Social Care Secretary Matthew Hancock to “intervene in this case, so far as possible, to prevent this gross injustice being inflicted by the State on this family and ensure this woman is not forced to have an abortion.”

Scottish Bishop John Keenan of the Diocese of Paisley encouraged people to sign the petition, asserting that Lieven’s ruling “introduces a dangerous new development in the overreach of the power of the state over its citizens,” and “has to be changed.” Bishop John Sherrington, an auxiliary bishop of the Archdiocese of Westminster, denounced Lieven’s decision, stating:

Forcing a woman to have an abortion against her will, and that of her close family, infringes upon her human rights, not to mention the right of her unborn child to life in a family that has committed to caring for the child. In a free society like ours there is a delicate balance between the rights of the individual and the powers of the state. This is a sad and distressing decision for the whole family whom we keep in our prayers. This case, for which all information is not available, raises serious questions about the meaning of “best interests” when a patient lacks mental capacity and is subject to the court’s decision against her will.

Press Association reports said that the triumvirate of judges that overruled Lieven’s decision stated that the case was “unique” and they would explain their decision later.

After Lieven’s decision was overruled, Clare McCarthy, spokesperson for Right To Life UK, stated:

This is a very welcome decision that will save the life of the unborn child and the mother from a forced late-term abortion and much undue distress. However, the horrific original ruling should never have happened. Unfortunately, we fear that this is not a one-off case. We are calling on the Department of Health to urgently reveal how many women have been forced to have an abortion in the UK over the last 10 years and make it clear how they will ensure it will not happen again.

As The Daily Wire reported last Friday:

The Catholic News Agency (CNA) reports that the pregnant woman is 22 weeks pregnant and has been described as “in her twenties.” CAN also noted that the woman is reportedly Catholic, with a mother from Nigeria, and has the mental capacity of a grade school-age child. CNA added, “The woman’s mother, reported to be a former midwife, registered her absolute opposition to the abortion citing the Catholic faith of herself and her daughter.”

The judge, Justice Nathalie Lieven, who serves in the Court of Protection, which deals with individuals deemed to lack the ability to make decisions for themselves, stated, “I am acutely conscious of the fact that for the State to order a woman to have a termination where it appears that she doesn't want it is an immense intrusion. … I have to operate in [her] best interests, not on society's views of termination.” Lieven added of the pregnant woman, “I think she would like to have a baby in the same way she would like to have a nice doll.”

Monday, June 24, 2019

Saybie, believed to be world's tiniest baby ever to survive, goes home

An infant girl who weighed about the same as a large apple when she was born five months ago and is believed to be the world's tiniest baby ever to survive has gone home from a San Diego hospital.

The baby, known as Saybie, weighed 8.6 ounces (245 grams) when she was born in December at Sharp Mary Birch Hospital for Women and Newborns, the hospital said in a statement announcing her birth and discharge on Wednesday.

Saybie weighed a little more than a large Golden Delicious apple, which usually is about 7.5 ounces. She is believed to have broken the record for the world's tiniest baby, according to the Tiniest Babies Registry. The record was previously held by a baby who weighed 8.9 ounces when she was born in Germany in 2015, according to the registry maintained by the University of Iowa.

In December, Saybie's mother, who wished to remain anonymous, gave birth through emergency cesarean section at 23 weeks, 3 days gestation in the womb, about 17 weeks earlier than the typical pregnancy, the hospital said.

“Doctors said the preterm birth was necessary after they found that the baby was not gaining weight and her mother's life was at immediate risk," the hospital said.

Saybie, considered a micro preemie, was treated in the hospital's neonatal intensive care unit until she was discharged to go home in May, when she weighed 5.6 pounds, according to the hospital.

"Saybie experienced virtually none of the medical challenges typically associated with micro preemies, which can include brain bleeds, and lung and heart issues," the hospital said.

Tick paralysis

A Colorado mother is sharing her daughter’s health scare in hopes of helping other parents stay vigilant about tick-related illnesses. Heidi Ganahl, a mother of four and founder of SheFactor, said she had noticed a few ticks hidden in her 7-year-old’s hair after she returned from an overnight
camp. Ganahl said she removed the ticks from Jenna’s hair and called the doctor, but 10 days later her daughter’s foot and shin “went to ‘sleep’ and was still that way Saturday am.” Ganahl said she called the doctor again and was told to bring her daughter to Children’s Hospital Colorado Anschutz Medical Campus.

“She had tick paralysis — it was only caught because of the great docs (most CU School of Medicine) that recognized the similarities to two other cases in recent weeks there (it’s extremely rare so it was very abnormal to see 3 cases in 3 weeks.),” Ganahl posted, in part, on Facebook. “It was a terrifying 12 hours as we waited to see if they were able to remove the tiny bit of tick left in her producing the toxin had been cleaned out of the wound (they didn’t see it). The only fix is to get it out or things get very bad. She is ok! Other then never wanting to go into the woods again.”

Tick paralysis is a rare disease thought to be caused by a toxin in tick saliva, according to the Centers for Disease Control and Prevention (CDC). The symptoms can include acute, ascending, flaccid paralysis that is often confused with other neurologic disorders or diseases such as Guillain-Barre or botulism. Symptoms typically resolve within 24 hours of removing the tick.

Simon LV, McKinney WP. Tick Paralysis. 2019 Mar 3. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from

Tick paralysis is an uncommon, noninfectious, neurologic syndrome characterized by acute ataxia progressing to ascending paralysis. It is caused by the salivary neurotoxin of several species of tick. Clinical findings are similar to and often confused with Guillain-Barre syndrome. Most human cases of tick paralysis occur in North America and Australia. If recognized early and treated promptly, complete recovery is expected with tick removal and supportive care alone. Untreated, it can advance to respiratory failure and death. It is important for healthcare workers to be familiar with this relatively rare but readily treatable cause of acute motor weakness and to maintain a high index of suspicion to avoid delays in diagnosis and treatment. Tick paralysis should be considered in all cases of acute ataxia, especially in children.

Borawski K, Pancewicz S, Czupryna P, Zajkowska J, Moniuszko-Malinowska A. Tick paralysis. Przegl Epidemiol. 2018;72(1):17-24.

Tick paralysis is caused by neurotoxins secreted by adult female ticks, primarily in North America and on the east coast of Australia. Sporadic illness is also recorded in Europe and Africa. In the European countries, including Poland, there are 6 species of ticks capable of causing tick paralysis. The disease occurs in people of all ages, but is most commonly diagnosed in children under 8 years of age. Paralysis can take different forms - from rare isolated cranial nerve infections to quadriplegia and respiratory muscles paralysis. After the tick remove, the symptoms resolve spontaneously. In severe cases with paralysis of respiratory muscles, when there is no possibility of mechanical ventilation, the disease may lead to death.

Sunday, June 23, 2019

The diagnostic accuracy of video electroencephalography without event capture

Knox A, Arya R, Horn PS, Holland K. The Diagnostic Accuracy of Video Electroencephalography Without Event Capture. Pediatr Neurol. 2018 Feb;79:8-13.


The aim of this study was to quantify the accuracy of 24-hour video electroencephalography (vEEG) for the diagnosis of epilepsy when a patient's typical paroxysmal event was not captured (no-event vEEG).

We performed a retrospective chart review of all first-time 24 hour no-event vEEG studies at Cincinnati Children's Hospital Medical Center. Clinician diagnosis of epilepsy with a minimum of one year follow-up was used as the reference standard to calculate diagnostic accuracy. Sensitivity and specificity of routine EEG (rEEG) and vEEG were compared in patients with both studies, and factors affecting the accuracy of vEEG were explored with a multivariable analysis.

No-event vEEG showed sensitivity of 0.54 (95% confidence interval [CI] 0.44 to 0.64) and specificity of 0.88 (95% CI 0.84 to 0.92) respectively, with a diagnostic odds ratio of 7.53 (95% CI 4.45 to 12.76). The sensitivity of vEEG was statistically superior to that of rEEG, whereas specificity was comparable. Age emerged as the only factor that affected the diagnostic accuracy of no-event vEEG.

Even in the absence of a typical seizure or spell, video EEG is a useful test for predicting or excluding epilepsy, with diagnostic accuracy that is superior to rEEG and unaffected by the presence of a chronic neurological condition.

Quick brain MRI as a first imaging modality in pediatric stroke

Christy A, Murchison C, Wilson JL. Quick Brain Magnetic Resonance Imaging With Diffusion-Weighted Imaging as a First Imaging Modality in Pediatric Stroke. Pediatr Neurol. 2018 Jan;78:55-60.


Diagnostic delay hinders management of pediatric arterial ischemic stroke. Quick brain MRI with diffusion-weighted imaging sequences may provide a rapid diagnosis without the ionizing radiation of a computed tomography (CT) scan.

This was a single center retrospective chart review of children one month to 18 years old with acute arterial ischemic stroke hospitalized between January 2010 and January 2017. We evaluated sensitivity and the time to diagnostic study based on the first imaging study (CT or quick brain MRI with diffusion-weighted imaging).

Twenty-five patients were included. Eleven patients (44%) were initially assessed with CT, 10 (40%) with quick brain MRI with diffusion-weighted imaging, and four (16%) with a full MRI. Compared with children undergoing CT, children with quick brain MRI with diffusion-weighted imaging as first study were younger (5.8 versus 14.1 years, P < 0.001) and were more likely to be hospitalized at stroke onset (70% versus 18.2%, P = 0.03). Quick brain MRI with diffusion-weighted imaging was more sensitive for ischemia than CT (100% versus 27.3%). The median time from presentation to diagnostic imaging was 4.3 hours, with no differences between CT and quick brain MRI with diffusion-weighted imaging groups, although the quick brain MRI with diffusion-weighted imaging group had a shorter median time from first imaging to diagnostic imaging (P = 0.002). There were no significant missed findings on quick brain MRI with diffusion-weighted imaging.

Quick brain MRI with diffusion-weighted imaging was more sensitive than CT for detecting ischemia and may be considered as the first study for some children presenting with suspected arterial ischemic stroke.

Friday, June 21, 2019

SUDEP in the full spectrum of epilepsies

Verducci C, Hussain F, Donner E, Moseley BD, Buchhalter J, Hesdorffer D, Friedman D, Devinsky O. SUDEP in the North American SUDEP Registry: The full spectrum of epilepsies. Neurology. 2019 Jun 19. pii:10.1212/WNL.0000000000007778. doi: 10.1212/WNL.0000000000007778. [Epub ahead of print]


To obtain medical records, family interviews, and death-related reports of sudden unexpected death in epilepsy (SUDEP) cases to better understand SUDEP.

All cases referred to the North American SUDEP Registry (NASR) between October 2011 and June 2018 were reviewed; cause of death was determined by consensus review. Available medical records, death scene investigation reports, autopsy reports, and next-of-kin interviews were reviewed for all cases of SUDEP. Seizure type, EEG, MRI, and SUDEP classification were adjudicated by 2 epileptologists.

There were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1-70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%.

NASR participants commonly have clinical features that have been previously been associated with SUDEP risk such as young adult age, ASM nonadherence, and frequent GTCS. However, a sizeable minority of SUDEP occurred in patients thought to be treatment responsive or to have benign epilepsies. These results emphasize the importance of SUDEP education across the spectrum of epilepsy severities. We aim to make NASR data and biospecimens available for researchers to advance SUDEP understanding and prevention.

SUDEP can affect men, women, and children. It can affect "children diagnosed with benign epilepsies who are told they don't need to be on medication, that they will outgrow the epilepsy. Unfortunately, [some] die before they have a chance to outgrow it," Devinsky said. The severity of epilepsy cases in which SUDEP occurs varies widely, from cases characterized by centrotemporal spikes to epileptic encephalopathies and failed resective surgeries...

SUDEP is not the only epilepsy-related cause of death — drowning, car accidents, falling down a flight of stairs, and severe burns also occur. Several risk factors are modifiable, so it is possible to lower the risk for SUDEP.

"Medication adherence is probably the most important one. Getting adequate sleep is probably a close second or tied, more or less, and in adult populations, it's also excess alcohol," Devinsky said.

Combining one or more of these risk factors, such as drinking more alcohol than usual while sleep deprived, has a synergistic impact on risk.

Many previous population-based studies, medical examiner case-control series, and clinical case-control studies have focused on subgroups of epilepsy patients or patients whose condition was refractory to medication or surgery. 

In contrast, Devinsky and colleagues evaluated a more general epilepsy population enrolled in a large international registry...

"The other finding from our paper, which has been identified 84% of the family members we spoke to had never heard of SUDEP, and they believed their loved one had never been told about SUDEP," Devinsky said.

Clinicians should discuss SUDEP with all patients with epilepsy for two reasons.

"First, some reassurance can be given to relieve anxiety for those at low risk (eg, focal aware or absence seizures only). Second and most important, patients and families must understand the critical — and potentially lifesaving — importance of seizure control," he said.

"Someone might think: 'If I have an occasional seizure because I missed a med, no big deal, I will be a little tired for an hour, and then I will be on my way.' But if they understand there is a chance they could die from that seizure, one would hope they would be better about being fully adherent with their medication," Devinsky added...

A conversation with a patient whose seizures are well controlled could start, for example, as follows: "Listen, I just want you to know you're doing fantastic. There is a problem called SUDEP, or sudden death in epilepsy. Your chances of suffering it are extremely low; however, they do exist. If you can take your medications religiously and you can get good sleep and avoid excess alcohol, you will dramatically reduce your chances of getting this from very low to close to zero. But if you miss a single dose of medication, unfortunately, you could have a big seizure, and that big seizure could be deadly,' " said Devinsky.

Going forward, the investigators will evaluate individuals who experienced seizures that were recorded in an epilepsy unit. They plan to assess those who subsequently died in order to identify distinguishing factors in their clinical histories or diagnostic test findings in comparison with age- and sex-matched control persons who had a similar seizure but did not die from SUDEP.

"We hope studies like this will allow us to identify markers that more accurately identify patients at high risk for SUDEP and inform us about the mechanisms for SUDEP so we can more effectively prevent it," he said.

"There are many unknowns about SUDEP, and we do not talk about it with our patients, likely because of the lack of knowledge about the mechanism causing this condition, or the risk factors associated with it," Jorge G. Burneo, MD, MSPH, FAAN, writes in an accompanying editorial.

The current study "represents a great effort, as it collected a substantial amount of data from different referral sources in the United States and Canada, and is the largest cohort of SUDEP cases so far," writes Burneo, the Jack Cowin Chair in Epilepsy Research at Western University and coleader of EpLink, the epilepsy research program of the Ontario Brain Institute.

"The important take-home message from this study is that from now on, clinicians should start conversations about SUDEP with their patients with epilepsy earlier rather than later," he notes.

Tuesday, June 18, 2019

Geniospasm,, a quiver of the chin

Colin P. McGrath, Kathleen M. Gorman and Mary D. King.  A Quiver of the Chin, Pediatric Neurology, in press

This 12-year-old boy presented with a one-year history of involuntary, painless twitching of the chin and lower lip. Speech and awareness were unaffected and there was no associated movement of the eyes, limbs, or head. The episodes lasted less than five minutes, triggered by stress and anxiety. Nine family members across four generations were affected. His neurological examination was otherwise normal.

Hereditary geniospasm is a rare autosomal dominant condition with incomplete penetrance. It produces paroxysms of involuntary rhythmic contractions of the mentalis muscle bilaterally, which cannot be suppressed. Episodes typically last between seconds and hours, interfering little with function but causing embarrassment, for which patients most commonly present. Tremor typically develops in childhood, peaks in early adulthood, and resolves by the fifth decade. No single gene has been elucidated for hereditary geniospasm. A locus on the proximal long arm of chromosome 9 (9q13-q21) has been identified; however, this has not been confirmed in other reports. Why only the mentalis muscle is affected is not known.

Although benign, chin trembling is a source of embarrassment. Injection of low-dose botulinum toxin into the mentalis muscle or low dose clonazepam are sometimes helpful.  No treatment was commenced in our patient. Although rare, it is important to recognize hereditary geniospasm in order to avoid unnecessary investigations.

[video with article]

Monday, June 17, 2019


Mariah Martinez was 9 years old when she got bad news about her chronic headaches: A doctor said she had epilepsy.

Over the next four years, the suburban Detroit girl took anti-seizure medicine that made her feel sluggish and was occasionally hooked to a machine that recorded her brain waves. She was told to avoid activities that would rouse her heart, making her the target of teasing by other kids at school.

But then a different doctor delivered astonishing news in 2007: Mariah didn't have epilepsy.

"How could that be?" her mother, Laura Abdel-Slater, recalled. "Epilepsy is something that's not curable."

Martinez, now 26, is the first of what could be many former patients to go to trial accusing Dr. Yasser Awaad and his former employer, Oakwood Healthcare, of malpractice and negligence. Jury selection starts Monday.

Awaad ordered tests on hundreds of Detroit-area children and intentionally misread the results, telling them they had epilepsy or some other seizure disorder, say lawyers for Martinez. The diagnoses disrupted their lives, forcing them to take medicines they didn't need and to undergo further tests during repeat visits. 

The lawyers allege that Oakwood was running an "EEG mill," a reference to an electroencephalogram, a test to measure brain activity. The Dearborn medical center was "ecstatic with Dr. Awaad's suspiciously high productivity because all it cared about was making money," they argue in a recent court filing....

Awaad was Oakwood's first pediatric neurologist when he was hired in 1999. Over nearly a decade, his annual salary rose from $185,000 to $300,000. He also qualified for a bonus as high as $220,000 if certain billing targets were met, documents show.

Awaad left Oakwood in 2007 for a job in Saudi Arabia. When his former patients visited new doctors, many diagnoses were reversed. Even other doctors consulted by defense lawyers said he misinterpreted EEG tests.

"If I made a mistake, I came up with a diagnosis to the best of my ability," Awaad told attorney Brian McKeen during a quarrelsome deposition in 2017. "That's a different story than intentionally telling them that you have epilepsy and they don't have epilepsy."

Oakwood merged into Beaumont Health in 2014, years after the first lawsuit was filed.

"While we cannot comment on the specifics of this case because of pending legal proceedings and patient privacy laws, it continues to be our position that patients were treated appropriately," Beaumont spokesman Mark Geary said.

In 2012, Awaad struck a deal with state regulators to settle claims that he unnecessarily gave anti-seizure medications to four children. He paid a $10,000 fine and agreed to have his work reviewed by another doctor for a period of time.

Lawyers representing about 300 former patients lost their bid to make this case a class-action lawsuit, so the first trial will center only on Martinez, who was sent to Awaad in 2003 over her headaches. She was given Lamictal, an anti-seizure medicine, and Awaad performed many follow-up EEGs until another doctor said she didn't have epilepsy.

Martinez's attorneys declined to make her available for an interview before trial. But in a deposition, she recalled being withdrawn as a child and teased by other kids because the epilepsy label limited her physical activities. She said her grades suffered.

"Once I was weaned off medication, my headaches became less frequent, less severe," said Martinez.

Attorneys for Oakwood asked the judge to give the medical center a separate trial, but he declined.

"You can't just look at the malpractice and not consider whether Oakwood should have and could have stopped what was happening," said Wayne County Judge Robert Colombo Jr., who last fall called some evidence "very damning."

Courtesy of a colleague

Association of perceived maternal stress during the perinatal period with electroencephalography patterns in 2-month-old infants

Pierce LJ, Thompson BL, Gharib A, Schlueter L, Reilly E, Valdes V, Roberts S, Conroy K, Levitt P, Nelson CA. Association of Perceived Maternal Stress During the Perinatal Period With Electroencephalography Patterns in 2-Month-Old Infants. JAMA Pediatr. 2019 Apr 8. doi: 10.1001/jamapediatrics.2019.0492. [Epub ahead of print]


Variation in child responses to adversity creates a clinical challenge to identify children most resilient or susceptible to later risk for disturbances in cognition and health. Advances in establishing scalable biomarkers can lead to early identification and mechanistic understanding of the association of early adversity with neurodevelopment.

To examine whether maternal reports of stress are associated with patterns in resting electroencephalography at 2 months of age and whether unique electroencephalographic profiles associated with risk and resiliency factors can be identified.

For this cohort study, a population-based sample of 113 mother-infant dyads was recruited from January 1, 2016, to March 1, 2018, during regularly scheduled pediatric visits before infants were 2 months of age from 2 primary care clinics in Boston, Massachusetts, and Los Angeles, California, that predominantly serve families from low-income backgrounds. Data are reported from a single time point, when infants were aged 2 months, of an ongoing cohort study longitudinally following the mother-infant dyads.

Maternal reported exposure to stressful life events and perceived stress.

Spectral power (absolute and relative) in different frequency bands (Δ, θ, low and high α, β, and γ) from infant resting electroencephalography (EEG) and EEG profiles across frequency bands determined by latent profile analysis.

Of 113 enrolled infants, 70 (mean [SD] age, 2.42 [0.37] months; 35 girls [50%]) provided usable EEG data. In multivariable hierarchical linear regressions, maternal perceived stress was significantly and negatively associated with absolute β (β = -0.007; 95% CI, -0.01 to -0.001; semipartial r = -0.25) and γ power (β = -0.008; 95% CI, -0.01 to -0.002; semipartial r = -0.28). Maternal educational level was significantly and positively associated with power in high α, β, and γ bands after adjusting for covariates (high school: γ: β = 0.108; 95% CI, 0.014-0.203; semipartial r = -0.236; associate's degree or higher: high α: β = 0.133; 95% CI, 0.018-0.248; semipartial r = 0.241; β: β = 0.167; 95% CI, 0.055-0.279; semipartial r = 0.309; and γ: β = 0.183; 95% CI, 0.066-0.299; semipartial r = 0.323). Latent profile analysis identified 2 unique profiles for absolute and relative power. Maternal perceived stress (β = 0.13; 95% CI, 0.01-0.25; adjusted odds ratio [AOR], 1.14; 95% CI, 1.01-1.28) and maternal educational level (high school: β = 3.00; 95% CI, 0.35-5.65; AOR, 20.09; 95% CI, 1.42-283.16; associate's degree or higher: β = 4.12; 95% CI, 1.45-6.79; AOR, 61.56; 95% CI, 4.28-885.01) were each associated with unique profile membership.

These findings suggest that unique contributions of caregiver stress and maternal educational level on infant neurodevelopment are detectable at 2 months; EEG might be a promising tool to identify infants most susceptible to parental stress and to reveal mechanisms by which neurodevelopment is associated with adversity. Additional studies validating subgroups across larger cohorts with different stressors and at different ages are required before use at the individual level in clinical settings.

Courtesy of:

Friday, June 14, 2019

New treatments for neuromyelitis optica

“This year has been the most exciting year for NMOSD in the past 200 [years],” Dr. Clardy, assistant professor of neurology at University of Utah, told the audience (The disease features were first recognized more than 200 years ago, and the term, neuromyelitis was coined more than 100 years ago.) She was referring to the fact that three phase 3 clinical trials found three different drugs with different mechanisms of action highly effective at reducing relapse in NMOSD, a rare autoimmune, inflammatory disorder of the central nervous system, for which there are currently no approved treatments. NMOSD causes recurrent optic neuritis and myelitis and can lead to paralysis and blindness as well as death.

At the AAN Annual Meeting, researchers presented data from phase 3 clinical trials—for eculizumab, inebilizumab, and satralizumab—which are all likely to gain Food and Drug Administration (FDA) approval for NMOSD in the months ahead, experts said. The drugs are particularly promising for NMOSD patients with antibodies to aquaporin-4 (AQP4-IgG)...
Various immunosuppressant drugs, including rituximab, are used off label to prevent recurrent attacks, he said, but about 25 to 60 percent of patients continue to have attacks despite treatment. With the current findings, he said, “it is a very bright day for patients.”

A breakthrough toward drug development came when it was discovered that about two-thirds of patients have antibodies against AQP4, a water channel protein expressed by astrocytes in the central nervous system, Dr. Pittock said.

Research indicates that AQP4-IgG triggers what's known as the complement cascade, which causes inflammation and formation of the membrane attack complex. Eculizumab inhibits the terminal complement protein, interrupting the inflammatory process that leads to an attack.

The findings of the phase 3 trial of eculizumab, known as PREVENT, were also published in the May 3 online edition of The New England Journal of Medicine...

The second set of results of the phase 3 study, called N-MOmentum, were presented at a plenary session by lead investigator Bruce Cree, MD, PhD, MAS, professor of clinical neurology at University of California, San Francisco...

The study reported that in the AQP4- positive patients inebilizumab resulted in a 86 percent reduction in risk of a recurrent attack compared with 57 percent in the placebo arm during the 28 weeks of the trial; 86 percent of those taking the drug remained relapse-free compared with 57 percent on placebo. For patients overall, there was a 73 percent reduction in attack recurrence for those on the drug compared to placebo.

The third trial involved satralizumab, which is an anti-IL 6 receptor monoclonal antibody. Takashi Yamamura, MD, PhD, director of the National Institute of Neuroscience in Tokyo, presented data at the AAN meeting showing that the drug achieved an overall 62 percent reduction in relapse compared to placebo and was especially beneficial for AQP4-IgG seropositive patients...

Steven L. Galetta, MD, FAAN, the Philip K. Moskowitz, MD, Professor and chair of neurology at NYU Langone Health, said he shares in the enthusiasm around the three new potential treatments for NMOSD, noting that “it is a devastating disorder” with attacks that can be “difficult and dramatic.”

He said that up to 60 percent of patients may become blind in one or both eyes and at least 50 percent develop ambulatory difficulties in five to 10 years if untreated.

“The disease, unlike MS, is marked more by distinct relapses and not disease progression,” Dr. Galetta said. “If you stop the relapses you stop the disease.”

He said some NMOSD patients already do well on drugs such as rituximab, so it remains to be seen what prescribing patterns will develop if the three new drugs come to market for NMOSD as expected.

“These are powerful options and it's always good to have powerful options when dealing with something like NMO,” he said. He said issues such as the price mode of drug delivery, patient preferences, and side effects will all factor into treatment decisions.
Dr. Clardy, a neurologist specializing in autoimmune diseases at the VA Salt Lake City and the University of Utah, reiterated in a follow-up interview with Neurology Today that the progress with NMOSD has been impressive.

“In the space of 15 years since the Mayo group identified the (AQP4) antibody, there have been three clinical trials completed,” she said. Another antibody known as MOG IgG has also recently been identified in association with some previously seronegative cases of NMOSD, and this will hopefully be a target of future research and trials, she said. Dr. Clardy noted that the Guthy-Jackson Charitable Foundation was integral in organizing and catalyzing many research efforts.

Though she is excited about the new therapies, Dr. Clardy said: “I don't think we are going to see people change (to them) if they have stable disease for a period of time on existing non-FDA approved therapies.”

At the same time, “the good news for patients is that we now have many options—we can outline a plan A, a plan B, a plan C, in the event one medication doesn't work for them.”... 

But she said the cost of the new drugs, which has yet to be determined (and could approach $500,000 or more annually for one of the drugs, she said), could in the end be the weightiest determinant of all.

“As neurologists in the modern era, we have an obligation to discuss the potential for personal financial toxicity with our patients. With new treatments comes great opportunities, but also costs, and I don't want my patients to go bankrupt paying for their therapies,” she said.

Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, Nakashima I, Terzi M, Totolyan N, Viswanathan S, Wang KC, Pace A, Fujita KP, Armstrong R, Wingerchuk DM. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 May 3. doi: 10.1056/NEJMoa1900866. [Epub ahead of print]


Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse.

In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death).

The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group.

Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT number, NCT01892345; EudraCT number, 2013-001150-10.). 

Cree B, Bennett J, Kim HJ, et al.AAN Abstract Plen02.001: A double-masked, placebo-controlled study with open-label period to evaluate the efficacy and safety of inebilizumab in adult subjects with neuromyelitis optica spectrum disorders–Top line efficacy


Objective: To evaluate the safety and efficacy on relapse prevention, of inebilizumab, an anti-CD19, B-cell depleting monoclonal antibody in neuromyelitis optica spectrum disorder (NMOSD).

Background: Currently there are no approved therapies for NMOSD. Empiric experience suggests that depleting B-cells may have therapeutic benefit in attack prevention.

Design/Methods: N-MOmentum is a phase III, double-masked, randomized, placebo-controlled trial of inebilizumab (MEDI-551) in NMOSD. A three-member eligibility committee confirmed entry criteria for AQP4-IgG seronegative subjects. Participants were randomized 3:1 to either treatment with inebilizumab or placebo. Concurrent treatment with other immune suppressants was prohibited. The placebo-controlled period was limited to 6.5 months in duration. The primary outcome measure was time to first adjudicated attack. Clinical criteria for NMOSD attacks were developed and implemented. A three-member committee adjudicated all investigator-reported attacks. Patients who either experienced an adjudicated attack or completed the controlled phase of the study were offered treatment with inebilizumab in an open label extension study. Acute attacks were treated with the investigator’s choice of therapy.

Results: On September 7, 2018, the external data safety monitoring committee (DSMC) concluded that continued enrollment with potential exposure to placebo was no longer ethical due to demonstrated efficacy and safety. The DSMC recommended that all participants in the randomized controlled period be moved to active treatment with inebilizumab and that all study participants continue in the open label extension protocol for ongoing safety assessments. 230 subjects from 24 countries were randomized and dosed (planned sample size: 252). 212 were seropositive and 18 were seronegative for anti-AQP4 antibodies. 42 adjudicated attacks occurred in the controlled period. The study remains masked and data lock will occur in December 2018 after which analysis of the primary and secondary endpoints and safety will occur.

Conclusions: Top-line data on inebilizumab’s efficacy and safety in NMOSD will be presented.

Yamamura T, Kleiter I, Fujihara K, et al.AAN Abstract S43.008: Efficacy of satralizumab (SA237) in subgroups of patients in SAkuraSky: A phase III double-blind, placebo-controlled, add-on study in patients with neuromyelitis optica spectrum disorder (NMOSD) (S43.008).


Objective: To evaluate the efficacy of satralizumab (SA237) in subgroups of the SAkuraSky study (NCT02028884).

Background: Satralizumab, a recycling anti-IL-6 receptor monoclonal antibody, significantly reduced the risk of experiencing a protocol defined relapse (PDR) in NMOSD patients by 62% compared with placebo, in addition to baseline treatment in the overall population of the SAkuraSky study. At baseline, 66.3% of patients were AQP4-antibody (Ab) positive and 33.7% were AQP4-Ab negative.

Design/Methods: SAkuraSky is a randomized, double-blind, phase 3 study of satralizumab compared to placebo as add-on to baseline treatment (immunosuppressants and/or corticosteroids, both at a stable dose). Subjects were randomized to satralizumab (120 mg s.c.) or placebo administered at weeks 0, 2, 4, and Q4W thereafter. The primary endpoint was time to first PDR, adjudicated by a clinical endpoint committee. Pre-specified subgroup analyses included assessing the response to treatment by AQP4-Ab serostatus, baseline treatment, and region. Between-group hazard ratios were based on Cox proportional hazards models.

Results: Satralizumab showed a 79% risk reduction of PDR compared to placebo in the NMO/NMOSD AQP4-Ab positive subgroup (HR, 0.21; 95% CI, 0.06–0.75). The proportion relapse free at weeks 48 and 96 were 91.5% (95% CI, 69.6%–97.8%) and 91.5% (95% CI, 69.6%–97.8%) with satralizumab and 59.9% (95% CI, 36.3%–77.3%) and 53.3% (95% CI, 29.3%–72.4%) with placebo, respectively. For the NMO/NMOSD AQP4-Ab negative subgroup, satralizumab showed a risk reduction of PDR of 34% compared to placebo (HR, 0.66; 95% CI, 0.20–2.23), and the proportion relapse free at weeks 48 and 96 were 84.4% (95% CI, 50.4%–95.9%) and 56.3% (95% CI, 24.2%–79.2%) with satralizumab, and 75.5% (95% CI, 41.6%–91.4%) and 67.1% (95% CI, 34.2%–86.2%) with placebo, respectively.

Conclusions: The subgroup data show that satralizumab is effective in reducing PDR, especially in NMO/NMOSD AQP4-Ab positive patients. Results and conclusions from additional subgroups will be presented at the conference.

Thursday, June 13, 2019

Remote poststroke headache in children. Characteristics and association with stroke recurrence

Ana B. Chelse, Jonathan E. Kurz, Kathleen M. Gorman, Leon G. Epstein, Lauren C. Balmert, Jody D. Ciolino, Mark S. Wainwright.  Remote poststroke headache in children.  Characteristics and association with stroke recurrence.  Neurology Clinical Practice. 9(3):194-200, June 2019


Background New-onset headache after stroke is common among adult stroke survivors. However, pediatric data are limited. The primary aim of this study was to investigate the prevalence of new-headache after pediatric ischemic stroke. Secondary outcomes were to describe the characteristics of patients experiencing poststroke headache and the association between poststroke headache and stroke recurrence.

Methods We conducted a single-center retrospective study on children aged 30 days to 18 years with a confirmed radiographic diagnosis of arterial ischemic stroke (AIS) from January 1, 2008, to December 31, 2016. Patients were identified from an internal database, with additional data abstracted from the electronic medical record. Poststroke headache (occurring >30 days after stroke) was identified through electronic searches of the medical record and confirmed by chart review.

Results Of 115 patients with confirmed AIS, 41 (36%) experienced poststroke headache, with headache developing a median of 6 months after stroke. Fifty-one percent of patients with poststroke headache presented to the emergency department for headache evaluation; 81% of the patients had an inpatient admission for headache. Older age at stroke (odds ratio [OR] 21.5; p = 0.0001) and arteriopathy (OR 8.65; p = 0.0029) were associated with development of poststroke headache in a multivariable analysis. Seventeen patients (15%) had a recurrent stroke during the study period. Poststroke headache was associated with greater risk for stroke recurrence (p = 0.049).

Conclusions Remote poststroke headache is a common morbidity among pediatric stroke survivors, particularly in older children. Headaches may increase health care utilization, including neuroimaging and hospital admissions. We identified a possible association between poststroke headache and stroke recurrence.

A new study has found a high incidence of headaches in pediatric stroke survivors and identified a possible association between post-stroke headache and stroke recurrence. Headache developed in over a third of participating children, on average six months after the stroke. Fifteen percent of patients suffered another stroke, typically in the first six to 12 months after the initial stroke. In the study, most children who experienced headache during stroke recurrence also had other associated neurologic symptoms, mostly weakness of one side of the body (hemiparesis) or facial asymmetry and brain malfunction (encephalopathy). Findings were published in Neurology: Clinical Practice, a journal of the American Academy of Neurology.

"In our study, post-stroke headache was more common in patients who experienced another stroke, which suggests that it might be a risk factor for stroke recurrence," says co-lead author Jonathan Kurz, MD, PhD, pediatric neurologist in the Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program at Ann & Robert H. Lurie Children's Hospital of Chicago, and Instructor of Pediatrics at Northwestern University Feinberg School of Medicine. "More research is needed to test this hypothesis, and it remains unclear if headache treatment would lower the risk for stroke recurrence. Children with post-stroke headache might need closer observation or different strategies to prevent another stroke. This requires more study."

Wednesday, June 12, 2019

Long-term disability progression of pediatric-onset multiple sclerosis

McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology. 2019 Jun 11;92(24):e2764-e2773.doi: 10.1212/WNL.0000000000007647. Epub 2019 May 15.


To evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).

This was a retrospective cohort study using prospectively collected clinical information from the Swedish MS Registry. Clinical features were compared and Kaplan-Meier and Cox proportional hazards regression were used to assess the risk of reaching sustained Expanded Disability Status Scale (EDSS) 3, 4, and 6 in POMS (multiple sclerosis [MS] onset <18 years) and AOMS (MS onset ≥18 years).

A total of 12,482 persons were included; 549 (4.4%) were classified as POMS. The POMS cohort took longer to reach all 3 disability milestones from their MS onset, but did so at a younger age than the AOMS cohort. Primary progressive course (hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.46-14.7), higher relapse rate in the first 5 years of disease (HR 5.35; 95% CI 3.37-8.49), and complete remission from the initial relapse (HR 0.41; 95% CI 0.18-0.94) were associated with an altered risk of progression to EDSS 4 among POMS cases. The same pattern emerged for the risk of reaching EDSS 3 and 6.

Patients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.

“POMS [pediatric-onset multiple sclerosis] differed from adult-onset cases in several ways, including an increased diagnostic delay and relapse rate and a higher proportion of cases with relapsing-onset MS,” researchers reported in the May 15 online edition of Neurology. “While the POMS cohort took longer to reach disability milestones from their MS onset, they did so at a younger age than the AOMS [adult-onset MS] cohort.”

The findings, which align fairly closely with previous smaller studies on the clinical course of pediatric MS, provide a decades-long view of a disease that usually strikes later in life, often in early adulthood. Pediatric-onset MS accounts for anywhere from 2 to 10 percent of all MS cases, according to background in the study…

“Persons who develop MS early in life appear to be vulnerable to heightened inflammation and axonal loss,” the study authors said. “At the same time, their younger age may provide protection through the brain's enhanced compensatory abilities.”…

Pediatric-onset patients with a higher annualized relapse rate in the first five years of disease were more likely to reach all three disability milestones, while those who had a complete remission from the initial relapse were less likely to reach EDSS 3, 4, and 6. Having a progressive course of disease at onset was associated with an elevated risk of disability compared to relapsing disease.

While overall trends aligned fairly closely with previous research, the researchers noted that the median time of 31 years from pediatric onset to EDSS 4 was much better than previous reports of 10.8 to 23.8 years.

“Disease progression appears to be slower than we previously thought,” study coauthor Kyla McKay, PhD, a postdoctoral researcher at Karolinska Institutet told Neurology Today in an email…
The new study hints that MS drugs may be making a difference. In a multivariate analysis of pediatric-onset cases, the researchers found that use of a second-line DMT was associated with a reduced risk of reaching EDSS 3 and 4, and they noted that “it's possible that DMT use has contributed to the extended period of time before reaching disability thresholds.”

But Dr. McKay reiterated a point made in the paper, that “this study was not designed to measure treatment effectiveness, nor the impact of interventions on disease outcomes.” Because of that, she said she could not comment “on disease management based on findings from this study.”

Dr. McKay said there is still much to be learned including “the longer-term socioeconomic consequences of pediatric-onset MS, the long-term effects of disease-modifying therapy exposure in terms of safety and effectiveness, as well as risk factors for the development of MS in childhood.”

Independent MS experts interviewed by Neurology Today said the new analysis of the Swedish registry data, which was collected during a time of changes in MS care, should help enhance the understanding of the expected course of pediatric-onset MS and perhaps provide some comfort to patients and families. And for the most part, they said it supports treating these children with early, aggressive therapy. 

“I think the optimistic message is that the time from the first attack to measurable disability is long,” said Brenda Banwell, MD, FAAN, chief of child neurology at The Children's Hospital of Philadelphia. At the same time, “the data show that patients with early relapses have an increased risk of disability, which emphasizes the importance of early treatment.”…

“The relapse rate in children is higher than in adults so it is even more pivotal to treat early,” she said. But she does not make light of safety considerations associated with the newer MS medications.

“I think we all use medications humbly, knowing we have to follow patients carefully,” Dr. Banwell said.

Leslie Benson, MD, assistant director of pediatric neuro-immunology at Boston Children's Hospital, said the findings from the Swedish registry raise some interesting questions that MS researchers like herself are interested in, including “why do kids recover better (from relapses) and take longer to hit EDSS landmarks.” She said kids may heal differently than adults from attacks, with their brains perhaps better able to rewire or develop work-around solutions.

When it comes to the use of second-line therapies, she said she tends “to be on the conservative side because these are young people with developing immune systems.”…

Emmanuelle Waubant, MD, PhD, FAAN, professor of neurology and pediatrics at University of California, San Francisco, said pediatric-onset MS “takes place during a very demanding time of life,” with challenging demands such as multitasking, and learning new material and skills in school.

She said that “cognitive problems related to MS with childhood onset can impair the ability to be successful in school and later become young adults with productive jobs.”

Dr. Waubant, director of the pediatric MS program at UCSF, said she is among the physicians who tend to treat pediatric MS aggressively early on, hoping to slow or prevent long-term impairment, and said evidence is starting to emerge from clinical trials on both the efficacy and tolerability of higher efficacy therapies in children…

She said what caught her eye the most in the new report was that “when they (researchers) did the regression analysis, going on a high-efficacy medicine was associated with a better outcome in the long run.” She said that suggestion supports her own tendency to favor aggressive treatment for pediatric patients.

Dr. Krupp said a conundrum that all doctors who treat MS face is that “at the moment we are not that great at figuring out who is going to do well and who is not. I can't say who is going to remyelinate, who can compensate, who can rewire.”

She said that her clinical experience has led her to believe that she'd rather over treat and assume the risk of possible a medication side effects, than leave a child at heightened risk of the life-long consequences of neurologic damage.