Thursday, November 30, 2017

Medication trials for migraine

Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017 Nov 30;377(22):2123-2132.

We tested erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene–related peptide receptor, for the prevention of episodic migraine.
We randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of migraine days per month. Secondary end points were a 50% or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine–specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning).
A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P<0.001 for each dose vs. placebo), and the number of days of use of acute migraine–specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P<0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P<0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo.
Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine–specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE number, NCT02456740.)

Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017 Nov 30;377(22):2113-2122

Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene–related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine.

In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose.
Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%).

Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; number, NCT02621931.)

Cerebral imaging evolution following a head injury

An almost 13 month old boy born at 34 weeks gestationwith a history of macrocephaly had a seemingly minor head injury.  He cried immediately but then became less responsive, leading to evaluation.  A cranial CT showed bilateral extraaxial fluid collections with superimposed acute hemorrhage.  Bilateral subdural drains were placed.

Focal seizures involving the left hand occurred.  Levetiracetam and subsequently fosphenytoin wereadministered, as well as lorazepam and midazolam.  Videoelectroencephalographic monitoring showed multiple focal seizures arising from the right posterior quadrant associated with rhythmic eye blinking, and one with left foot movements.  There were  independent focal seizures from the left hemisphere without clear clinical correlate. The interictal background showed diffuse slowing, and lack of organizational features. 

On the fourth day a cranial MRI was obtained showing on diffusion imaging a diffuse pattern of cytotoxic edema/diffusion restriction extending throughout the bilateral cerebral hemispheres, with some sparing of the anterior temporal and anterior/inferior frontal lobes. A diffuse pattern of white matter involvement, with transcortical extension was most conspicuous in the posterior temporal, occipital, and parietal lobes. There was notable focal involvement of the caudate nuclei, bilaterally.

When the MRI was repeated after 5 days, the widespread diffusion changes were no longer present.

In their stead were bilateral diffusion and T2 changes involving the posterior limb of the internal capsule and the ventral cerebral penduncles.

Seizure activity abated clinically and electrographically.  A skeletal survey showed no bony injury.  There were bilateral retinal hemorrhages.

Role of perinatal inflammation in neonatal arterial ischemic stroke

Antoine Giraud1, Clémence Guiraut,  Mathilde Chevin,  Stéphane Chabrier, Guillaume Sébire. Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke.  Front. Neurol., 16 November 2017 |

Based on the review of the literature, perinatal inflammation often induced by infection is the only consistent independent risk factor of neonatal arterial ischemic stroke (NAIS). Preclinical studies show that acute inflammatory processes take place in placenta, cerebral arterial wall of NAIS-susceptible arteries and neonatal brain. A top research priority in NAIS is to further characterize the nature and spatiotemporal features of the inflammatory processes involved in multiple levels of the pathophysiology of NAIS, to adequately design randomized control trials using targeted anti-inflammatory vasculo- and neuroprotective agents.

Given that the diagnosis of NAIS is often delayed due, in most cases, to the prenatal onset and/or to the absence, or paucity and diagnostic delays, of neonatal symptoms, future therapies should focus on the control of preinsult determinants most often acting prenatally—e.g., through anti-inflammatory intervention, such as IL-1Ra, or on postinsult neonatal mechanisms—e.g., through hypothermia therapy (HT)—rather than on less feasible per-insult acute interventions...

IL-1 Blockade
Our team and others uncovered that the upregulation of IL-1 plays a key role in chorioamnionitis, and in associated neonatal ischemic brain injuries. Our preclinical studies, and others, showed that prenatal IL-1 blockade using IL-1Ra is protective against chorioamnionitis, associated FIRS, and subsequent brain injuries. Postnatal administration of IL-1Ra is also effective in alleviating mortality (from 40 to 18%) as well as morbidities arising from postnatal inflammatory-sensitized NAIS: 66% decrease of the core (cavitary lesion), and 54% decrease of the penumbra (rim of mild to moderately ischemic tissue lying between the core and the unaffected tissue), and preventing the loss of motor skills. IL-1Ra is an already approved drug to treat chronic inflammatory conditions, including those affecting pregnant mothers and newborns. IL-1Ra is, among the various molecules interfering with the IL-1 signaling, the one which dominates its pharmacological field due to its: (i) blocking effect on both IL-1α and IL-1β; (ii) short 4–6 h half-life (blood levels falling within a few hours of treatment stoppage); (iii) multiple routes of administration; (iv) approval for several pediatric inflammatory conditions (1–10 mg/kg/24 h), knowing that the repurposing of well-studied drugs used in the pediatric population is a cost-effective and efficient strategy to identify new therapies for pediatric diseases; and (v) excellent safety record (absence of opportunistic infection; reversible increase of liver enzyme, decrease of polymorphonuclear cells, slight increase of infection, that are mostly observed in patients on chronic treatment) after more than 10 years of use in more than 150,000 patients. Altogether, this provides encouraging preclinical evidence in favor of the efficacy and feasibility of end-gestational or neonatal interventions using IL-1Ra.

Hypothermia Therapy
Hypothermia therapy is now a mandatory standard of care for term newborns suffering for diffuse HI encephalopathy. However, cooling treatment is modestly effective and leaves 50% of the treated patients with major sequelae. Besides, it is uncertain why HT is effective for some, but not all, human newborns. Clinical studies reported that HT might have less beneficial effects on newborns exposed to infection-inflammation plus HI, than those exposed to HI alone. Furthermore, evidence in favor of an anti-inflammatory role of HT within the newborn brain is limited and conflicted. Only a few clinical or preclinical models address this question. However, a well-established anti-inflammatory effect of HT is the down regulation of oxidative stress within the brain. It has also been reported that HT is neuroprotective by limiting apoptotic cascades in human term newborns. The potential effect of HT on neuroinflammatory cytokines expression has been poorly investigated up to now in preclinical models as well as in term newborns. It has been recently shown that HT did not modulate inflammatory molecules, including IL-1β, TNF-α, IL-1Ra and MMP-9, on LPS plus HI-exposed pups. Other downregulating effect of HT within preclinical NAIS brains remained unclear. In the clinical settings, HT has not been tested yet in NAIS patients, even though it is feasible and possibly effective.

Erythropoietin presents anti-inflammatory and neuroprotective properties mainly through dampening free radical release and neural cells apoptosis that have been well-established on preclinical models of neonatal brain infarcts. Erythropoietin seems to be well-tolerated and neuroprotective against perinatal brain lesions of premature newborns: Benders et al. performed a study in 21 consecutive NAIS patients diagnosed by magnetic resonance imaging (MRI) using erythropoietin (1,000 IU/kg intravenously administered just after the diagnostic confirmation by MRI, and repeated at 24 and 48 h).

There was no adverse effect on blood cells counts, or coagulation. The residual versus initial MRI injuries were quantitatively compared at 3 months of age between the erythropoietin-treated patients versus 10 untreated matched historical controls. The percentage of tissue loss within the ischemic area was not different between the treated versus untreated group. Hence, the effectiveness of erythropoietin in terms of neuroprotection in the NAIS context remains to be established. 

Wednesday, November 29, 2017

I will fight for our right to exist for the rest of my life

A member of the United Nations Human Rights Committee has defended the use of abortion to eliminate babies with Down syndrome and other disabilities as a “preventive measure” to “avoid the handicap.”

In a meeting of the U.N. Human Rights Committee this month, Mr. Yadh Ben Achour, a Tunisian lawyer and committee member, argued that one can be an advocate for handicapped people while still encouraging abortion in the case of fetuses with permanent disabilities.

Captured on videotape, the commissioner defended the inviolable right of women to an abortion, especially when her child has been diagnosed with Down syndrome or another disability.
Mr. Ben Achour said in French:

If you tell a woman, “Your child has Dow…” — what is it called? Down syndrome, Dawn syndrome — if you tell her that, or that he may have a handicap forever, for the rest of his life, you should make this woman… it should be possible for her to resort to abortion to avoid the handicap as a preventive measure."

While describing himself as “an ardent defender of the handicapped,” Ben Achour insisted that the State must do everything possible to protect the handicapped “and ensure they have a life, a possible living.”

“But that does not mean that we have to accept to let a disabled fetus live,” he said. “This is a preventive measure.”

Advocating the abortion of handicapped children “doesn’t mean that we are against the disabled or that we won’t help the disabled when born disabled,” Ben Achour said.

The commissioner went on to contend that the key difference lies in catching the disability before the child is born so that it can be aborted because afterward society is obliged to defend the child’s right to live—even if the child has a genetic anomaly.

“So this is where we will find the difference between the birth of the human being. Once he is born, it is finished; with a handicap or without a handicap, he must live and we must protect absolutely, in an absolute manner, his right to life,” he said.

“So us, we defend the right of the handicapped, but, but we can avoid the handicaps, and we must do everything we can to avoid them,” he added. “And it is not contradictory.”

In response to Mr. Ben Achour’s speech, a young woman with Down syndrome made her own YouTube video in response, suggesting that the commissioner apologize for his “horrible comments.”

“I’m a human being just like you,” said the woman, identified only as Charlotte. “Our only difference is an extra chromosome.”

“My extra chromosome makes me far more tolerant than you, sir,” she said. “If any other heritable traits, like skin color, were used to eradicate a group of people, the world would cry out. Why are you not crying out when people like me are being made extinct? What have we done to make you want us to disappear?”
“As far as I know, my community doesn’t hate, discriminate, or commit crimes,” Charlotte said. “What you are suggesting is eugenics. It’s disgusting and evil.”

“You need to apologize for your horrible comments,” the woman continued. “You should also be removed from the Human Rights Committee as an expert. You are not an expert about Down syndrome. You, sir, do not speak for my community.”

“I will fight for our right to exist for the rest of my life,” she said.

Cerebral dysplasia

A currently 12 1/2  year old boy was found to have hydrocephalus on prenatal imaging.  He was born at 38 weeks gestation, weighing  5790 g (12.7 lbs).   The birth head circumference was 57 cm. A ventriculoperitoneal shunt was placed.  A brain biopsy showed gliovascular tissue with focal dense astrogliosis and fragments of grey matter with marked vascular congestion.  There was no definite evidence of neoplasm.His subsequent history has been one of developmental delay and cognitive compromise, intractable epilepsy and motor impairment.  He has a vagal nerve stimulator.  He receives antiseizure pharmacotherapy with felbamate and lacosamide. A recent electroencephalogram showed essentially continuous paroxysmal/electrographic ictal appearing discharges that waxed and waned with altering morphologies, amplitudes and frequencies over the left hemisphere. In addition, subclinical ictal appearing discharges were present in the right hemisphere. Clinical seizure could not be correlated with such observations. For behavioral and sleep issues he receives risperidone and clonidine.  He can ambulate independently, but uses a wheelchair for community ambulation. On the K-BIT2 his IQ composite was 40, verbal 43 and nonverbal 40.

T2 images There is a masslike region throughout nearly the entire left cerebral hemisphere with areas of cystic change posteriorly. Numerous cystic structures with failure of CSF suppression (suggesting complexity) were present. 

FLAIR image  A large dysplastic, mass like, FLAIR hyperintense region is present in the left frontal, parietal, and occipital region.

Tuesday, November 28, 2017

Diagnosing functional acute neurological disorders in children

A thorough neurological exam may be more effective in diagnosing functional acute neurological disorders in children than ordering diagnostic tests, according to a retrospective examination of medical charts at Children's Hospital of Michigan affiliated with the Wayne State University School of Medicine. The findings were presented here at the Child Neurology Society annual meeting in October.

Rajkumar Agarwal, MD, assistant professor of neurology and pediatrics, and his colleagues reviewed the medical charts of 222 patients (156 females and 66 males) with a mean age of 13.9 years who presented to the emergency room with neurologic symptoms that pushed clinicians to consider seizure disorders or stroke. The presenting symptoms included seizure-like symptoms in 143 children, stroke-like symptoms in 51 children, acute vision problems in 11 children, gait problems in nine, and a combination of these symptoms in eight children.

About 82 children diagnosed with a functional neurological disorder also had scans done: magnetic resonance imaging (MRI) of the brain (37) and the spine (eight); 37 had computed tomography of the head; and 56 had electroencephalography. Fifteen children also had lumbar puncture. All tests came back negative.

Dr. Agarwal said that those more likely to have further diagnostic testing were non-African-Americans (54 percent versus 40 percent of African-Americans), patients who present with new symptoms (compared to recurring symptoms), as well as those who were admitted to the hospital and were evaluated by either a neurologist (75 percent) or a psychiatrist (60 percent); 145 children were hospitalized, and the average length of stay was 63.8 hours. The others were sent home from the emergency room with a diagnosis of functional acute neurological disorder.

“There is often clinical suspicion of conversion disorder,” said Dr. Agarwal. He explained that there are well-described signs for functional syndromes: A child whose whole body shakes, but he or she can focus and track the examiner or if the eyes are forcefully closed, is more likely to have a functional seizure. If a child has a stroke-like presentation — he can't move his arm — a good way to assess whether it is a functional disorder is to put the arm over the child's face and drop it. If it is a true weakness, the arm will fall on the child's face. If the arm moves around to avoid the face, you should expect a conversion disorder, Dr. Agarwal said.

“Despite clinical suspicion of conversion disorder, often children are subjected to a variety of tests, sometimes even invasive and potentially harmful. The need for these tests should be considered judiciously on a case-by-case basis.”

Many of the children did not report any serious acute stressors that could have sparked a conversion disorder. “The stressors were commonplace,” said Dr. Agarwal. “It tells us that a catastrophic stressor is not required to trigger a conversion disorder.”

Also, 67 percent did not have a prior psychiatric diagnosis, suggesting that these are often otherwise “healthy” children who may have an underlying unresolved psychological conflict. Neurological exams were also normal in more than 90 percent of the children…

He said that the lessons learned are that in a child presenting to the emergency room with a suspected functional symptom and a normal clinical exam, further testing should be considered on an outpatient basis.

“We found that 46 percent who went on to have further testing in the hospital were all normal,” Dr. Agarwal added. “Inpatient admission and testing increases health care costs and resource utilization should be optimized.”

[Joseph Jankovic, MD] “The diagnosis of functional movement disorders should be based not only on exclusion of organic causes but also on positive criteria, such as sudden onset, distractibility, and phenomenology that is incongruous with organic movement disorder. One organic disorder that is commonly misdiagnosed initially as ‘psychogenic’ is anti-NDMA encephalopathy.”

[Barbara Ann Dworetzky, MD] “Functional disorders are common and it is important for patients to feel that their doctors believe they have a real disorder, that they are not making their symptoms up. It is the brain's automatic response (‘like a reflex’) to an accumulation of stressors that occur over time.”

Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Höhne W, Noegel AA, Al-Owain M, Hörtnagel K, Stöbe P, Baig SM, Nürnberg P, Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577.

Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis.
Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy.
We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells.
Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations.

Response to second treatment after initial failed treatment of infantile spasms

Knupp KG, Leister E, Coryell J, Nickels KC, Ryan N, Juarez-Colunga E, Gaillard WD, Mytinger JR, Berg AT, Millichap J, Nordli DR Jr, Joshi S, Shellhaas RA, Loddenkemper T, Dlugos D, Wirrell E, Sullivan J, Hartman AL, Kossoff EH, Grinspan ZM, Hamikawa L; Pediatric Epilepsy Research Consortium. Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort. Epilepsia. 2016 Nov;57(11):1834-1842.

Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.
The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models.
One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040).
Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Notwithstanding the non-randomized design and observational nature of this study, a large number of children were studied, so some useful conclusions can be drawn:

Standard treatments (ACTH, steroids, and VGB) are superior to nonstandard treatments and should be the preferred initial treatment for infantile spasms;

Hormonal treatments (ACTH, oral steroids) are superior to VGB except in children with TS for whom VGB is clearly more effective. Response to ACTH was higher than for VGB and also somewhat higher than oral steroids. Similar findings emerged from the UKISS trial favoring hormonal treatments over VGB after 14 days of treatment although this difference was not evident at 14 months. Infants with cryptogenic etiology receiving hormonal treatment had higher developmental scores than those receiving VGB;

The NISC studies were not sufficiently powered to detect differences between various nonstandard treatments. Published reports suggest that some therapies (ketogenic diet, valproate, topiramate) may be more effective than others such as phenobarbital, oxcarbazepine, or pyridoxine (at least in North America);

Response to a second standard treatment with different mechanism of action was superior to response to a second treatment with a similar mechanism of action.

A shorter time (<4 weeks) to starting standard treatment is associated with a higher response to the second therapy, suggesting that the window for optimal seizure control starts to close somewhere between 4 and 8 weeks after spasm onset.

An interesting open-label trial published earlier this year by the International Collaborative Infantile Spasms Study (ICISS) recruited 766 children with infantile spasms from 102 hospitals in 5 countries. The 377 children who met inclusion criteria (reasons for exclusion were not recorded) were randomly assigned 1:1 to receive either hormonal therapy alone or hormonal therapy with VGB. Cessation of spasms occurred in 133/186 (72%) of those assigned to a combination of hormonal treatments with VGB versus 108/91(57%) of those receiving hormonal treatment alone (p=0.002). Infants receiving combination therapy also had a significantly shorter time to cessation of spasms (p<0.001). These results indicate that some infants clearly respond better to combination therapy than to hormone treatment alone. given the urgency of fully controlling spasms, combination treatment may be ideal as response rates dropped in those initiating treatment greater than 2 months after spasm onset. A limitation of this study was the large proportion of infants who were excluded from the study and the failure to randomize the type of hormonal treatment used. (parents could choose between tetracosactide depot or prednisolone). However, the group receiving tetracosactide had greater electroclinical response than the prednisolone group. These results need to be replicated before tetracosactide can be recommended over prednisolone.

Oral steroids are a reasonable option in certain situations (socioeconomic, parental educational level and choice) but doses greater than or equal to 2 mg/kg/day are needed. A 2012 review of available data concluded that the efficacy of high-dose corticosteroids was similar to low-dose ACTH and inferior to high-dose ACTH.

Simvastatin therapy in Smith-Lemli-Opitz syndrome

Wassif CA, Kratz L, Sparks SE, Wheeler C, Bianconi S, Gropman A, Calis KA, Kelley RI, Tierney E, Porter FD. A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genet Med. 2017 Mar;19(3):297-305.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles.
Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period.
No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin.
This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297-305.

Can a full mutation allele in the FMR1 gene contract to a normal size?

Esther Manor, Azhar Jabareen, Nurit Magal, Arei Kofman, Randi J. Hagerman and Flora Tassone. Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?  Front. Genet., 03 November 2017 |  

Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range.

From the article

The case described here represents a rare case of transmission from a full mutation mother to her offspring with an allele pattern different from what we would have expected in such cases. It is a prenatal diagnosis case of a male fetus that inherited an allele with a CGG repeats number in the normal size range (19 CGG repeats) derived from the unstable expanded maternal allele (160, >200 CGG repeats). It is well known that the majority (near to 100%) of the male fetuses that inherited unstable FMR1 allele from mosaic mothers are expected to inherit a full mutation allele. Contraction of a maternal high premutation (>100 CGG repeats)/full mutation FMR1 allele during transmission has been rarely described.

To our knowledge this is the first report of a prenatal diagnosis case showing a pattern of contraction of an expanded FMR1 unstable allele to a normal size allele. Tabolacci et al. (2016) previously described a case of a healthy 10-year-old boy who inherited a contracted unstable FMR1 allele from his mother. The authors described a family with a carrier mother (190 CGG repeats) and her three children. Two of them presented with FXS and had expanded alleles in the full mutation range (265–830 and 430–790 CGG repeats, respectively). In contrast, the healthy boy inherited a contracted allele of 43 CGG repeats. Another study (Maia et al., 2017) described four FXS boys carrying mosaic alleles ranging from the normal (35, 26, 39, and 18 CGG repeats) to the full mutation range (>200 CGG repeats). These studies sharpen the obscure mechanism of expansion of the trinucleotide repeat in the FMR1 gene, indicating that the same allele during the generation might expand or contract and possibly undergo methylation.

Since this is a prenatal diagnosis case, the questions are as follows: Is the unstable allele contracted to the normal range able to become a stable normal allele with no phenotypic consequences? Is it a normal unstable allele that may lead to some clinical involvement? Will it expand during transmission in the following generations? Is it a case of mosaicism through an undetected expanded allele of the FMR1 gene, which may cause features of FXS?
It is of importance to understand the consequence of contraction of high premutation/full mutation FMR1 allele as understanding the mechanism of FMR1 instability can improve genetic counseling of the family…

Although PCR-based approach and the sequencing tests used in the present study have shown to be very reliable, we cannot categorically exclude the presence of an expanded allele. However, the results demonstrate the presence of a normal size allele with no mosaicism, most likely leading to a normal phenotype as the case described by Tabolacci et al. (2016).

Our hypothesis is that the maternal premutation/full mutation allele contracted pre-zygotically either in the mitotic or in the meiotic stage resulting in a normal size allele in the fertilized egg with no syndromic consequence.

Monday, November 27, 2017

GABA alterations in pediatric sport concussion

Friedman SD, Poliakov AV, Budech C, Shaw DWW, Breiger D, Jinguji T, Krabak B, Coppel D, Lewis TM, Browd S, Ojemann JG. GABA alterations in pediatric sport concussion. Neurology. 2017 Nov 21;89(21):2151-2156.

To evaluate whether frontal-lobe magnetic resonance spectroscopy measures of γ-aminobutyric acid (GABA) would be altered in a sample of adolescents scanned after sport concussion because mild traumatic brain injury is often associated with working memory problems.
Eleven adolescents (age 14-17 years) who had sustained a first-time sport concussion were studied with MRI/magnetic resonance spectroscopy within 23 to 44 days after injury (mean 30.4 ± 6.1 days). Age- and sex-matched healthy controls, being seen for sports-related injuries not involving the head and with no history of concussion, were also examined. GABA/creatine + phosphocreatine (Cre) was measured in left-sided frontal lobe and central posterior cingulate regions. The frontal voxel was positioned to overlap with patient-specific activation on a 1-back working memory task.
Increased GABA/Cre was shown in the frontal lobe for the concussed group. A decreased relationship was observed in the parietal region. High correlations between GABA/Cre and task activation were observed for the control group in the frontal lobe, a relationship not shown in the concussed participants.
GABA/Cre appears increased in a region colocalized with working memory task activation after sport concussion. Further work extending these results in larger samples and at time points across the injury episode will aid in refining the clinical significance of these observations.


From the article:

GABA is the major inhibitory neurotransmitter and is an important factor in both normal cognitive function and the sequelae of traumatic brain injury. While spectroscopy has now been widely applied in traumatic brain injury, primarily to look for markers of neuronal loss before the development of DTI, to the best of our knowledge, no study to date has evaluated changes in GABA. Relative to structural markers of injury (e.g., N-acetylaspartate and choline-containing compounds), GABA is unique in that levels have been shown to be associated with cognitive functioning. For example, correlation of magnetoencephalographymeasures of gamma band activity (likely mediated by GABAa), fMRI, and GABA was demonstrated in the visual cortex in response to a visual discrimination tasks. Similar findings have been found for motor control and GABA in the supplementary motor area, tactile discrimination and GABA in the sensorimotor cortex, and gaze shifting and GABA levels in the frontal eye fields. In 2 of these studies, control regions, chosen to assess cortical GABA levels remote from the site of interest, demonstrated no concordance to performance.  Although GABA level changes do no incorporate measurement of other factors (e.g., receptor density changes, enzyme alterations), the concordance between GABA and discrete task performance supports the need to evaluate this biomarker in conditions in which structural changes may be difficult to characterize.

Evidence on a cellular level also supports that GABA may be a particularly important marker of injury and recovery in concussion. Alterations in GABA, especially GABA transport, have been seen in trauma models, both fluid percussion injury and shear injury to the developing brain. GABA-mediated inhibition can increase after injury such as stroke in response to transport and receptor dysregulation, and the corresponding increase in tonic inhibition may be deleterious to recovery from injury. Intervention, by pharmacologic inhibition of specific GABA subunits, improved motor function recovery in an animal model. This is a proposed mechanism for impaired recovery after cortical injury, with pharmacologic interventions potentially available to reverse this process. GABA changes may alter postconcussive motor plasticity. However, excessive impairment in GABA can also lead to deleterious effects such as seizures, and the understanding of the complexities of GABA after injury is critical to guiding future interventions. It is plausible that our finding of elevated GABA is imaging evidence of changes known to occur with cellular injury. The selective change in the frontal lobe would be consistent with the increased vulnerability of this region to traumatic injury.

The potential that GABA provides a protective effect or corresponds to the postconcussive cognitive symptoms or impairment often observed remains unresolved from this work. While no child in the study was experiencing headaches that would be classified as migraines, literature supporting GABA elevations in this condition provides interesting fodder for consideration. If elevated GABA occurs as a byproduct of injury, it could be envisioned to influence local activity. In general, elevated GABA is associated with improved tuning and performance, suggesting that GABA elevation could be the result of recovery attempts or possibly increased cognitive effort to perform the task as well as healthy controls. Somewhat concordant with this idea, increased activation in the frontal lobe has been described after injury or in impaired states. The correlation between GABA and fMRI activation has been studied, with how well abnormal tissue fits these associations not known. Our GABA voxels included areas outside the strongest activation, but we did find a GABA/fMRI ratio in the frontal lobe that was consistent across the healthy control sample and much higher, and varied, in the concussion group. Elevated GABA was not seen in the other area studied, the medial parietal lobe. Thus, there is some selectivity to the GABA elevation, suggesting that it is related to the function of this brain region or perhaps the task load being applied. This seems possible but, without differences in behavioral performance between groups, premature to conclude. Whether the GABA elevation is causal or only indirectly associated with postconcussive symptoms, it may provide an objective measure for following disease progression and offering a target for modulation.

Saturday, November 25, 2017

Parental perception of comorbidities in children With Dravet syndrome.

Knupp KG, Scarbro S, Wilkening G, Juarez-Colunga E, Kempe A, Dempsey A. Parental Perception of Comorbidities in Children With Dravet Syndrome. Pediatr Neurol. 2017 Nov;76:60-65.

We hypothesized that children with Dravet syndrome may have additional common features beyond seizures and cognitive impairment. To address this gap in knowledge, we conducted a survey of caregivers of children with Dravet syndrome to identify and quantify their perception of associated symptoms in this population.
An electronic survey was developed in REDcap (Research Electronic Data Capture) and sent via e-mail to the participants on the Dravet Syndrome Foundation e-mail list. Questions focused on eating, sleep, behavior, and other symptoms that might be related to Dravet syndrome. The questions were assessed using a four-point Likert scale (e.g., strongly agree to strongly disagree). Results were later dichotomized for analysis. Logistic regression was used to calculate odds ratios of various demographic factors potentially associated with symptoms. Multivariable models were constructed using backward elimination to assess the relationship among a variety of symptoms.
There were 202 respondents, 96% were parents of a child with Dravet syndrome (the remainder were grandparents or guardians); 90.5% were female. The median age of the affected child was eight years (interquartile range five to 14), 50% were male, and 90.5% were reported to have a known SCN1A mutation. At least one symptom associated with appetite was reported in 99% of respondents, 82% reported a disturbance of sleep, one third reported autonomic symptoms, and 75% reported problems with gait. Inattention and perseveration were reported more commonly than other behavioral disturbances.
Caregivers have the perception of many symptoms in children with Dravet syndrome in addition to those that have been previously reported, including appetite, sleep, gait, and behavior. Many of these can significantly affect quality of life for both the child and the caregiver.

The impact of hypsarrhythmia on infantile spasms treatment response

Demarest ST, Shellhaas RA, Gaillard WD, Keator C, Nickels KC, Hussain SA, Loddenkemper T, Patel AD, Saneto RP, Wirrell E, Sánchez Fernández I, Chu CJ, Grinspan Z, Wusthoff CJ, Joshi S, Mohamed IS, Stafstrom CE, Stack CV, Yozawitz E, Bluvstein JS, Singh RK, Knupp KG; Pediatric Epilepsy Research Consortium. The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium. Epilepsia. 2017 Nov 3. doi: 10.1111/epi.13937. [Epub ahead of print]

The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia.
Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation.
Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) .
First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.

Wednesday, November 22, 2017

UBA5 mutation

Arnadottir GA, Jensson BO, Marelsson SE, Sulem G, Oddsson A, Kristjansson RP, Benonisdottir S, Gudjonsson SA, Masson G, Thorisson GA, Saemundsdottir J, Magnusson OT, Jonasdottir A, Jonasdottir A, Sigurdsson A, Gudbjartsson DF, Thorsteinsdottir U, Arngrimsson R, Sulem P, Stefansson K. Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters. BMC Med Genet. 2017 Oct 2;18(1):103.

Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.
We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.
We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.

Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, Khiati S, Denommé AS, Amati-Bonneau P, Charif M, Procaccio V, Reynier P, Aleck KA, Botto LD, Herper CL, Kaiser CS, Nabbout R, N'Guyen S, Mora-Lorca JA, Assmann B, Christ S, Meitinger T, Strom TM, Prokisch H; FREX Consortium, Miranda-Vizuete A, Hoffmann GF, Lenaers G, Bomont P, Liebau E, Bonneau D. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):695-703.


Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.

Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T, Keski-Filppula R, Herva R, Rantala H, Paetau A, Pöyhönen M, Obata M, Uemura T, Karhu T, Bizen N, Takebayashi H, McKee S, Parker MJ, Akawi N, McRae J, Hurles ME; DDD Study, Kuismin O, Kurki MI, Anttonen AK, Tanaka K, Palotie A, Waguri S, Lehesjoki AE, Komatsu M. Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):683-694.

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.

Cryptogenic NORSE

Takahiro Iizuka, MD, Naomi Kanazawa, BS, Juntaro Kaneko, MD, Naomi Tominaga, MD, Yutaka Nonoda, MD, Atsuko Hara, MD, Yuya Onozawa, PhD, Hiroki Asari, MD, Takashi Hata, MD, Junya Kaneko, MD, Kenji Yoshida, MD, Yoshihiro Sugiura, MD, PhD, Yoshikazu Ugawa, MD, PhD, Masashi Watanabe, MD, Hitomi Tomita, MD, Arifumi Kosakai, MD, Atsushi Kaneko, MD, Daisuke Ishima, MD, Eiji Kitamura, MD and Kazutoshi Nishiyama, MD, PhD. Cryptogenic NORSE.  Its distinctive clinical features and response to immunotherapy.  Neurol Neuroimmunol Neuroinflamm November 2017 vol. 4 no. 6 e396.  Published online September 25, 2017


Objective: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments.

Methods: A retrospective study was conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSE were identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE).

Results: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6–111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with C-NORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had a worse outcome. The C-NORSE score was higher in patients with C-NORSE than those with NMDARE.

Conclusions: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy.

From the article:

New-onset refractory status epilepticus (NORSE) is a rare but neurologic emergency condition characterized by refractory status epilepticus (RSE) without readily identifiable cause in otherwise healthy individuals. “NORSE” is currently viewed as a syndrome, not a distinct entity, and has received several names, including devastating epileptic encephalopathy in school-age children (DESC),4 febrile infection-related epilepsy syndrome (FIRES), acute encephalitis with refractory repetitive partial seizures (AERRPS), or NORSE. DESC, FIRES, and AERRPS are terms more frequently used in pediatric patients, whereas NORSE is more frequently used in adults. The concept of “acute encephalopathy with inflammation-mediated status epilepticus (AEIMSE)” has also been proposed.

Since the discovery of autoimmune encephalitis (AE) and autoantibodies against neuronal cell-surface antigens or synaptic proteins (NSA antibodies), a few cases of FIRES15 or NORSE16 associated with NSA antibodies have been documented. Furthermore, a recent large cohort demonstrated that a half of 130 patients with NORSE remained cryptogenic, but 37% were immune mediated; among those, the most common etiology was anti-NMDA receptor (NMDAR) encephalitis (NMDARE).

Therapeutic approach with IV cyclophosphamide (IVCPA) has also been proposed in even cryptogenic cases. However, only 1 of 63 patients (2%) with cryptogenic NORSE (C-NORSE) received IVCPA in the cohort. In an emergency condition, antibody testing results may not be readily accessible, but it is important to differentiate C-NORSE from antibody-mediated encephalitis at an early stage…

The treatment strategy was decided by individual patients' physicians. Treatments were classified into (1) conventional AED treatment (AED, and continuously infused anesthetic agents [midazolam, propofol, thiopental, thiamylal, phenobarbital, or pentobarbital]), (2) the first-line immunotherapy (IV high-dose methylprednisolone [IVMP], 1,000 mg/day, for 3–5 days; IV immunoglobulin [IVIg], 0.4 g/kg/day for 5 days; and plasma exchange [PLEX] alone or combined), (3) the second-line immunotherapy (IVCPA [500 mg/m2, monthly for 1–6 cycles] or rituximab [375 mg/m2, once weekly, 4 doses]), (4) chronic immunosuppression (prednisone, tacrolimus, cyclosporine, azathioprine, or mycophenolate mofetil), and (5) tumor resection when appropriate…

The first-line immunotherapy was considered “not effective” in 8 of the 10 treated patients, but IVCPA was presumed to be “effective” in 4 of the 5 treated patients who failed to respond to the first-line immunotherapy. In IVCPA-responsive 4 patients (#3, 5, 9, and 11), IVCPA was started between days 20 and 59, but nonresponsive patient (#4) received IVCPA on day 173. In patient 3, the first-line immunotherapy started on day 6; nevertheless, symmetric brain lesions developed (figure 2). Because NMDARE was initially suspected, IVCPA was started on day 20, followed by PLEX, and IVCPA was repeated on day 52 with the first-line immunotherapy, resulting in marked improvement with resolution of brain MRI abnormalities. The patient became able to walk without assistance 11 months after the symptom onset; IVCPA was considered effective. By contrast, patient 4 was admitted to a city hospital and treated with conventional AED treatment and IVMP started on day 3. However, the patient became a state of unresponsive wakefulness with diffuse brain atrophy. Five months later, the patient was transferred to our hospital and treated with IVCPA (day 173) combined with the first-line immunotherapy because we had a few successful experiences of immunotherapy initiated 8–12 months after the symptom onset in patients with NMDARE with diffuse brain atrophy.26 Gadolinium enhancement disappeared after the immunotherapy, but IVCPA was considered not effective because this patient's mental status remained unchanged. In the other 3 treated patients, IVCPA was presumed to be effective…

The first-line immunotherapies are usually not effective in patients with NORSE,3 FIRES,5 or AERRPS.6 Lack of response is consistent with the absence of NSA antibodies; however, inflammation-mediated epileptogenesis has increasingly been proposed. One study showed upregulation of interleukin (IL)-6, C-X-C motif chemokine 10, and IL-8 in CSF of patients with AERRPS, suggesting a role for the innate and adaptive immune system,35 since IL-6 is a booster of adaptive immune mechanisms while IL-8 and CXC-10 enhance the innate immunity; IVCPA exerts its main activity rather on the T-cells than on the B-cells. Although we did not examine CSF cytokine or chemokine levels in our cases, IVCPA might have some beneficial effects on inflammation-mediated mechanisms.

In practice, physicians must judge whether their patients with NORSE are cryptogenic or immune mediated based on initial clinical assessments because antibody testing results are usually not readily accessible. Therefore, we listed 8 distinctive features in table 2 and created the C-NORSE score. When the patient has 5 or more of the first 6 clinical features without etiology readily identified, NSA antibodies would be less likely detected, and conventional AED treatments would not be expected to provide remarkable beneficial effects. In our cases, all had 5 or more C-NORSE scores. This scoring strategy may help physicians to identify cryptogenic cases, but this scoring system should be validated in the different cohort in the future.

It is known that 80% of patients with NMDARE achieve a good outcome at 24 months.36 Such a good outcome and lack of evident brain damage on MRI are strongly related to early and intensive immunotherapy, and the absence of a substantial infiltration of the brain with inflammatory cells and the lack of complement activation may protect the brain from massive structural damage.37 However, epilepsy-related irreversible brain damage occurs quickly in C-NORSE; therefore, it may require more aggressive and early initiation of immunotherapy such as IVCPA than antibody-mediated encephalitis…

Many issues remain unknown, including etiology, epileptogenesis, and response to immunotherapy in C-NORSE. Genetic analysis was not performed in our patients. One might argue that these patients may include those with seronegative autoimmune limbic encephalitis or genetic epileptic disorder underdiagnosed or with some new antibodies not detected yet. We cannot rule out such possibilities. It remains to be determined whether early administration of IVCPA and IVMP or IVIg with conventional AED treatment would improve long-term outcomes. These issues should be addressed in the future.

Monday, November 20, 2017

Prader-Willi syndrome?

Luis Manuel, who is just 10 months old, weighs in at 30 kilogrammes (four stone 10 lbs). 

Doctors have told his parents, from the city of Tecoman in the western Mexican state of Colima, that they fear the youngster may have Prader-Willi syndrome (PWS). 

His family have launched a fundraising appeal as they say they will not be able to afford medical treatment for their little boy if the diagnosis is confirmed. Treatment would consist of a series of hormone injections, with each one reportedly costing 10,000 MXN (about £404). 

Luis Manuel weighed a healthy 3.5 kilogrammes (7 pounds 11 ounces) at birth but began to put on weight at an alarming rate. His mother, Isabel Pantoja, said: ‘After only one month we noticed that clothes did not fit him and we had to dress him in clothes for a one-year-old, and even a two-year-old.

‘We saw our baby gain weight so fast. Sometimes, he could not sleep because he felt like he was suffocating due to his weight.’ 

Doctors say Luis Manuel is currently the normal weight for a nine-year-old boy even though he is still two months short of his first birthday. 

Prader-Willi syndrome is a genetic disorder caused by a loss of function of specific genes which causes sufferers to feel constantly hungry, often leading to obesity and type 2 diabetes. 

Doctors in Tecoman say Luis Manuel would be the first ever recorded case of the condition in the city. 

Mario Gonzalez, the boy’s father, said he was worried about the health implications for his son. He said: ‘In some cases, kids have died because of a heart attack due to being so overweight.’

Saturday, November 18, 2017

Mitochondrial DNA depletion syndromes

El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 2013 Apr;10(2):186-98.


Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.

Therapies for mitochondrial diseases

El-Hattab AW, Zarante AM, Almannai M, Scaglia F. Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab. 2017 Sep 18. pii:S1096-7192(17)30531-0. doi: 10.1016/j.ymgme.2017.09.009. [Epub ahead of print]

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.

From the article:


There are still no satisfactory therapies available for mitochondrial disorders.

Several agents are currently used and being evaluated for mitochondrial diseases.

Agents enhancing electron transfer chain function or mitochondrial biogenesis are used in mitochondrial diseases.

Energy buffer, antioxidants, and cardiolipin protector are also used in mitochondrial diseases.

Role of liver transplantation and gene therapy in treating mitochondrial diseases are also discussed.

An increased number of clinical research evaluates agents targeting different aspects of mitochondrial dysfunction…

Subsequently, different agents aiming to enhance mitochondrial function and treat the consequences of mitochondrial dysfunction are presented. These treatment include: 1) agents enhancing ETC function (coenzyme Q10 (CoQ10), idebenone, riboflavin, dichloroacetate, and thiamine), 2) energy buffer (creatine), 3) antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), 4) amino acids restoring nitric oxide production (arginine and citrulline), 5) cardiolipin protector (elamipretide), 6) agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), and 7) nucleotide bypass therapy…

It was suggested that CoQ10 supplementation to individuals with other mitochondrial diseases would improve the efficacy of electron transfer through ETC. Some case reports and open-label studies suggested that CoQ10 treatment may have beneficial effects in individuals with mitochondrial diseases. However, a randomized double-blinded study only showed minor effects of CoQ10 supplementation on cycle exercise aerobic capacity and post-exercise lactate and did not show any effect on other clinically relevant variables such as strength or resting lactate. Therefore, apart from CoQ10 deficiency, this supplementation has limited benefits on other mitochondrial diseases…
Thiamine supplementation in a family with MELAS syndrome and thiamine deficiency was reported to improve lactic acidosis and myopathy. The use of thiamine, along with CoQ10, carnitine, and vitamins C and E, resulted in a marked clinical recovery in an individual with adult-onset Leigh disease presenting as severe brainstem encephalopathy of subacute onset…

Some agents used to treat mitochondrial diseases are antioxidants that alleviate the toxic effect of excessive ROS produced in these diseases. Vitamin C and vitamin E are occasionally used in individuals with mitochondrial diseases in combination with other agents. A limited number of case reports and small studies has noticed modest benefits for these supplements in some individuals with mitochondrial diseases...

Flow-mediated vasodilation (FMD), which is a function of NO synthesized by endothelial cells in response to re-perfusion, was found to be impaired in individuals with mitochondrial myopathy, MELAS, MERRF (myoclonic epilepsy with ragged red fibers), MIDD (maternally inherited diabetes and deafness), and CPEO, providing further evidence of NO deficiency in mitochondrial diseases. NO deficiency in mitochondrial disorders is believed to be multifactorial in origin due to impaired NO production and postproduction NO sequestration ...

The therapeutic effect of arginine in stroke-like episodes in MELAS is proposed to be due to increased NO availability leading to improving intra-cerebral vasodilation and blood flow. This has been supported by the demonstration that arginine supplementation to subjects with MELAS resulted in increased NO production rate and improved FMD. The use of oral arginine as maintenance therapy and intravenous arginine during the stroke-like episodes have become commonly used in treating individuals with MELAS syndrome.

The clinical effects of citrulline administration in mitochondrial diseases have not been studied, however, stable isotope studies have demonstrated that, similar to arginine supplementation, citrulline supplementation can increase NO production in children and adults with MELAS syndrome. Interestingly, citrulline supplementation induced a greater increase in the NO synthesis rate than that associated with arginine supplementation, indicating that citrulline is a more effective NO precursor than arginine. This can be due to the superiority of citrulline in raising plasma and intracellular arginine levels, leading to more arginine availability for NO synthesis...

Currently, a randomized crossover study is conducted to assess the effect of arginine and citrulline supplementation on endothelial dysfunction in children with mitochondrial diseases. The primary outcome measure is the changes in reactive hyperemic index, which reflects endothelial function, after arginine or citrulline supplementation (

Several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. The use of these agents is based on limited number of studies and can be beneficial only in some mitochondrial disease. Therefore, treatment of mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Although, there is a lack of therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future. Agents currently being evaluated for mitochondrial diseases include antioxidants (RP103 and EPI-743), cardiolipin protector (elamipretide), and mitochondrial biogenesis enhancers (bezafibrate, epicatechin, and RTA 408). Gene therapy has shown promising results in treating LHON.

Thursday, November 16, 2017

Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ,  Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638.


In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.
We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.
A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.
Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. 

Fifteen of 17 boys with cerebral adrenoleukodystrophy (ALD) are doing well after receiving a novel gene therapy, scientists at Massachusetts General Hospital and Boston Children's Hospital reported at the Child Neurology Society annual meeting here in October.

The scientists reported interim results of the STARBEAM trial, an ongoing multicenter, open label phase 2-3 study. Eleven of the 17 boys were treated in Boston and the others were from centers in the United States and Europe. The primary endpoint was being alive and having no functional disability 24 months after infusion of the gene therapy.

“It appears to be the first successful gene therapy treatment to halt a fatal brain disease,” said Florian S. Eichler, MD, director of the leukodystrophy service at the MassGeneral Hospital for Children and lead author of the study that was simultaneously published in the October 26 issue of The New England Journal of Medicine (NEJM).

ALD affects 30 to 40 percent of boys between 4 and 8 years old who are born with a mutation in the X-linked ATP-binding cassette, subfamily D, member 1 (ABCD1) gene. Hyperactivity and behavior changes are often the first sign so the disease is often missed. The boys with ALD quickly begin to lose their ability to walk and talk. By the time a diagnosis is suspected, a brain scan shows a massive lesion in white matter tracts around the corpus callosum….

The boys, whose average age was 6 years old, were identified through screening and family history. They were asymptomatic at the time of the transplant but were accepted into the study because they had evidence of early white matter inflammation on a magnetic resonance imaging (MRI) scan.

One patient in the study died from disease progression. In hindsight, Dr. Eichler said that his disease had been advancing more rapidly at the time of enrollment. Another patient withdrew from the study after the transplant, and his parents decided to have him undergo allogeneic bone marrow transplant. He too died.

The boys are being closely followed. MRI scans show that the early lesions have stopped spreading. There haven't been any engraftment problems or graft-versus-host issues. The 15 boys have minimal or no symptoms, Dr. Eichler said. Two years later, these boys are leading normal lives, he added.

None of the 15 children have more than minimal signs of disease. “The efficacy (ability to stop lesion progression and clinical decline) is similar to what is seen with allogeneic bone marrow transplantation. The difference is that we saw no engraftment and no graft-versus-host disease, complications commonly encountered with allogeneic bone marrow transplantation. We think the procedure is stopping the inflammatory degeneration.”

Dr. Eichler added that eight more boys have undergone the gene therapy since the study was submitted to the NEJM.  The Boston team is continuing to enroll patients into the trial and monitoring the boys who had the gene therapy. Bluebird Bio, the biotechnology company that sponsored the trial, plans to apply for federal approval to use the ex-vivo technique for the treatment of ALD. It is not known how much the one-time gene therapy treatment might cost.

The Boston scientists are now working on another gene therapy using the AAV-9 vector to deliver the ABCD1 gene into the intrathecal space in the spinal cord. It worked in animal models, and they are doing more studies before human trials begin. They will recruit adult patients who often have spinal cord defects.