Thursday, December 31, 2020

Diagnosis, prognosis, and treatment of leukodystrophies

van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol. 2019 Oct;18(10):962-972. doi: 10.1016/S1474-4422(19)30143-7. Epub 2019 Jul 12. PMID: 31307818.


Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.

Courtesy of a colleague

Wednesday, December 30, 2020

Enhanced mesenchymal stromal cells or erythropoietin after neonatal stroke

Larpthaveesarp A, Pathipati P, Ostrin S, Rajah A, Ferriero D, Gonzalez FF. Enhanced Mesenchymal Stromal Cells or Erythropoietin Provide Long-Term Functional Benefit After Neonatal Stroke. Stroke. 2021 Jan;52(1):284-293. doi: 10.1161/STROKEAHA.120.031191. Epub 2020 Dec 22. PMID: 33349013; PMCID: PMC7770074.


Background and purpose: Perinatal stroke is a common cause of life-long neurobehavioral compromise. Mesenchymal stromal cells (MSCs) and EPO (erythropoietin) have each demonstrated short-term benefit with delayed administration after stroke, and combination therapy may provide the most benefit. The purpose of this study is to determine the long-term histological and functional efficacy of enhanced, intranasal stem cell therapy (MSC preexposed to EPO) compared with standard MSC or multidose systemic EPO. 

Methods: Transient middle cerebral artery occlusion or sham surgery was performed in postnatal day (P) 10 Sprague-Dawley rats, who were treated with single-dose intranasal MSC, MSC preexposed to EPO (MSC/EPO), multidose systemic EPO (EPO3; 1000 u/kg per dose×3 every 72 hours), or cell-conditioned media on P13 (day 3 [P13-P19] for EPO), or on P17 (day 7 [P17-P23] for EPO). At 2 months of age, animals underwent novel object recognition, cylinder rearing, and open field testing to assess recognition memory, sensorimotor function, and anxiety in adulthood. 

Results: MSC, MSC/EPO, and EPO3 improved brain volume when administered at 3 or 7 days after middle cerebral artery occlusion. MSC/EPO also enhanced long-term recognition memory with either day 3 or day 7 treatment, but EPO3 had the most long-term benefit, improving recognition memory and exploratory behavior and reducing anxiety. 

Conclusions: These data suggest that single-dose MSC/EPO and multidose systemic EPO improve long-term neurobehavioral outcomes even when administration is delayed, although EPO was the most effective treatment overall. It is possible that EPO represents a final common pathway for improved long-term repair, although the specific mechanisms remain to be determined.

Courtesy of:

Saturday, December 26, 2020

Subtle seizures

 Every day for several years, the young man had experienced brief episodes, which he later described as “hearing all the music in the world at once for 30 seconds.” All the things people around him were saying would fade out. It was only when he experienced a new-onset convulsive seizure and was referred to epileptologist Jacqueline A. French, MD, FAAN, professor of neurology at the NYU Langone Health and director of translational research and clinical trials for epilepsy, that he realized that those recurrent episodes had also been a type of seizure. 

Dr. French uses the term “subtle seizures” to describe these episodes, which she defines as involving primarily motor arrest. Subtle seizures roughly correspond to the International League Against Epilepsy classification of “focal non-motor,” distinguishing them from disruptive seizures involving motor activity or disruptive vocalizations, including bilateral tonic-clonic seizures. 

Dr. French and a multi-institutional group of colleagues reported in an October 20 study online in the journal Epilepsia that patients with these types of seizures experience significantly longer delays in diagnosis and, when there is impaired awareness, this produces significantly greater risk for motor vehicle accidents. 

The study is among the first to pinpoint failure to recognize symptoms of subtle seizures as a main reason for delays in diagnosing epilepsy…

“Many of these patients are getting missed in primary care settings, emergency departments, and even sometimes by neurologists,” Dr. French said. “The man who had music in his head was one patient who came to me after having been seen by other neurologists. Another woman was having episodes that she called her ‘panic attack.’ She had seen two previous neurologists, and after she had a convulsive seizure, she was treated for that, but her doctors were unaware that she was having other seizures as well, and the medications they gave her didn't stop those smaller seizures. When she came to me, she explained that during her ‘panic attacks,’ she would be driving and suddenly find her feet off the pedals. When we brought her to our monitoring unit, we recorded five such subtle seizures in two days.”…

Most epilepsy specialists have seen patients like these, said Nathan B. Fountain, MD, FAAN, professor of neurology and director of the F.E. Dreifuss Comprehensive Epilepsy Program at the University of Virginia School of Medicine. 

“I just recently saw someone who had had subtle seizures since childhood but wasn't diagnosed until she had her first major motor seizure in her 30s. But then she described for me strange instances like when she would be standing at the bus stop only to realize that the school bus had come and went, and she hadn't realized it.”…

Fred A. Lado, MD, director of epilepsy for Northwell Health Central and Eastern Regions, agreed. “It really is a common situation for the epileptologist that you speak to someone in the clinic who is presenting with a first seizure, and when you take the history, you find out they have been having subtle events going back years or decades. You ask what they make of that, and they say, ‘I thought everyone had something like this.’ Your subjective experience is just that, yours and people don't realize that what they're experiencing is unique or even reportable.” 

“I wasn't surprised by the high proportion of patients who had subtle seizures, but the fact that there were so many motor vehicle accidents in that group, as compared to the disruptive group, is important, and that hasn't really been quantified before,” Dr. Lado said…

That can be challenging, said Dr. Fountain. “Many people have unusual sensations that aren't seizures—in fact, I suspect the majority of people with unusual sensations aren't having seizures, so it's up to physicians to identify the characteristics that suggest that unusual, subtle symptoms are likelier to be seizures. For example, they are stereotyped, usually highly so, each time the same, and paroxysmal—coming on suddenly and stopping in a discrete episode rather than waxing and waning all day long.”

Pellinen J, Tafuro E, Yang A, Price D, Friedman D, Holmes M, Barnard S, Detyniecki K, Hegde M, Hixson J, Haut S, Kälviäinen R, French J; Human Epilepsy Project Co-Investigators. Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy. Epilepsia. 2020 Dec;61(12):2643-2652. doi: 10.1111/epi.16707. Epub 2020 Oct 19. PMID: 33078409.


Objective: To test the hypothesis that people with focal epilepsy experience diagnostic delays that may be associated with preventable morbidity, particularly when seizures have only nonmotor symptoms, we compared time to diagnosis, injuries, and motor vehicle accidents (MVAs) in people with focal nonmotor versus focal seizures with motor involvement at epilepsy onset. 

Methods: This retrospective study analyzed the enrollment data from the Human Epilepsy Project, which enrolled participants between 2012 and 2017 across 34 sites in the USA, Canada, Europe, and Australia, within 4 months of treatment for focal epilepsy. A total of 447 participants were grouped by initial seizure semiology (focal nonmotor or focal with motor involvement) to compare time to diagnosis and prediagnostic injuries including MVAs. 

Results: Demographic characteristics were similar between groups. There were 246 participants (55%) with nonmotor seizures and 201 participants (45%) with motor seizures at epilepsy onset. Median time to diagnosis from first seizure was 10 times longer in patients with nonmotor seizures compared to motor seizures at onset (P < .001). The number and severity of injuries were similar between groups. However, 82.6% of MVAs occurred in patients with undiagnosed nonmotor seizures. 

Significance: This study identifies reasons for delayed diagnosis and consequences of delay in patients with new onset focal epilepsy, highlighting a treatment gap that is particularly significant in patients who experience nonmotor seizures at epilepsy onset.

Pohlmann-Eden B, Hynick N, Legg K. First seizure while driving (FSWD)--an underestimated phenomenon? Can J Neurol Sci. 2013 Jul;40(4):540-5. doi: 10.1017/s0317167100014633. PMID: 23786737.


Background: Seizures while driving are a well known occurrence in established epilepsy and have significant impact on driving privileges. There is no data available on patients who experience their first (diagnosed) seizure while driving (FSWD). 

Method: Out of 311 patients presenting to the Halifax First Seizure Clinic between 2008 and 2011, 158 patients met the criteria of a first seizure (FS) or drug-naïve, newly diagnosed epilepsy (NDE). A retrospective chart review was conducted. FSWD was evaluated for 1) prevalence, 2) clinical presentation, 3) coping strategies, and 4) length of time driving before seizure occurrence. 

Results: The prevalence of FSWD was 8.2%. All 13 patients experienced impaired consciousness. Eleven patients had generalized tonic-clonic seizures, one starting with a déjà-vu evolving to visual aura and a complex partial seizure; three directly from visual auras. Two patients had complex partial seizures, one starting with an autonomic seizure. In response to their seizure, patients reported they were i) able to actively stop the car (n=4, three had visual auras), ii) not able to stop the car resulting in accident (n=7), or iii) passenger was able to pull the car over (n=2). One accident was fatal to the other party. Twelve out of 13 patients had been driving for less than one hour. 

Discussion: FSWD is frequent and possibly underrecognized. FSWD often lead to accidents, which occur less if preceded by simple partial seizures. Pathophysiological mechanisms remain uncertain; it is still speculative if complex visuo-motor tasks required while driving play a role in this scenario.

Tuesday, December 22, 2020

Another PANDAS tale

About 400 miles away from the Baiers, another family's child was suffering in suburban Minnesota. 

Natalie and Brian Barnes' son Parker had been having seizures and dealing with debilitating anxiety, rage and depression for months.

"I would liken it to an abduction. Something came in the window and stole our child and left behind this shell. Our kid is gone!" Brian Barnes told "20/20."

The Barnes family's lives changed in April 2017 when Parker, the oldest of four children, was just 10. He was a rambunctious and outgoing boy. But midway through fourth grade, Parker began acting differently, with odd tics and strange moodiness.

Then one day, his brother Stetson was heading to the family's upstairs bathroom and ran into Parker.

"I'm like, 'Mom! Dad! He's going to stab himself!'" Stetson told "20/20."

"I ran up to the bathroom and there he stood with a knife in his hand," Natalie Barnes told "20/20."

"Bawling uncontrollably," Brian Barnes said.

"He was, like, in a trance, and I just grabbed the knife. And I'm just hugging him, and he's like, 'I just didn't want me to hurt anybody with the strep anymore,'" Natalie Barnes said.

One doctor told Parker Barnes' parents that his change in behavior may be caused by something...Read More

Parker said he was not sure if he really wanted to hurt himself with the knife that day.

An emergency room doctor recommended that Parker be evaluated by a psychiatrist, and just like the Baier family, the Barneses checked Parker into a psychiatric hospital.

"That was a nightmare," Parker, now 12, told "20/20." "That was like a prison for children 'cause all the children didn't want to see their families, because they were all so like angry or mean or something."

As Parker was evaluated, one doctor became struck by one factor in his case. She learned that Parker's symptoms had first begun months earlier, when he had been diagnosed with strep throat.

"She said he might have something called PANDAS, and we're like, 'PANDAS?'" Natalie Barnes said...

"I'm thinking, 'Great. Good. PANDAS. Is there a syrup for that?'" Brian Barnes said. "They're going to have the right thing -- the anti-PANDAS pill -- and whatever that is, it'll be gone and we'll be down the road and get our kid back, OK?"

Brian and Natalie Barnes took Parker to more than a dozen doctors in Minnesota looking for a remedy for PANDAS, showing them videos of his erratic behavior. They got limited results.

"I would have to say most the time they would go, 'Hmm.' Nobody ever said, 'O.M.G., I can't believe he's doing that. Let's figure it out!'" Brian Barnes said. 

Their quest for better treatment took them to Dr. Beth Latimer, a pediatric neurologist in Washington D.C. who takes on the PANDAS cases that many other doctors don't.

"I have felt tremendous amount of responsibility for these kids," Latimer told "20/20." "I've seen people move from one side of the country to the other. Parents get divorced because they can't deal with the trauma of this illness."

Latimer started seeing PANDAS patients 15 years ago and quickly became a last resort for parents who say they are unable to find help elsewhere.

She spent more than two hours evaluating Parker medically and learning his developmental history, but perhaps the most compelling visual evidence Latimer saw was the dramatic and, at times, disturbing home video Brian and Natalie Barnes had taken to document their son's ordeal.

Their videos show Parker's behavior ranging from unresponsive to full-on rage. Parker is shown moaning and whining.

"He would just freeze up," Natalie Barnes said. "You can't get him out of it."

Latimer said she knows PANDAS when she sees it -- even though she said PANDAS can look completely different from patient to patient -- and believes Parker has the disorder.

As Kathryn progressed, the Barnes family continued searching for answers. Natalie and Brian Barnes had every intention of putting Parker through the intensive treatment that Latimer had suggested -- plasmapheresis, a process to remove the antibodies attacking his immune system -- even though it would mean Parker would have to spend a week at a hospital in the intensive care unit. 

"Parker suffers every day," Natalie Barnes said. "He has no childhood right now. It's like if you had a child that was told they had leukemia and they had to be hospitalized to get chemotherapy, you would not hesitate." 

But again, some doctors consider the treatment controversial and don't accept it as a proper course, including, the Barneses said, their local immunologist. 

"He said, 'I will not participate on any level with your son if you give him that treatment. I don't agree with it and I won't touch him,'" Brian Barnes said. 

Because Latimer could not admit Parker to a Minnesota hospital and the family's local immunologist was unwilling to participate in the process and lengthy follow-up, plasmapheresis was scrapped as an option for now. 

"The logistical problem of trying to get it arranged was confounding," Brian Barnes said. 

The Barnes say, as for next steps, "There's a million ways and ... it depends on what your doctor considers serious ... [and] what they're comfortable ordering," Natalie Barnes said...

Parker's parents kept trying to find a solution for him. This summer, there seemed to be some progress. Doctors increased the frequency of his medications, steroid treatments and injections to boost or supplement his immune system and by the time he turned 12, they say things seemed to be getting better.

But it didn't last. His parents said he started hearing voices and having hallucinations -- symptoms they hadn't seen in him in more than a year.

"He had moments where he would be OK and then he would just dive down to a place we hadn't seen," Brian Barnes said. "It's back in the scary places where he's become very unpredictable. ... He would sit there and chant, 'Die, suffer, bleed. ... Die, suffer, bleed.'"

During this chanting, Brian Barnes said Parker would go on to say, "I should bleed. I should make myself bleed."

As a parent, "panic can set in very quickly," Brian Barnes said.

He and Natalie Barnes began yet another search for another doctor. They were finally able to get an appointment for later this month with a specialist who, they say, is open to the idea of giving Parker plasmapheresis in Minnesota. They estimated that the cost would be as much as $100,000 for treatment and follow-ups.     See very interesting video at this link 

Our son Parker was a wonderful 10-year-old boy.

As the eldest of our four kids, he was a most capable young man. He got good grades in school, was popular among his classmates, adored by his teachers and loved by his family. We nicknamed him "The Lead Dog" as in how a dog team is directed by a natural leader at the head of the team.

He was organized, stone reliable and obviously smart with a dry sense of humor and a wry smile that gave the impression of an old soul. His reliability was way above his peers. You could count on him every time you needed him.

Somewhere in the night Parker's immune system responded to a typical infection and quietly began a dysfunctional campaign against his brain. In a matter of months he had descended into psychosis, hallucinations, suicidal actions, rages, torturous anxiety, obsessive behavior, compulsions and seizures. He experienced a loss of his fine motor skills and a loss of appetite. He lost weight and eventually lost the ability to speak for more than four months.

After repeated evaluations from multiple medical specialists along with exhaustive research and data collection from every possible angle, we were left with a diagnosis of a little-known condition called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) or sometimes called Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Because Parker was 10 years old and we had a decade of rock-solid experience with his personality and character, his abrupt transformation is a classic presentation of this hideous disease.

Oftentimes for days on end he would be reduced to a crying ball in a corner of his room, unable to speak, interact or function. Huge tears would flow down his cheeks for hours, day after day, as he cried out in his mental agony. It is a nightmare the likes of which we never knew existed. Our lives were turned upside down in an instant and everything we knew had changed. We battled disbelief, confusion, disinformation and finally the realization that this monster had consumed our boy and that we were in for the fight of our lives.

I used to think that the medical system was by design steadfast and determined to find a cure for whatever ails you, and certainly for whatever ails your child. To my surprise, I found that we were expected to be the number-one care coordinator and researcher for our son's condition. In fact, many in the medical community flatly turned a blind eye, alluded that we were making it up or incorrectly diagnosed our son with a psychiatric disorder. We were later warned that psychiatric drugs will typically make it worse.

Our insurance company did not want to pay for treatment even after a correct diagnosis. We were forced to fight with uninformed doctors, tight-fisted insurance companies and disbelieving but well-intentioned family and friends, all while caring for our disintegrating child.

To compound matters, there is a small group of vocal doctors that, for their own reasons, stubbornly lead the opposition to this disease on the national stage and seemingly have a stranglehold on the progression of treatment. They dispute the science and ignore successful treatments.

Our story is not unique, but frighteningly common. When children begin demonstrating the rapid dysfunctional symptoms of PANDAS/PANS, the kids suffer terribly and as a result the parents are driven insane trying to battle the onslaught of symptoms. To say that it's maddening would be a huge understatement.

We are here. Our kids are here. We need help and it can be a lonely battle. The worst part is that there may be a one in 200 chance that it will happen to your child or a child you know.


Sunday, December 20, 2020

Reversible child cognitive impairment and suprasellar arachnoid cyst

François Lechanoine, Antoine Listrat, Julien Francisco Zaldivar‐Jolissaint, Emmanuel De Schlichting. Reversible Child Cognitive Impairment and Suprasellar Arachnoid Cyst. First published: 22 September 2020

A 4‐year‐old girl was addressed to our department with a 1‐year clinical history of clumsiness, gradual cognitive decline, language disorders, and chronic headaches. Her parents reported a dramatic drop in school performance. Clinical evaluation showed no macrocrania and no abnormalities in long tracts, cranial nerves, or cerebellar function. Neuropsychological evaluation revealed alterations of executive functions (nonverbal solving tasks, visuospatial planning, and organization), attention and concentration, short and long‐term memory (visuospatial, story, and word‐list recalls), motor apraxia (skilled movements, imitation, and pantomime of gestures), lower phonemic verbal fluency and speech apraxia (initiation, articulation, and prosody)...

Endocrinological investigations showed preserved pituitary function and ophthalmological examination was normal, without papillary edema. We performed a minimally invasive neuroendoscopic procedure to fenestrate the cyst with the ventricles and basal cisterns...

The patient recovered fully after a few weeks and went back to school with complete resolution of symptoms. Neuropsychological evaluation was normal at 5‐year follow‐up.



MOG antibody disease differs for children and adults

Cobo-Calvo A, Ruiz A, Rollot F, Arrambide G, Deschamps R, Maillart E, Papeix C, Audoin B, Lépine AF, Maurey H, Zephir H, Biotti D, Ciron J, Durand-Dubief F, Collongues N, Ayrignac X, Labauge P, Meyer P, Thouvenot E, Bourre B, Montcuquet A, Cohen M, Horello P, Tintoré M, De Seze J, Vukusic S, Deiva K, Marignier R; NOMADMUS, KidBioSEP, and OFSEP study groups. Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Ann Neurol. 2021 Jan;89(1):30-41. doi: 10.1002/ana.25909. Epub 2020 Oct 15. PMID: 32959427.


Objective: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD). 

Methods: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives. 

Results: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280). 

Interpretation: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ___________________________________________________________________________

.“We used to think of this disease as having a single phenotype,” commented Michael Levy, MD, PhD, FAAN, director of the Neuromyelitis Optica Clinic and Research Laboratory and research director of the division of neuroimmunology and neuroinfectious disease at Massachusetts General Hospital, who was not involved in the study.

“But as we have been able to do antibody tests on more and more patients, we have come to recognize that it actually has a broader spectrum of features, and one of the biggest points of stratification is age.”

Children and adults “really do have different disease courses and different manifestations,” he said...

“Children were more likely to have a substantial recovery than adults among the whole cohort after a similar follow-up,” the authors noted. “Based on the different disease course, specific management and treatment guidelines should differentiate between children and adults in MOGAD.”...

Just over half of both adults and children experienced at least one relapse, but adults had a higher risk of relapse than children younger than 10 years of age (p=0.011). Women had a higher risk of relapse than men, and use of multiple sclerosis DMDs increased relapse risk as well...

“Neurologists can use this study to understand that there are differences between children and adults and that you don't just treat them as one patient type. If you encounter a patient with MOG antibody disease, you need to consider their age and clinical course before you decide which treatment to start and before you advise the patient on prognosis.”

“We know that children have a good chance of being monophasic, with only a single attack and never experiencing a relapse,” he said. “I think in this cohort it happened more often than we expected, but I would take that with a bit of caution because the follow-up period was not as long as we would like, to really be certain these patients are truly monophasic.”




Thursday, December 10, 2020

Pharmacological intervention in children with autism spectrum disorder with standard supportive therapies significantly improves core signs and symptoms

Alsayouf HA, Talo H, Biddappa ML, Qasaymeh M, Qasem S, De Los Reyes E. Pharmacological Intervention in Children with Autism Spectrum Disorder with Standard Supportive Therapies Significantly Improves Core Signs and Symptoms: A Single-Center, Retrospective Case Series. Neuropsychiatr Dis Treat. 2020 Nov 16;16:2779-2794. doi: 10.2147/NDT.S277294. PMID: 33235453; PMCID: PMC7678471.


Purpose: Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with high heterogeneity and no clear common cause. Several drugs, in particular risperidone and aripiprazole, are used to treat comorbid challenging behaviors in children with ASD. Treatment with risperidone and aripiprazole is currently recommended by the Food and Drug Administration (FDA) in the USA for children aged 5 and 6 years and older, respectively. Here, we investigated the use of these medications in younger patients aged 4 years and older. 

Patients and methods: This retrospective case series included 18 children (mean age, 5.7 years) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai. These patients began treatment with risperidone or aripiprazole at the age of 4 years and older, and all patients presented with comorbid challenging behaviors that warranted pharmacological intervention with either risperidone or aripiprazole. 

Results: All 18 children showed objective improvement in their ASD core signs and symptoms. Significant improvement was observed in 44% of the cases, and complete resolution (minimal-to-no-symptoms) was observed in 56% of the cases as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales. 

Conclusion: Our findings indicate that the chronic administration of antipsychotic medications with or without ADHD medications is well tolerated and efficacious in the treatment of ASD core and comorbid symptoms in younger children when combined with standard supportive therapies. This is the first report to suggest a treatment approach that may completely resolve the core signs and symptoms of ASD. While the reported outcomes indicate significant improvement to complete resolution of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. Furthermore, the findings support the critical need for double-blind, placebo-controlled studies to validate the outcomes.

Courtesy of:

Three-year longitudinal motor function and disability level of acute flaccid myelitis

Pin Fee Chong, Ryutaro Kira, Hiroyuki Torisu, Sawa Yasumoto, Akihisa Okumura, Harushi Mori, Keiko Tanaka-Taya, for the AFM Study Group.  Three-year longitudinal motor function and disability level of acute flaccid myelitis.  Pediatric Neurology. Published:December 03, 2020 DOI:



We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 (EV-D68) outbreak in 2015.


This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (6 months) and chronic (3 years) stages. We use the Barthel index which measures ten variables describing activity of daily living and mobility to assess the disability level.


Clinical data of 33 patients with AFM (13 females, 20 males; median age=4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, 2/7, 4/13, and 2/13 exhibited complete recovery without paralysis, out of those 5/7, 8/13, and 2/13 who showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of EV-D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed [ p<0.001; median difference (95% confidence interval), 53 (40–63)], implying an improved disability level even in patients with persistent motor deficits.


AFM has a high rate of persistent motor deficits showing 1–2 limb paralysis. Disability level of patients with AFM, however, generally improved at the 3-year time point.

Courtesy of:

Wednesday, December 9, 2020

ALDH7A1 mutations

Coughlin, C.R., Swanson, M.A., Spector, E. et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis (2018).


Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin, and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.

TANGO2 mutations

Mingirulli N, Pyle A, Hathazi D, Alston CL, Kohlschmidt N, O'Grady G, Waddell L, Evesson F, Cooper SBT, Turner C, Duff J, Topf A, Yubero D, Jou C, Nascimento A, Ortez C, García-Cazorla A, Gross C, O'Callaghan M, Santra S, Preece MA, Champion M, Korenev S, Chronopoulou E, Anirban M, Pierre G, McArthur D, Thompson K, Navas P, Ribes A, Tort F, Schlüter A, Pujol A, Montero R, Sarquella G, Lochmüller H, Jiménez-Mallebrera C, Taylor RW, Artuch R, Kirschner J, Grünert SC, Roos A, Horvath R. Clinical presentation and proteomic signature of patients with TANGO2 mutations. J Inherit Metab Dis. 2020 Mar;43(2):297-308. doi: 10.1002/jimd.12156. Epub 2019 Aug 13. PMID: 31339582; PMCID: PMC7078914.


Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.

Bérat CM, Montealegre S, Wiedemann A, Nuzum MLC, Blondel A, Debruge H, Cano A, Chabrol B, Hoebeke C, Polak M, Stoupa A, Feillet F, Torre S, Boddaert N, Bruel H, Barth M, Damaj L, Abi-Wardé MT, Afenjar A, Benoist JF, Madrange M, Caccavelli L, Renard P, Hubas A, Nusbaum P, Pontoizeau C, Gobin S, van Endert P, Ottolenghi C, Maltret A, de Lonlay P. Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect. J Inherit Metab Dis. 2020 Sep 14. doi: 10.1002/jimd.12314. Epub ahead of print. PMID: 32929747.


TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.

Friday, December 4, 2020

LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.

Dallabona C, Abbink TE, Carrozzo R, Torraco A, Legati A, van Berkel CG, Niceta M, Langella T, Verrigni D, Rizza T, Diodato D, Piemonte F, Lamantea E, Fang M, Zhang J, Martinelli D, Bevivino E, Dionisi-Vici C, Vanderver A, Philip SG, Kurian MA, Verma IC, Bijarnia-Mahay S, Jacinto S, Furtado F, Accorsi P, Ardissone A, Moroni I, Ferrero I, Tartaglia M, Goffrini P, Ghezzi D, van der Knaap MS, Bertini E. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain. 2016 Mar;139(Pt 3):782-94. doi: 10.1093/brain/awv392. Epub 2016 Jan 29. Erratum in: Brain. 2018 Nov 1;141(11):e82. PMID: 26912632.


This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.

Tuesday, December 1, 2020

First-line medication dosing in pediatric refractory status epilepticus

Vasquez A, Gaínza-Lein M, Abend NS, Amengual-Gual M, Anderson A, Arya R, Brenton JN, Carpenter JL, Chapman K, Clark J, Farias-Moeller R, Gaillard WD, Glauser T, Goldstein JL, Goodkin HP, Guerriero RM, Kapur K, Lai YC, McDonough TL, Mikati MA, Morgan LA, Novotny EJ, Ostendorf AP, Payne ET, Peariso K, Piantino J, Riviello JJ, Sannagowdara K, Tasker RC, Tchapyjnikov D, Topjian A, Wainwright MS, Wilfong A, Williams K, Loddenkemper T; Pediatric Status Epilepticus Research Group (pSERG). First-line medication dosing in pediatric refractory status epilepticus. Neurology. 2020 Nov 10;95(19):e2683-e2696. doi: 10.1212/WNL.0000000000010828. Epub 2020 Sep 10. PMID: 32913024.


Objective: To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation. 

Methods: This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation. 

Results: We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95). 

Conclusion: BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation. 

Classification of evidence: This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.