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.

Wednesday, November 25, 2020


Wearing a white T-shirt with a massive star in sparkling shades of pink, yellow and seafoam green on the front, Morgan Kozole sits in front of a fold-up chalkboard in the living room of her family's Detroit-area home and starts to draw.

Using pink and yellow chalk, she sketches Mickey and Minnie Mouse. The Disney characters are dominant fixtures in the 5-year-old's life and therefore become a soundtrack for the Kozole family: Morgan constantly saying "Mickey," with her long, blond ponytail bouncing to whatever song happens to be playing on the Mickey Mouse Club.

"These are the two Mickeys," Morgan says, pointing to the chalkboard. Her mother, Detroit Lions senior vice president of business development Kelly Kozole, explains that this is her way of communicating that she would like a visitor to draw Mickey too. If it's close, Morgan accepts it. Another Mickey to fawn over.

For Morgan's birthday earlier this year, the family went to Disney World. On this trip, the Kozoles saw what they had longed for: the potential of progress.

"She knew where we were. She knew Mickey Mouse," Kelly said. "Before, she wouldn't go to the characters, and now she's jumping up and down, hugging. She really, along those lines, is also really into birthdays.

"The 'Happy Birthday' song. Before that, she was just kind of looking. Sometimes it was too much for her with everyone singing -- sometimes loud noises are too much. This year, we had to sing 'Happy Birthday' to her three times."

Birthdays, for children, are happy occasions -- reasons for grand celebrations of progress toward adulthood. For the rest of Morgan's family it is more complicated.

Morgan has a rare neurological disease called beta-propeller protein-associated neurodegeneration, known as BPAN. It's a disorder, more prevalent in girls than boys, that causes delayed development and seizures, communication issues and, sometimes, motor dysfunction. It's unclear exactly how many people are living with BPAN worldwide due to its rarity, although Dr. Sami Barmada, a scientist at the University of Michigan studying BPAN, estimates roughly 500 to 600 people.

It's rare enough that Dr. Henry Paulson, the director of the Michigan Alzheimer's Disease Center, said there are experts in neurodegeneration who are unfamiliar with BPAN. While Kelly is trying to advocate for her daughter and others with BPAN through fundraising for research, science moves only so fast.

The Kozoles understand that. So birthdays for the family aren't always happy. They are a reminder of what could come.

"That ticking time clock," Kelly said. "Every birthday isn't exciting for me for her. Because it's one year closer to when this bomb is going to go off." 

BPAN's rarity makes the reality heartbreakingly simple: There are very few effective treatments, little research and no cure. As Morgan learns how to organize her Peppa Pig characters and learns new words on her iPad -- her future looms.

At some unpredictable point in Morgan's teen and adult years -- the average is around age 25, according to Barmada -- development will just stop. Progress will decline and, in some cases, disappear. Those afflicted with BPAN begin suffering from progressive dystonia parkinsonism -- making it difficult to walk, talk or stand.

"Any day," Kelly said, "it could be like, 'Oh, your daughter's gone.'"

When Morgan was born on Jan. 12, 2015, she was, largely, a healthy baby. She was a little jaundiced but nothing worrisome.

When she would go to the doctor's office for shots, Morgan didn't cry. It was a little abnormal, but when you're a parent of a young child, no crying is viewed as a minor miracle. Kelly and her husband, Kevin, took this as a sign of a tough kid. Nurses even said how great it was.

Looking back, it was a warning sign that something was wrong. BPAN causes a high pain tolerance. Before long, more concerns popped up. Morgan wasn't crawling at nine months, wasn't walking at a year. Expected milestones passed without Morgan reaching them. Kevin and Kelly put her in therapy in late 2016 to work up to these childhood progressive traits and began researching potential causes. They wouldn't find an answer for more than two years.

"She was diagnosed with cerebral palsy at first. One doctor diagnosed her with that, and then another, our neurologist, said she doesn't have that," Kelly said. "Then there was speculation but not a full diagnosis she had autism, so we did all the tests for that.

"So through this kind of journey of trying to find out what was wrong, it was exciting that she didn't have something that you were going to this test for, but you still had so many more questions as you were eliminating all these potential diseases that she could have."

Befuddled, they began genetic testing and in November 2018 received a letter about a mutation on Morgan's WDR45 gene. Kelly Googled it, stumbled upon BPAN and freaked out, calling their neurologist. The neurologist told Kelly not to worry -- BPAN was very rare, and Morgan didn't have it.

Doctors diagnosed her with epilepsy because of seizures. Morgan took Keppra, which helped accelerate her vocabulary to about 50 words, typical for a 1-year-old, when she was 3. Then doctors said no, it wasn't epilepsy either. 

Another meeting with another neurologist led to a different diagnosis. Three days after she and Kevin returned to Michigan from Super Bowl LIII in February 2019, they received a call. Doctors figured out what was wrong.

It was BPAN.

"In my mind, it's worse than cancer," Kelly said. "How is this even possible? That this can even be so painful for kids later on in life. You try so hard to gain all these abilities, and then early adolescence or early adulthood, it's just [gone] one day, and I've seen a lot of these stories.

"There's a BPAN Facebook website, and that's where the doctors sent us. There's no cure. There's no therapy. 'Go to this website.' That's what I was told."

For months Kellycried, angry and heartbroken. The Kozoles initially told their families and no one else.

In May 2019, Kelly went to her first Neurodegeneration with Brain Iron Accumulation (NBIA) conference. She met other parents, heard their stories and began the new normal.

She used her skills -- organization, fundraising and business -- to brainstorm ways to help. Hardly anyone had researched BPAN. Without it, there would be no chance for a cure -- not in Morgan's lifetime, which could reach her 40s, and not in the lifetime of those who might come after.

She shared what was happening with her boss, Detroit Lions president Rod Wood, and his wife, Susan, using a website link to explain BPAN. Wood knew something was wrong because of texts and emails saying they had to take Morgan to this specialist or that appointment.

"As that was confirmed and became her reality, she is now able to talk about it, in a way," Wood said. "Because she's full bore on trying to help generate awareness and financial resources to find a cure for it.

"She went from the unknown to the very tragic known to, 'OK, what are we going to do about it?'"

Kelly consulted her aunts, both of whom worked in medicine. Linda Narhi worked in biotechnology for Amgen for more than 30 years; Dr. Diane Narhi was the first female chief of staff at Simi Valley (California) Hospital. From talking with another group of fundraising BPAN parents -- BPAN Warriors -- Kelly found a guide.

"Any day, it could be like, 'Oh, your daughter's gone.'"

If her aunts had not been resources, she might have joined BPAN Warriors. But Kelly admittedly needs to be in control, and this was her daughter. She needed to manage this herself. She created a nonprofit called Don't Forget Morgan.

Kelly's aunts provided guidance, and Wood offered contacts he had in the finance industry and Silicon Valley. Wood and Lions general counsel Jay Colvin sit on the board. Other Lions coworkers -- with Wood's blessing -- built the website, designed the logo and created social media plans and the first pitch video for Don't Forget Morgan's rollout in 2020.

Progress started with a $15,000 grant to help with a mouse model study at Sanford Research in South Dakota, with another, larger, potential grant to come. In recent months, Kelly has focused largely on fundraising, and another parent of a child with BPAN, Christina Mascarenhas Ftikas, has focused on the medical side of the nonprofit.

"This is why I'm here," Kelly said. "I'm supposed to be a vehicle to get all of this awareness and hopefully a cure for BPAN so the child one, two, three, five years from now, there is hope.

"There is no, 'Go to Facebook.' There is something where you can actually give a parent, 'Here's the symptoms to look for.'"

About an hour away in Ann Arbor, Michigan, Kaci Kegler and her husband, Brian, had been in the same Facebook community. Kelly, new to the group and looking for a nearby connection, wrote Kaci a message.

"Hey, my daughter was just diagnosed, could we connect?"

Kaci understood. She did the same thing, reaching out without success in 2016 after her daughter, Elle, was diagnosed. Kaci wanted to be a resource.

They talked for an hour. There wasn't much Kaci could say to soothe her. Kelly pinged a year later with another message: I'm starting a nonprofit. Kaci offered to help.

Despite suffering from BPAN, Morgan is like any other 5-year-old who enjoys playing with her brother, Connor. Michael Rothstein

Days later, on Feb. 28, Kaci and her husband, Brian, an assistant athletic director for development at the University of Michigan, had their yearly fundraiser for BPAN research on Rare Disease Day at Pizza House in Ann Arbor. They met a doctor who had a connection to researchers at Michigan.

"I literally came home and texted [Kelly] and was like, 'Oh my gosh, we may have inroads,'" Kaci said. "We just started texting. I have never met Kelly face-to-face. We still haven't. But we've texted a lot and we've emailed quite a bit.

"It just kind of started."

By summer, they went from nothing to putting pieces in place for a full-fledged research project with a two-year, $140,000 grant for Barmada and Dr. Jason Chua to help start to solve BPAN.

Chua was working on the regulation of autophagy, which is the cleaning out of damaged cells, and studying BPAN became a natural extension of the work he had already been putting in. BPAN alters that in neurons. Barmada said Chua's research provided a "rare win-win situation" to potentially help with BPAN and other diseases too.

"There are a set of questions in BPAN that nobody has the answer to," Barmada said. "And Jason and myself, we just seem to be in the right position, the right place to be able to help out."

The goal is to understand what is happening within BPAN itself and how people end up with it, while also trying to find therapies for existing patients. Within a year, they are hoping to grow stem cells from people with BPAN in their lab, allowing for the creation of their own stem cells missing the WDR45 gene. Then they will try to either replace the gene or "stimulate autophagy through genetic or pharmacologic means," Barmada said. The hope is this can prevent neurodegeneration.

So far, they've hired a research assistant to work with Chua, developed tools to manipulate the gene using the genome-editing tool CRISPR and applied for approval from Michigan and the institutional review board to get skin biopsies to obtain stem cells from BPAN patients.

It's a process, but it's also a start.

After partnering with Michigan and Sanford, Don't Forget Morgan also began working with Dr. Kathrin Meyer, a researcher at the Center for Gene Therapy at Nationwide Children's Hospital at Ohio State.

"Solving this disease is going to require more than Jason and Sami," Paulson said. "It's going to be a first shot across the bow, but it's going to require more than that. I'll say this, being in the field for a long time. Scientists who are coming up the pike say they want to look at Alzheimer's, want to look at epilepsy. They don't say, 'I want to look at a rare disease.'

"The only way to solve a rare disease is to get someone hooked. Sometimes when you hook a really good one, as I think we have with Jason here, you hook them for life and they make a difference."

Morgan is bouncing around the Kozoles' suburban Detroit home on this late August day. They just returned from northern Michigan, and having two kids, especially one with special needs, makes tidiness unrealistic.

COVID-19 changed things. Morgan hadn't been to many of her therapies for months. Online school barely kept her attention. There was concern she would have regression in her learning. Instead, her speech advanced by being around Kelly, Kevin and her older brother, Connor, all day. She has sung more songs recently to help increase her vocabulary. Sometimes, she'll listen 20 times in a row.

"Even more than that," Connor said. They aren't sure how much she's truly learning versus memorization. But it is something.

Morgan Kozole has inspired her mother, Detroit Lions VP Kelly Kozole, to marshal researchers and other advocates to develop a cure for BPAN, and perhaps help future generations of children who live with the disorder. Michael Rothstein

The family gathers inside Morgan's bedroom -- complete with a special Haven Bed with a zipper to keep her safe from wandering around at night, when she could accidentally turn on the stove and hurt herself or others -- sleep disorders are another BPAN issue. She sits on the floor and starts playing with her small, yellow dollhouse and a fake ice-cream maker. Kelly asks for an ice cream. Morgan makes one for herself instead and pretends to eat it.

Later, outside, Morgan kicks a soccer ball and plays a modified game of catch with a squishy football. Football, no surprise, is big. She says "hike" a lot. "She knows that term," Kevin says, laughing.

In these moments, Morgan seems like any other young child. She attends St. Hugo of the Hills Parish School in Bloomfield Hills, Michigan, but has a one-on-one para nanny to help. She interacts with people, often overly affectionate.

Sitting at the kitchen table after playtime outside, she plays with Starfall, a children's learning app, on her iPad. They hope it accelerates her word recognition. Morgan is entranced watching "Farmer in the Dell" and using her hands to eat orange slices and Cheerios. She needs a mirror in front of her to provide her a target for her mouth. She listens to books, another way to try absorbing information.

Morgan can now count to 20 and say three sentences in a row. Kelly and Kevin have tried to give Morgan a normal life in an abnormal situation, but they worry about the future -- what she won't have and won't be able to experience.

But Morgan has changed some of that outlook too.

"Focus on how she is so loving and has so much pure joy. A lot of parents of special needs [kids] say you can learn so much from these kids, and you really can," Kelly said. "She is, every morning, just so happy, and 'Mama!' Hugs and kisses to strangers. She has none of those behaviors you learn as an adult where you're not kind to people or you don't want to talk to someone.

"She is just open arms, will give you a hug and is so loving, and it's like, 'Wow, this is really what life is about.'"

Courtesy of a colleague



Dr. Death revisited 2

Kellie Martin and her husband Don were taking Christmas decorations down from the attic of their suburban Garland, Texas, home in late 2011 when their lives changed forever.

Kellie, 54, missed a step on a ladder and fell, resulting in a herniated disk in her back. After physical therapy and muscle relaxers, their family doctor recommended neurosurgeon Christopher Duntsch. The couple agreed to visit the doctor — a decision that will forever haunt Don and their two daughters.

The case of Duntsch is explored in the new Oxygen docu-series, “License to Kill,” premiering on June 23. The show, hosted by renowned plastic surgeon Dr. Terry Dubrow of “Botched," chronicles the harrowing accounts of patients put into jeopardy by medical professionals’ insidious use of their expertise. It highlights interviews with families, medical professionals and law enforcement.

Duntsch was recently the subject of a true crime podcast earlier this year titled “Dr. Death” by Wondery — the same podcast network behind their hit series “Dirty John.”

“From the initial fall, it wasn’t that super great,” Don told Fox News about his wife’s injury. “It was a lingering pain. It never went away. We did all kinds of treatments to help alleviate the pain, but it just remained persistent. We were planning on going to an out of country trip, so we thought we might get this fixed before we did. And she was in more pain than she led on. I could see it. I didn’t want her to go through that if we could avoid it. That’s when we started exploring surgery options.”

The couple soon found themselves in Dr. Duntsch’s office scheduling surgery for during the elementary school teacher’s March 2012 spring break. Duntsch insisted the 45-minute procedure was routine and simple to do.

 “He sounded very articulate,” reflected Don. “It sounded like he knew what he was doing. We figure it wouldn’t be an issue… He said it was a minor surgery, but that she would be OK after the procedure. A very simple, common procedure — that’s what we were hoping for. A quick recovery."

But on the day of surgery, Don found himself waiting, not knowing what happened to Martin.

“About an hour later, I’m still sitting in the waiting room and I hadn’t heard from anybody,” he explained. “I asked one of the nurses to check and see what was going on. Then 15-20 minutes later, [Duntsch] came out. He tells me the surgery went well and she’s moving around, but was in obvious pain so they gave her more medicine. She may have to go up to the ICU or maybe stay overnight, but she was going to be OK… That’s when I called my daughters to come up to the hospital. That’s when I realized this is not good.”

The wait continued and Don agonized over Martin, wondering what was happening behind closed doors.

 “I’m starting to freak out,” he said. “Something just wasn’t right because no one was telling me, ‘Hey, she’s recovering, you can come to see her.’ Instead, they’re continuing to work on her. This is going on now for two hours. My girls were holding on to hope, but I just knew something was seriously wrong."

Don said the ICU physician, as well as Duntsch and the anesthesiologist, came to see him and the couple’s two daughters to deliver the devastating news — the beloved matriarch was dead.

“They told us they tried everything they could, but they couldn’t save her,” said Don. “That’s when the girls lost it. I lost it. That’s when the nightmare started… We didn’t get a chance to say goodbye to her. We went in there with good faith, believing in the doctors and the medical world so they could help us. Instead, they ended up turning our world upside down. It was pure misery. I was totally lost. My world just ended right then and there.”

People magazine reported the medical examiner confirmed Don’s fears. It turned out Martin had bled to death after Duntsch sliced an artery. According to the outlet, Don also learned that Duntsch had earlier operated on one of the coroner’s office employees and left the man paralyzed. The Dallas County district attorney’s office would later learn that that out of 38 surgeries undertaken by Duntsch in less than two years, 33 had gone wrong. Two patients had died, one was rendered a quadriplegic and many were left with permanent injuries.

“I was angry,” said Don when he learned of Duntsch’s other victims. “I was angry at the medical world. If this doctor had previous bad outcomes, why did he still had the ability to do surgery? It was such a cover-up. As things progressed, I got angrier and angrier with the system. But by the grace of God, other doctors started voicing their opinions about [Duntsch]. But how was I going to survive? How am I going to live day by day now?”

Between 2011 and 2013, Rolling Stone previously reported, Duntsch was employed by four Dallas-area hospitals and nearly all of his patients, those who survived, came out in far worse shape than ever before.

During the trial, Dallas surgeon Randall Kirby, who assisted on one of Duntsch’s surgeries in 2012, told jurors he sent information to the Texas Medical Board, warning them of Duntsch’s botched procedures. D Magazine shared that despite receiving complaints dating back to 2012, the Texas Medical Board reportedly didn’t revoke Duntsch’s privileges until 2013. Texas Observer clarified that the Texas Medical Board is "limited" in its ability to investigate malpractice, which could have possibly resulted in the delay.

According to records, Duntsch was booked into the Dallas County Jail in 2015. He was charged with five counts of aggravated assault causing serious bodily injury and one count of injury to a child, elderly or disabled person.

D Magazine reported that in July 2016, the Dallas County District Attorney’s Office followed through and a grand jury returned five indictments of aggravated assault and one of harming an elderly person. Duntsch pleaded not guilty and alleged in emails that he was at the center of “a vast conspiracy to bilk money from the hospitals where he practiced.”

The indictment accused Duntsch of wide-ranging malpractice, including improper placement of screws and plates along patients’ spines, a sponge left in one patient, and a major vein cut in another. Records also showed that Duntsch operated on the wrong part of a patient’s spine, damaged nerves and left one woman with chronic pain and dependent on a wheelchair.

At the time, Duntsch was struggling financially and had racked up a series of arrests, including stealing Walmart merchandise.

During the trial, prosecutors said Duntsch’s hands and surgical tools amounted to “deadly weapons,” and contended that he “intentionally, knowingly and recklessly” harmed up to 15 of his patients. Prosecutors also claimed that in a 2011 email to a girlfriend, Duntsch said he would “become a cold-blooded killer.”

Dallas surgeon Randall Kirby says his former colleague, Dr. Christopher Duntsch, managed to commit crimes so heinous that patients everywhere are still struck by fear when they hear about the case for the first time.

However, Duntsch’s attorneys argued that he was not a criminal but just a lousy surgeon committing malpractice in chaotic operating rooms in hospitals in Dallas and its northern suburbs. They also said the tone of the email in question was unclear and could have been meant as sarcasm.

The New Yorker reported Duntsch was ultimately stopped after the combined involvement of the Dallas Country district attorney, an attorney, a journalist, and the state medical board with the efforts initiated by Kirby and Dr. Robert Henderson, a veteran surgeon at the Dallas Medical Center.

In 2017, a jury sentenced Duntsch to life in prison for maiming patients who had turned to him for surgery to resolve debilitating injuries. The decision came almost a week after the Dallas County jury convicted Duntsch of first-degree felony injury to an elderly person.

But life for Don and his family still isn’t easy.

“I’m not gonna lie, I think this puts a strain on our relationship a little bit,” said Don about his daughters. “We were such a close-knit family. It was difficult for them. It was difficult for all of us. They were trying to be careful around me, trying not to say anything or do anything that will upset me. My whole lifestyle has changed. Everything is different now. I look at life differently totally differently. Life is just too precious, too short. We can’t take the little things for granted. We’re just trying to make the best of each day.”

Don hopes viewers will be compelled to conduct no-nonsense on any physician or surgeon they’re considering — and to never take any kind of procedure for granted. 

“Get a second opinion no matter what,” he said. “Evaluate everything to make sure you really want to do this surgery. Explore all options. And realize that no surgery is a routine, simple surgery. Everything can be a life or death situation.”

Medical mayhem 16

When Patricia Hester was given the news from Dr. Farid Fata that she had cancer in Feb. 2010, she instantly went into survival mode. 

In a concerted effort to get the jump on her diagnosis, Hester – a relatively healthy emergency room technician at the time and now-fitness instructor – against her better judgment of pumping herself with chemotherapy, heeded the advice of Fata and began cancer treatments after looking into Fata’s credentials and performance records. However, there was one big problem, Hester didn’t actually have cancer. 

“It's very surreal. It's an out-of-body experience,” Hester told Fox News of being told she had cancer. “If you're not feeling sick, you don't expect that type of news and so you feel like you're watching this whole interaction go on and you're an observer – you're not actually the person [receiving the news]." 

Hester's story will be featured in the second season of "Dr. Death" from podcast network Wondery, which delves into the mistreatment and misdiagnosing of hundreds of patients who were under the care of Dr. Farid Fata in Michigan. In 2015, a judge sentenced the Detroit-area cancer doctor to 45 years in prison – out of a possible 175 years he was eligible to receive – for collecting millions from insurance companies while poisoning more than 500 patients through needless treatments that wrecked their health.

At the time of his sentencing, Fata offered no excuses before he was handed his punishment. He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering. 

“The sheer volume of the cases was definitely eye-opening,” Wondery podcast producer and director Marshall Lewy said. 

“For one thing, [Fata] was incredibly well respected. He was the most decorated doctor in the area when it came to cancer and oncology and hematology,” Lewy explained when asked how Fata was able to take advantage of so many patients and remain undetected for so long.

On the podcast, George Karadsheh, who was hired in Sept. 2011 as his office manager, described Fata’s office as “grand," complete with expensive art and a piano in its lobby. 

Dr. Farid Fata was sentenced to 45 years in prison in 2015<strong>. </strong>He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering.

Dr. Farid Fata was sentenced to 45 years in prison in 2015<strong>. </strong>He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering. (My Fox Detroit) 

He further explained that the bustle of the infusion room “was like a parking lot for chemo chairs,” adding, “it would be like in a barbershop. There was never a moment where that chair wasn't being used.”

Fata shaped a revolving door of some 50 to more than 70 patients who would visit for cancer treatments per day, according to the podcast. In addition, the program reported that Fata only saw them for minutes at a time before he recommended and billed treatments later deemed unnecessary to many of them who had waited hours in the office before seeing Fata. 

“That was only one part of it. And I think the other part was he really built a system where he would have total control,” said Lewy. “So as the years went on, outside referrals he dealt with in-house, he set up his own pharmacy, he set up his own palliative care, the hospice that he would recommend was run by a relative. So it just was this sort of closed-loop where if anybody went to try to get a second opinion, they often ended up with someone who he referred them to.”

So when Fata broke the news to Hester that she had cancer that would likely turn terminal, Hester said she was in a deep state of denial.

“I had recovered from being ill with pneumonia and had chronic asthma. So it was unbelievable,” she lamented. “The first thought was 'No way.' I was in denial, of course. You have so many thoughts flying through your head at the same time and it's like, 'OK, if I'm sick,' before you move on to the next step, first of all, you just have to mull that over.”

Continued Hester: “It's like, 'OK, I'll do everything I can to live my best life, my best quality of life. I'll be as proactive as possible and I'll get on a waiting list for a stem cell.' You know, assuming that this is actually me and this is actually going on, if I'm going to walk out these steps, this is what I'm going to do. I need to beat this. I need to be the healthiest of healthy.”

Hester maintained that despite being in a state of denial and disbelief, “I just knew that I had to do all that I could to avoid a horrific death.”

“People say, 'Oh, I'm going to beat this,' but my thought wasn't to load me up with chemo and if there's a tumor, let's get radiation,' said Hester. “My thoughts were different than where a lot of people would go. Mine were more fight-or-flight. I kind of wanted to bolt, like this wasn't even possible.”

The fallout from Fata’s unnecessary treatments left Hester with severe damage to her teeth and her immune system.

Hester said in the years since she ended Fata's ill-prescribed cancer treatments, she later found out through meetings with another oncologist, who had read her chart, that the damage to her teeth was imminent and likely only happened as a direct result of the previous treatments she had undergone.

“I had two back teeth that I started having problems with, and I was at the dentist, and the dentist was like this tooth looks really weird and there was no problem with it before – and this other tooth is just really strange,” recalled Hester. “And I never have had a bunch of root canals or anything like that so I ended up going to an endodontist and he sent me to an oral surgeon, and then he did surgery and took them out, and he wrote a big paper on it on the fact that this is from overtreatment that was deemed unnecessary.

“I know that sounds small, but that was pretty traumatic,” she added.

To this day, Hester still has regular doctor visits to treat her immune system and every four weeks receives treatment at the University of Michigan to combat the effects

In addition to the iron, intravesical therapy (IVT) and myriad of medications Hester was administered by Dr. Fata, she recalled also receiving "huge quantities of things that I didn't need because they didn't co-exist with the labs and didn't add up and I shouldn't have been treated with these drugs."

"So, for three years I was treated unnecessarily to do harm, not to do no harm," Hester lamented of her ordeal with Fata.

Hester said in the office Fata “always got his way” and recalled him often petitioning her husband to convince her to accept his cancer treatments.

“As time went on, it was almost a ‘do-or-die’ attitude,” said Hester. “It was like, you’re going to die if you don’t do these treatments.”

She maintained that whenever she expressed her desire to end treatments, Fata would go as far as to bring up other patients who he claimed had just died from their own cancer.

“He always had a backdoor attitude,” said Hester. “I got caught up in this whole evil web.”

First-trimester maternal serum biomarkers and the risk of cerebral palsy

Peris M, Reid SM, Dobie S, Bonacquisto L, Shepherd DA, Amor DJ. First-trimester maternal serum biomarkers and the risk of cerebral palsy. Dev Med Child Neurol. 2020 Nov 18. doi: 10.1111/dmcn.14732. Epub ahead of print. PMID: 33206412.


Aim: To investigate whether combined first-trimester screening (cFTS) biomarkers are associated with cerebral palsy (CP) and to identify CP characteristics associated with abnormal biomarker levels. 

Method: In this retrospective case-control data linkage study, we matched mothers of 435 singletons with CP from a population register to their cFTS records and selected 10 singleton pregnancy controls per case. We compared mean and abnormal levels (expressed as multiples of the median [MoMs]) of pregnancy-associated plasma protein-A (PAPP-A), beta subunit of human chorionic gonadotrophin (β-hCG), and nuchal translucency between cases and controls and between CP subgroups. 

Results: Compared with control pregnancies, CP pregnancies had lower mean levels of PAPP-A (0.95 vs 1.01 MoM, p=0.02) and β-hCG (0.93 vs 0.99 MoM, p=0.02). Biomarker levels in CP pregnancies were 1.8 times more likely to be associated with abnormally low levels of PAPP-A (p<0.01), 1.4 times for β-hCG (p=0.12), and 2.6 times for low PAPP-A and β-hCG together (p=0.04). In cases with CP, an abnormally low PAPP-A level was associated with moderate preterm birth, low Apgar scores, and Gross Motor Function Classification System level V. Low β-hCG was associated with very low birthweight. 

Interpretation: Low first-trimester biomarker levels suggest a role for early pregnancy factors in some causal pathways to CP.

Courtesy of:

Tuesday, November 24, 2020

Mother's email--child with CLN2

Today would have been his 82nd brineura treatment. We did not go today and won't be going to anymore. 5 years ago he was diagnosed and had 3 years of treatment. The crying/screaming has gotten really bad and it is everyday despite med changes and working with palliative care. It was a very emotional hard decision for me but I have to think about him and I'm not giving up, I'm just fighting harder for peace and comfort. I will forever be grateful for treatment and more time with him. Because of treatment he had so many great days, we love you all for everything you have done. Thank you so much. All our love,

Mom and son

Dangers of a medical board investigation

Cynthia H. Moran, MD, has a medical degree, a passion for treating the elderly, and a desire to work. What she doesn't have is a job or hopes of getting one anytime soon. 

The Houston physician has never been charged with a crime, but she did run afoul of the Texas Medical Board, an experience she said has left her destitute and virtually unemployable in the medical field. 

"By the time the board gets through with you, you will be bankrupt and have nothing," she said. 

Moran has a long, tangled history with the board involving self-prescribing, opioid abuse, depression, and unprofessional conduct. After years of license suspension, drug testing, additional CME, substance abuse treatment, and work restrictions, her supervision by the board ended in 2019, but she has been largely unable to find work as a physician. 

"I feel like a felon. I really understand what it's like to be someone who does their time but then can't get a job, can't get an apartment. It's in your record and there's nothing you can do about it," she said. 

Although Moran largely created her own troubles, her experience shows the power state medical licensing boards have when it comes to disciplining physicians. 

Reprimands to Revocations

Many physicians think of their state medical boards as simply the bodies that issue their medical licenses, but the boards have other functions, including investigating complaints against licensed medical professionals and, sometimes, disciplining them. 

According to 2017 statistics from the Federation of State Medical Boards (FSMB) (the most recent available), state boards took 8813 actions that year. These included 796 suspensions, 764 probations, 570 surrendered licenses, and 264 revoked licenses. 

Boards also can order doctors to enter state-run physician health plans to receive treatment for substance abuse, or they can allow physicians to practice only under the supervision of colleagues. 

Although they vary by state, the boards are fundamentally similar. Members are appointed by the governor. A majority of them are physicians, and the remainder are nonmedical professionals. Their investigators, often retired law enforcement officials, have broad powers to collect evidence, including medical records. Their authority is backed by the state attorney general. 

Although physicians tend to worry more about being sued for malpractice, a medical board investigation can be more worrisome, said William Sullivan, DO, JD, an emergency department physician and attorney in Illinois who has represented doctors before that state's board. Board disciplinary actions outnumber malpractice awards by four to one in that state, he estimated. 

"The gravity of this is something that many physicians don't understand," he said.

You Can Be the Subject of Anonymous Complaints and Investigations

Anyone can file a complaint against a physician with a state board. The grievances can be about anything from a crowded waiting room to physician impairment. 

Of course, the most trivial complaints (out-of-date magazines in the waiting room) are dismissed out of hand, but boards have the authority to investigate whatever it chooses. The most common investigations center around complaints of impairment, substance abuse, improper prescribing, faulty medical records, mental and physical health problems, and standard of care. Boards also will act if a physician is found guilty of a crime or misconduct unrelated to his or her medical practice. 

"There are a lot of ways doctors get into trouble," said Edward Dauer, MD, a radiologist who served on the Florida board for 11 years. 

Investigations often expand beyond their original scope into all aspects of a practice. "Once you're on their radar, they can find something," Sullivan said. 

All punitive actions taken by state boards are reported to the Department of Health and Human Services' National Practitioner Data Bank, which is accessible to all state boards. Sanctioned physicians who set up practice in another state often find that their new home has adopted the sanctions leveled by the original state, something boards can do without conducting their own investigations. 

"For doctors, discipline is forever. It never goes off your record," Dauer said. 

In addition, Medicare, Medicaid, and private insurers can exclude disciplined physicians, which can cripple a practice's finances. So what can doctors do to avoid problems with the boards? 

Don't Do Anything Wrong

That sounds glib and obvious, but many physicians get into trouble by unwittingly violating state medical regulations regarding such things as CME, insurance requirements, failure to notify the board of address changes, and personal relationships with current or former patients. 

"The best advice to avoid these issues is to do a Google search for the Medical Practice Act in the state in which they practice," said Sullivan. He noted that doctors should regularly check for changes in regulations. 

Keeping on good terms with colleagues and patients also helps, he said. He noted that many complaints stem from personal disputes and grievances. 

But what if a physician becomes the subject of an investigation? What should they do? 

Take Any Complaint Seriously

Too many physicians dismiss investigations initially. "Some people have the wrong idea that if they ignore it, it will go away. It won't go away," Sullivan said. 

Whether the initial contact comes through a letter or a visit from a board investigator, it should be treated with urgency. Ohio attorney Beth Collis said one client angrily scrawled one-word answers with a Sharpie on the questionnaire he was mailed — answers he was stuck defending throughout the rest of the investigation. Other doctors have ordered investigators out of their offices — another mistake. Failure to cooperate can result in an immediate license suspension. 

"They should be speaking to these investigators like they were talking to a highway patrolman on the side of the road. They hold all the cards," said Collis, who specializes in representing professionals before licensing boards. 

Some physicians mistakenly assume that because their state board is made up mostly of fellow doctors, they will be able to make a complaint go away with some collegial chat. 

Not so. "Medical board members see themselves as protecting the public. They're very punitive," Collis said. 

At one time, state boards might have been lax in their supervision of physicians, but that changed in the 1980s when the watchdog group Public Citizen began ranking state medical boards by how effective they were in policing doctors.

Public Citizen used FSMB data on serious disciplinary actions per 1000 doctors in each state to calculate its rankings, a practice that FSMB called incomplete and a misuse of its statistics. Nonetheless, the annual rankings generated a lot of publicity critical of state boards and might have spurred a tougher approach by regulators. 

Public Citizen stopped publishing its annual rankings in 2013 after FSMB ceased supplying the data, but the get-tough approach remains, lawyers said. 

About 95% of complaints are dismissed with nothing more serious than a letter to the doctor, but boards don't hesitate to act when the misconduct is serious, said Dauer, the former Florida board member. "I felt it was my obligation to protect the public," he said. 

Don't Try to Fix It Yourself

Although many complaints are anonymous, doctors can often figure out what or who it involves. Their impulse might be to contact a patient who complained, correct a medical record, or otherwise try to resolve the matter personally. 

It's better to leave things alone, the experts said. Don't contact a patient. Give the board access to whatever information it asks for, but don't alter anything, particularly medical records. "That's how you're going to get your license revoked," Dauer said. He noted that when doctors add notations to records, they must date them. 

Hire a Lawyer

Many physicians assume they can resolve the complaint easily by explaining themselves to the board or investigators, or they don't realize their license or practice could be at stake. 

They're better off letting a lawyer speak for them. Attorneys knowledgeable in this realm specialize in representing licensed professionals before regulatory boards and have the greatest knowledge of administrative law and how to negotiate the hearings and procedures. 

Typically, a hearing is held before a subcommittee of the board, which can recommend a settlement to the full panel. Cases in which a settlement is not reached can go before the entire board. 

Although full hearings can be similar to a trial, there are crucial differences regarding evidentiary rules and other matters, Collis said. For example, in Ohio, defendant physicians do not get to see the board's full case against them before the hearing, which can make preparing a defense difficult. And the standard for burden of proof is a preponderance of evidence, as in civil suits, not evidence beyond a reasonable doubt, as in a criminal trial. 

Cases that go to full hearings and beyond to appeals in state courts can take years to resolve, and a physician's license can be suspended for the duration. 

Get Help Before It's Too Late

Physicians looking for support and advice can turn to organizations such as the Coalition for Physician Rights (CPR), an organization formed in 2018 by Kernan Manion, MD, a former psychiatrist who was forced to deactivate his license after an investigation by the North Carolina medical board. 

CPR has advised hundreds of physicians, most of whom he said come to him once they realize they're in over their heads. "Almost everyone comes in too late," Manion said. "They're sitting ducks. They don't know how to respond." 

In addition to offering advice and support, CPR lobbies for reform in how boards operate. A number of states, including Oklahoma, have made reforms in recent years. 

The appointed boards are too reliant on their administration and staff and usually rubber-stamp disciplinary recommendations, Manion said. He also criticized the boards' lack of accountability: "A board operates without external or internal oversight. It is an autonomous entity operating on its own." 

As for Moran, the Houston doctor sanctioned by the board, at age 61, she's interviewing for physician jobs around the country, refusing to give up medicine. 

"What else can I do?" she said. "It's what I've done my entire life. It's what I went to school for. I don't know how to do anything else." 

James F. Sweeney is a freelance healthcare writer based in Cleveland, Ohio.