Sunday, June 27, 2021

Road rage

It was a 95-degree day in July 2015, and emergency physician Martin Maag, MD, was driving down Bee Ridge Road, a busy 7-lane thoroughfare in Sarasota, Florida, on his way home from a family dinner. To distance himself from a truck blowing black smoke, Maag says he had just passed some vehicles, when a motorcycle flew past him in the turning lane and the passenger flipped him off. 

"I started laughing because I knew we were coming up to a red light," said Maag. "When we pulled up to the light, I put my window down and said, 'Hey, you ought to be a little more careful about who you're flipping off! You never know who it might be and what they might do.' " 

The female passenger cursed at Maag, and the two traded profanities. The male driver then told Maag, "Get out of the car, old man," according to Maag. Fuming, Maag got out of his black Tesla, and the two men met in the middle of the street.

"As soon as I got close enough to see him, I could tell he really looked young," Maag recalls. "I said, 'You're like 12 years old. I'm going to end up beating your ass and then I'm going to go to jail. Go get on your bike, and ride home to your mom.' I don't remember what he said to me, but I spun around and said, 'If you want to act like a man, meet me up the street in a parking lot and let's have at it like men.' " 

The motorcyclist got back on his white Suzuki and sped off, and Maag followed. Both vehicles went racing down the road, swerving between cars, and reaching speeds of 100 miles per hour, Maag says. At one point, Maag says he drove in front of the motorcyclist to slow him down, and the motorcycle clipped the back of his car. No one was seriously hurt, but soon Maag was in the back of a police cruiser headed to jail. 

Maag wishes he could take back his actions that summer day 6 years ago. Those few minutes of fury have had lasting effects on the doctor's life. The incident resulted in criminal charges, a jail sentence, thousands of dollars in legal fees, and a 3-year departure from emergency medicine. Although Maag did not lose his medical license as a result of the incident, the physician's Medicare billing privileges were suspended because of a federal provision that ties some felonies to enrollment revocations. 

Maag, 61, shared his story with Medscape to warn other physicians about the wide-ranging career ramifications that can happen as a result of offenses unrelated to medicine… 

Maag ultimately accepted a plea deal from the prosecutor's office and pled no contest to one count of felony criminal mischief and one count of misdemeanor reckless driving. In return, the state dropped the two more serious felonies. A no contest plea is not considered an admission of guilt...

The plea deal was a favorable result for Maag considering his original charges, Fayard said. He added that the criminal case could have ended much differently...

With the plea agreement reached, Maag faced his next consequence — jail time. He was sentenced to 60 days in jail, a $1000 fine, 12 months of probation, and 8 months of house arrest. Unlike his first jail stay, Maag said the second, longer stint behind bars was more relaxing. 

"It was the first time since I had become an emergency physician that I remember my dreams," he recalled. "I had nothing to worry about, nothing to do. All I had to do was get up and eat. Every now and then, I would mop the floors because I'm kind of a clean freak, and I would talk to guys and that was it. It wasn't bad at all."

Maag told no one that he was a doctor because he didn't want to be treated differently. The anonymity led to interesting tidbits from other inmates about the best pill mills in the area for example, how to make crack cocaine, and selling items for drugs. On his last day in jail, the other inmates learned from his discharge paperwork that Maag was a physician...

About the time that Maag was released from jail, the Florida Board of Medicine learned of his charges and began reviewing his case. Fayard presented the same facts to the board and argued for Maag to keep his license, emphasizing the offenses in which he was convicted were significantly less severe than the original felonies charged. The board agreed to dismiss the case… \

Once home, Maag was on house arrest, but he was granted permission to travel for work. He continued to practice emergency medicine. After several months, authorities dropped the house arrest, and a judge canceled his probation early. It appeared the road rage incident was finally behind him…

But a year later, in 2018, the doctor received a letter from the Centers for Medicare & Medicaid Services (CMS) informing him that because of his charges, his Medicare number had been revoked in November 2015.

"It took them three years to find me and tell me, even though I never moved," he said. "Medicare said because I never reported this, they were hitting me up with falsification of documentation because I had signed other Medicare paperwork saying I had never been barred from Medicare, because I didn't know that I was."


Maag hired a different attorney to help him fight the 3-year enrollment ban. He requested reconsideration from CMS, but a hearing officer in October 2017 upheld the revocation. Because his privileges had been revoked in 2015, Maag's practice group had to return all money billed by Maag to Medicare over the 3-year period, which totaled about $190,000…


Maag went through several phases of fighting the revocation, including an appeal to the US Department of Health and Human Services Departmental Appeals Board. He argued that his plea was a no-contest plea, which is not considered an admission of guilt. Maag and his attorney provided CMS a 15-page paper about his background, education, career accomplishments, and patient care history. They emphasized that Maag had never harmed or threatened a patient, and that his offense had nothing to do with his practice…

Unable to practice emergency medicine and beset with debt, Maag spiraled into a dark depression. His family had to start using retirement money that he was saving for the future care of his son, who has autism.


Slowly, Maag climbed out of the despondency and began considering new career options. After working and training briefly in hair restoration, Maag became a hair transplant specialist and opened his own hair restoration practice. It was a way to practice and help patients without having to accept Medicare. Today, he is the founder of Honest Hair Restoration in Bradenton. Hair restoration is not the type of medicine that he "was designed to do," Maag said, but he has embraced its advantages, such as learning about the business aspects of medicine and having a slower-paced work life. The business, which opened in 2019, is doing well and growing steadily.

Earlier this month, Maag learned CMS had reinstated his Medicare billing privileges. If an opportunity arises to go back into emergency medicine or urgent care, he is open to the possibilities, he said, but he plans to continue hair restoration for now. He hopes the lessons learned from his road rage incident may help others in similar circumstances.  


"If I could go back to that very moment, I would've just kept my window up and I wouldn't have said anything," Maag said. "I would've kept my mouth shut and gone on about my day. Would I have loved it to have never happened? Yeah, and I'd probably be starting my retirement now. Am I stronger now? Well, I'm probably a hell of a lot wiser. But when all is said and done, I don't want anybody feeling sorry for me. It was all my doing and I have to live with the consequences."


Wednesday, June 23, 2021

Gottesfeld update 3

Many of you know that I’ve written about whistleblower Marty Gottesfeld in the past. Marty was sentenced to a draconian 10 years in prison for initiating a denial-of-service attack against a hospital in defense of a young girl whom the hospital’s doctors were later found to have abused.  Even worse than the duration of his sentence, Marty was placed in the Communications Management Unit (CMU) of the notorious federal penitentiary at Terre Haute, Indiana, the site of federal death row. 

The CMU was created after the Sept. 11 attacks to house terrorists and to ensure that they could not communicate with the outside world.  This is where the Justice Department put Marty for taking down a website over the course of a weekend. 

One of the reasons that I admire Marty is that, no matter how tough things get for him, he continues to push forward.  Being gutsy is one thing.  Being gutsy in the face of abuse and violence is something altogether different. 

Marty and I are in irregular touch, not because he’s not a faithful correspondent, but because his communications are routinely interrupted by prison officials.  For example, Marty is currently appealing his sentence, and he has a fighting chance at having it overturned.  As a result, the prison administrators have reacted by cutting off his email access to the outside world, including to his attorneys, cutting off his phone privileges for more than six months at a time, and illegally reading his incoming and outgoing legal mail.  But still Marty pushes ahead. 

Imagine how difficult — and frustrating — it would be to be mounting a legitimate appeal to a conviction and to be constantly harassed by people with complete control and authority over you, people who don’t care at all that you have legal rights.  After all, what are you going to do about it?  Sue them?  Good luck. 

The New Unit Manager 

I received a rare email from Marty earlier this week.  He wrote to tell me about his new “unit manager.”  The unit manager is the person responsible for the day-to-day running of the housing unit, in this case the Communications Management Unit.  To give you an idea of the kind of environment Marty lives in, his unit manager is also responsible for nearby death row.  Want to schedule a time to talk to your attorney?  Need some help reaching out to a pastor or priest?  Tough luck.  You’re on death row.  You won’t need any of that stuff soon. 

The problem with the new unit manager is more sinister than just not being responsive, though. 

First, he only recently became the unit manager.  He was a Bureau of Prisons guard and administrative functionary before that.  In his email, Marty said prisoners have filed multiple complaints against him over the past few years alleging sexual abuse. 

Many of the prisoners filing the complaints were being held in the CMU.  So instead of conducting an investigation of the allegations, what did the warden do?  He put the same man in charge of the very prisoners who had complained about him.  And what did this man do when he became the unit manager?  He ordered prisoners to be strip searched for no other reason than for him to stand there and stare at their naked bodies. 

Last week, the unit manager inexplicably stuck his hands in the shower when Marty was bathing, naked, of course.  Was it meant to intimidate?  Was it to cop a feel?  It was a violation of the Prison Rape Elimination Act (PREA) regardless of the reason. 

Prison Legal News (PLN) magazine has published extensively on violations of the PREA.  The consensus of universities and organizations that follow the issue is that the act is doing little-to-nothing to protect prisoners — not from other prisoners — but from guards.  As I’ve written previously, the complaint procedure in the federal prison system is designed to protect the wrongdoer.  Here’s how it works. 

Filing Forms 

Let’s say a perverted prison administrator orders you to strip so that he can ogle you.  You know this is a violation of the PREA.  You must then file a form called a BP-8.5, which goes to the person you are accusing, saying, “Hey, you violated the PREA.”  His response, of course, will be “No I didn’t.”  You then have 14 days to file a Form BP-9, which goes to the warden.  The warden, not surprisingly, almost always supports his staff member.  You then have 60 days to file a form BP-10, which goes to the Bureau of Prisons regional office.  Once the prisoner loses there, which is almost guaranteed, he can file a Form BP-11, which goes to the Bureau of Prisons headquarters in Washington.  No prisoner ever wins at BOP headquarters. 

There are common ways in which the prisoner is stymied in his attempt to file a complaint.  The filing of every form is time sensitive.  So the warden and others will withhold their responses, backdate them, and then send the responses to you so that you only have a day or two to respond.  You can’t possibly get it done in time, so it’s dismissed as “not responsive in a timely fashion.”  You have no recourse because the federal courts have ruled that a prisoner must exhaust the “administrative complaint process” before going to the courts.  But if the complaint is dismissed by the BOP as “not responsive” because of time, you’re out of luck.  And those people who violate the Prison Rape Elimination Act get off scot free. 

That’s what is happening here.  Marty’s hands are tied.  He tried to go through the process, but the process is stacked against him.  He won’t find justice in the “Justice” Department.  So it’s up to the rest of us to call out illegality.  Marty’s appeal hearing took place on June 10.  I listened to it and it seemed to go well.  Hope isn’t a strategy, but his attorney seems to truly know what he’s doing.  

In the meantime, I want the world to know what goes on in these sickening prison units.  I want people to know how Americans are treated.  Remember, as Martin Luther King said, “The arc of a moral universe is long, but it bends toward justice.” 

John Kiriakou is a former CIA counterterrorism officer and a former senior investigator with the Senate Foreign Relations Committee. John became the sixth whistleblower indicted by the Obama administration under the Espionage Act—a law designed to punish spies. He served 23 months in prison as a result of his attempts to oppose the Bush administration’s torture program.

See: et al.  

Levetiracetam as the first-line treatment for neonatal seizures

Hooper RG, Ramaswamy VV, Wahid RM, Satodia P, Bhulani A. Levetiracetam as the first-line treatment for neonatal seizures: a systematic review and meta-analysis. Dev Med Child Neurol. 2021 Jun 13. doi: 10.1111/dmcn.14943. Epub ahead of print. PMID: 34124790.


Aim: To assess the effectiveness and safety of levetiracetam when used as first-line treatment of neonatal seizures. 

Method: Four electronic databases, Medline, Embase, Web of Science, and were systematically searched from inception until 20th November 2020. Randomized controlled trials (RCTs) and observational studies that included neonates born preterm and term were eligible for inclusion. The primary outcome measure was levetiracetam effectiveness, defined as seizure cessation within 24 hours of starting treatment. Secondary outcomes included short-term adverse events, mortality before discharge, and long-term neurodevelopmental outcomes. 

Results: Fourteen studies assessing 1188 neonates were included: four RCTs, three observational trials with phenobarbital as the control arm, and seven observational studies of levetiracetam with no control arm. Pooled efficacy of levetiracetam from observational studies was 45% (95% confidence interval [CI] 34-57%) (GRADE - very low). Meta-analysis of RCTs evaluating levetiracetam versus phenobarbital showed that both were equally effective (risk ratio [95% CI] 0.6 [0.30-1.20]) (GRADE - very low). Levetiracetam resulted in a lower risk of short-term adverse events compared to phenobarbital (risk ratio [95% CI] 0.24 [0.06-0.92]) (GRADE - moderate). 

Interpretation: Very low certainty of evidence suggests levetiracetam might not be more effective than phenobarbital. Moderate certainty of evidence indicates levetiracetam is associated with a lower risk of adverse events. Future trials on neonatal antiseizure medication therapy should include continuous electroencephalogram (EEG) monitoring as standard of care and enrol a homogenous population with similar seizure aetiology.

Courtesy of:

Monday, June 21, 2021

Sudden unexpected death in epilepsy. A personalized prediction tool

Ashwani Jha, Cheongeun Oh, Dale Hesdorffer, Beate Diehl, Sasha Devore, Martin J. Brodie, Torbjörn Tomson, Josemir W. Sander, Thaddeus S. Walczak, Orrin Devinsky. Sudden Unexpected Death in Epilepsy. A Personalized Prediction Tool. Neurology May 2021, 96 (21) e2627-e2638; DOI: 10.1212/WNL.0000000000011849


Objective To develop and validate a tool for individualized prediction of sudden unexpected death in epilepsy (SUDEP) risk, we reanalyzed data from 1 cohort and 3 case–control studies undertaken from 1980 through 2005.

Methods We entered 1,273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model.

Results Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalized tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM ± 12.5, and 22.9, SEM ± 11.0, respectively). The mean cross-validated (95% bootstrap confidence interval) area under the receiver operating curve was 0.71 (0.68–0.74) for our model vs 0.38 (0.33–0.42) and 0.63 (0.59–0.67) for the baseline average and generalized tonic-clonic seizure frequency models, respectively. Model performance was weaker when applied to nonrepresented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age at epilepsy onset, and family history of epilepsy. Antiseizure medication adherence was associated with lower risk.

Conclusions Even when generalized to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations, it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not focus only on the frequency of  convulsions. ________________________________________________________________________

From the manuscript:

Why do some people experience SUDEP after their second seizure while others survive thousands of convulsive seizures? Ongoing convulsions are a major prognostic factor6,7 but adjusted analyses are less consistent as to whether early age at epilepsy onset, long epilepsy duration, symptomatic etiology, nocturnal convulsions, and a high number or nonadherence of antiseizure medications are independently predictive.8,9 We cannot, however, accurately predict individualized SUDEP risk...

We found that an increased frequency of convulsions (including GTCS and focal to bilateral tonic-clonic seizures) and nongeneralizing focal-onset seizures conferred a higher risk of SUDEP. This is a departure from previous reports that estimate a higher average relative risk from GTCS frequency8,9 and have found no significant association between focal-onset seizures and SUDEP.7,9 These differences could be explained by variation in the data themselves or the strategies used for analysis. No significant relation was found between focal-onset seizures and SUDEP from analyses not only in the most recent and homogeneously ascertained data9 but also in one of our source studies.7 In fact, stratified relative risk from convulsions was higher in a previous analysis of the same combined source data as ours,8 suggesting that differences in data can only partially explain the conflicting results. An alternative reason is that, uniquely, our analysis aimed to provide individualized predictions, whereas others aimed to infer average effects over a population. Subsequently, we include as many data features as possible in the same single model (22 clinical factors), rather than seeking to interpret the output of multiple smaller models. We also removed arbitrary seizure frequency cutoffs (e.g., <3 per year) to improve individualization and interstudy comparability but assumed a monotonic relation between seizure frequency and outcome. We sought to identify prognostic rather than causal risk factors and within these constraints convulsion frequency was not the only predictor of SUDEP risk,10 and indeed performs poorly if used as the sole predictive factor. The novel finding that nongeneralizing focal-onset seizure frequency is prognostic conflicts with other major analyses9 and requires further investigation as it has potentially wide-ranging implications for clinical practice. Whether nongeneralized focal seizures can directly cause SUDEP or may be proxies for breakthrough tonic-clonic seizure risk in individuals who were previously free of convulsions also remains uncertain. Lastly, some predictors were variably clinically defined and so our interpretations must be made with caution. Even so, medication adherence was associated with reduced risk, while alcohol/drug abuse was associated with increased risk. This highlights 2 modifiable behaviors that, if causal, could reduce risk if addressed.

The independent associations between various treatments and SUDEP risk also require further explanation. Whereas our results support prior studies that have found a protective role for epilepsy surgery, almost all antiseizure medications are independently associated with slightly increased SUDEP risk. This needs to be interpreted cautiously since adjusted ORs represent the effect of adding antiseizure medications without any benefit on seizure control—a situation that may either represent increased risk due to the medication or increased risk due to selection of those with treatment resistance. Excluding vigabatrin, which is rarely used and probably falls into the second category, lamotrigine, benzodiazepines, and carbamazepine were associated with increased SUDEP risk compared to other medications, but interventional trials would be needed to determine whether this association is causal or not. Similarly, although cardiac and respiratory comorbidity is associated with reduced risk, this observation may be confounded by a competing risk (these individuals are more likely to die from a non-epilepsy-related cause) or by increased prevalence of coexistent pathologic findings associated with SUDEP misclassification (e.g., 40% left anterior descending coronary artery occlusion).

A higher likelihood of COVID-19 infection and subsequent symptoms in migraine patients

People with migraines appeared to have a higher likelihood of COVID-19 infection and subsequent symptoms of the disease, but they were less likely to receive health care, according to a study presented at the American Headache Society's 2021 annual meeting. 

"These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both," Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. "Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both." 

In providing background information, Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival. 

Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It's unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research. 

Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels. 

For the study, Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%). 

The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).

Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%). 

Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms: 

Difficulty breathing or shortness of breath (P = .005).


Headache, sore throat, and/or congestion. 


Loss of smell and taste. 

Chills and body aches. 

Persistent pain or pressure in the chest. 

Confusion or inability to arouse. 

Digestive issues (P = .005). 

Bluish lips or face. 

For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.

Changes in Health Care Utilization

"I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person," Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines. 

Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn't (RR = 4.9). 

Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. "There are people with migraine who go to the emergency room all the time, but then there's most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it's just a horrible place to be if you have migraine," Friedman said. "I think the majority of people would prefer not to go to the emergency room if given the choice." 

Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant. 

Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality. 

"A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses," Shapiro said. "For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread."

The researchers did not receive external funding. Shapiro has consulted for Eli Lilly and Lundbeck. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.

Uncommon epileptic syndromes in children

Josefina de la Jara, Carla Vásquez-Hernández, Elías Ramírez-Rojo and Juan Moya-Vilches.  Uncommon epileptic syndromes in children: a review. Seizure: European Journal of Epilepsy, Copyright © 2021 


• Lesser-known epileptic syndromes in children represent a diagnostic challenge.

• Refractory seizures and developmental deficits can be part of the clinical picture.

• Diagnosis of these syndromes is essential for timely workup and intervention.

• Genetic workup is useful for prognosis and can guide treatment in particular cases.


Epileptic syndromes are well-defined conditions comprising particular clinical features [seizure types, age of onset, response to treatment] and characteristic electroencephalographic changes, while their etiology and subsequent prognosis may vary. The recognition of these syndromes is fundamental for pediatric neurology practice, representing an essential learning topic in this field. Nevertheless, many epileptic syndromes are still quite unfamiliar to students, residents and even neurologists, because of their low incidence and their minimal representation in the literature. This narrative review discusses the concept of epileptic syndromes and revisits seven lesser-known or uncommon syndromes in order to summarize their core clinical features, which can become important clues for daily neurological practice, namely epilepsy of infancy with migrating focal seizures, myoclonic epilepsy of infancy, self-limited infantile epilepsy, myoclonic encephalopathy in nonprogressive disorders, Jeavons syndrome, and epilepsy with myoclonic absences. 

From the manuscript:

Conclusions and final thoughts

For decades, the categorization of epileptic syndromes has been a difficult task. The most constant feature present in all classification systems is differentiation by age at onset, which may be helpful to bear in mind when seeking the correct diagnosis in paediatric patients with suspected epilepsy (even though a high percentage of cases will not meet the criteria for a well-defined syndrome). 

Most of the ‘uncommon’ syndromes described in the present review have an onset during infancy; while West and Dravet syndromes have been extensively investigated and represent ‘must-learn’ topics in academic fields, the remaining syndromes are either clinically rare or are rarely mentioned in relevant literature. On the other hand, while most epileptic syndromes presenting in childhood are well known by general paediatric neurologists, EMA [epilepsy with myoclonic absences] and JS [Jeavons syndrome] (both presenting during infancy) merit a directed approach, as publications related to EMA are scarce, and JS has yet to be formally recognised as a syndrome. 

There are many compelling reasons to discuss these types of underdog syndromes. Myoclonic status epilepticus in nonprogressive encephalopathies, EMA, and EIFMS [epilepsy of infancy with migrating focal seizures] are true developmental and epileptic encephalopathies, in which early diagnosis and opportune treatment are essential for improving outcomes, even in patients with previous DDs. JS does not constitute an encephalopathy itself, but refractoriness and cognitive impairment are common features, prompting the need for an adequate therapeutic plan that considers non-pharmacological tools (such as blue lenses). Finally, many of these syndromes seem to have a genetic aetiology to some extent; therefore, a comprehensive workup should consider epilepsy gene panels or other studies guided by clinical suspicion. A positive finding may help to clarify prognosis, determine the relevance of genetic counselling, and guide treatment choices in some cases. 

The aforementioned reasons are the basis for the purpose of this review: to compile a summary of these lesser-known syndromes in a single document that might be of benefit to medical students, future neurologists, and scholars. Discussion regarding the categorization of these ‘uncommon’ syndromes as legitimate syndromes is still needed; however, that type of debate goes beyond the scope of this review, as it has even proven difficult to accomplish, even for panels of experts. 

While some specific aspects of each syndrome may not have been covered in detail, we hope that the present manuscript comprises a general depiction of these ‘uncommon’ syndromes, providing a starting point for further exploration.


Sunday, June 20, 2021

Hydroxychloroquine and azithromycin as a treatment of COVID-19 4

Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic

Leon G. Smith, Nicolas Mendoza, David Dobesh, Stephen M. Smith


This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.


Introduction This observational study looked at 255 COVID19 patients who required invasive mechanical ventilation (IMV) during the first two months of the US pandemic. Through comprehensive, longitudinal evaluation and new consideration of all the data, we were able to better describe and understand factors affecting outcome after intubation. 

Methods All vital signs, laboratory values, and medication administrations (time, date, dose, and route) were collected and organized. Further, each patient’s prior medical records, including PBM data and available ECG, were reviewed by a physician. These data were incorporated into time-series database for statistical analysis. 

Results By discharge or Day 90, 78.2% of the cohort expired. The most common pre-existing conditions were hypertension, (63.5%), diabetes (59.2%) and obesity (50.4%). Age correlated with death. Comorbidities and clinical status on presentation were not predictive of outcome. Admission markers of inflammation were universally elevated (>96%). The cohort’s weight range was nearly 7-fold. Causal modeling establishes that weight-adjusted HCQ and AZM therapy improves survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum levels. 

Discussion This detailed approach gives us better understanding of risk factors, prognostic indicators, and outcomes of Covid patients needing IMV. Few variables were related to outcome. By considering more factors and using new methods, we found that when increased doses of co-administered HCQ and AZM were associated with >100% increase in survival. Comparison of absolute with weight-adjusted cumulative doses proves administration ≥80 mg/kg of HCQ with > 1 gm AZM increases survival in IMV-requiring Covid patients by over 100%. According to our data, HCQ is not associated with prolongation. Studies, which reported QTc prolongation secondary to HCQ, need to be re-evaluated more stringently and with controls. 

The weight ranges of Covid patient cohorts are substantially greater than those of most antibiotic RCTs. Future clinical trials need to consider the weight variance of hospitalized Covid patients and need to study therapeutics more thoughtfully.

Treatment options have been limited in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Earlier optimism regarding immunomodulatory drugs such as azithromycin (AZM) and hydroxychloroquine (HCQ) seemed to be undermined by results of large interventional trials. 

However, a fascinating new study posted to the medRxiv* preprint server (not peer-reviewed), suggests that such disappointment may have been both premature and unwarranted, based on a re-analysis of over 250 patients on invasive mechanical ventilation (IMV) during the first two months of the pandemic. 

Using computational modeling, the use of weight-adjusted HCQ and AZM appears to be associated with a more than 100% increase in survival, without a clear correlation with ECG abnormalities.

Study details

In this study, based on a subset of critically ill COVID-19 patients, consisting of patients who required intubation and IMV, data from the medical records were analyzed using several novel methods. This included not only the vital signs and laboratory values but the therapeutic methods. 

The study was carried out on patients at Saint Barnabas Medical Center, New Jersey, with just over 1% having been clinically diagnosed to have COVID-19. Of the 255 patients, almost 80% died during the study period. Seven patients were transferred to another hospital on the ventilator, mostly after day 40 of hospitalization. 

Parameters were broadly comparable between survivors and non-survivors, except that all patients with an active malignancy, dementia, chronic obstructive pulmonary disease, and stroke failed to survive. However, sex, race, presentation severity, and blood type had no association with survival chances. 

A pre-print version of the research paper is available on the medRxiv* server. A preprint is a version of a scholarly or scientific paper that precedes formal peer review and publication in a peer-reviewed scholarly or scientific journal.

Laboratory markers

Laboratory markers of inflammation, such as Ferritin, D-dimer, Lactate Dehydrogenase (LDH), and C-reactive protein (CRP), were above average in almost every patient (96%). While all parameters, except the LDH, were equivalent in survivors and non-survivors, three patients had D-dimer values above 69,000 ng/mL. LDH values were higher in non-survivors by almost 30%. 

The increase in these parameters over time was characteristically steeper in patients who did not survive. 

Clinical complications

More than three in four non-survivors developed acute kidney injury (AKI), of which a tenth received renal replacement therapy (RRT). Of this latter group, a fifth survived. 

Almost 60% of patients were intubated within three days of hospitalization. The time to intubation did not predict survival, but intubation beyond day 15 was associated with survival in only 1 of 16 patients. 

More than 90% of the patients in this cohort had high blood glucose levels above 140 mg/dL, peak at >200 mg/dL, without corticosteroid therapy. Although none were known to be diabetics, most probably had impaired glucose tolerance before they acquired SARS-CoV-2. 

This prevalence is higher than in most other studies, probably because the researchers looked actively for hyperglycemia 


While half of the patients were obese, and 30% were overweight, the older patients were significantly heavier. That is, 74% of those above 60 were obese, vs 37% of those below this age. 

The mean body weight was approximately 90 kg, but unlike most antibiotic clinical trials, the range of body weight was extensive. The heaviest patient thus weighed approximately seven times more than the lightest.

 Notably, blood glucose levels or obesity did not predict a good clinical outcome. 

Therapeutic drugs

The chief therapeutic classes included steroids, tocilizumab, convalescent plasma, hydroxychloroquine, and azithromycin. 

Corticosteroids, when given at 6 mg or more, reduced the mortality risk 1.4 times. Meanwhile, the interleukin-6 receptor blocker) tocilizumab had two-fold lower mortality. 

Convalescent plasma (CP) was used only from week 4, in a fifth of the patients, mostly younger than those who did not receive it. The survival of the group which received CP was almost doubled from CP non-users. 

HCQ was used in 94% of patients within 48 hours of emergency room arrival, while >55% received 2,000-3,000 mg, cumulatively. Of this number, approximately 63% also received AZM. This combination fell out of favor over the study period based on external recommendations. 

Effect of HCQ/AZM on mortality

With every log increase in the cumulative dose of HCQ, the mortality rate fell by 1.12 times, such that at 3 g HCQ, survival odds rose by 2.5 times. 

When given together with AZM, the benefit was still more significant. Chances of survival increased further. Among those who received both > 3g HCQ and >1g AZM, almost half survived, compared to one in seven (16%) among patients who received one of these drugs at the same dosages. 

Number of patients by Date of Admission and breakdown by treatment with HCQ/AZM, HCQ alone or no HCQ therapy. Shown are the number of patients in the Cohort by admission date, from March 12 – May 1, 2020. HCQ therapy for each patient is demonstrated by use of color. Blue means the patient received HCQ and AZM therapy together, Gold, HCQ therapy without AZM, and Red, the patient did not receive HCQ.

Number of patients by Date of Admission and breakdown by treatment with HCQ/AZM, HCQ alone or no HCQ therapy. Shown are the number of patients in the Cohort by admission date, from March 12 – May 1, 2020. HCQ therapy for each patient is demonstrated by use of color. Blue means the patient received HCQ and AZM therapy together, Gold, HCQ therapy without AZM, and Red, the patient did not receive HCQ.

This means a 32% absolute difference in survival, or a relative improvement in survival odds of 200%, with the combination of HCQ/AZM at this dosage. This far exceeds the survival benefit cited in any study of any intervention so far. 

When HCQ/AZM was given at lower dosages, the risk of death was over three times higher relative to the above combination and dosage regimen. 

When the cohort was divided into patients who received >3g HCQ/>1g AZM and those who did not, overall, the absolute chances of survival were 23% higher for the first group. The 17% survival in the second group would have increased to 39% with the former treatment, predicted the researchers. 

This indicates that treatment with >3g HCQ/>1g AZM was associated with a more than 130% increase in survival rate compared to any other standard therapy. 

Weight-adjusted cumulative dosage

The researchers also found that when adjusted for weight, the cumulative dose would have a still greater effect. In fact, the average treatment effect (difference in mean survival, in this case) shows a steep increase between 40-50 mg/kg to peak at 46% for a dose of 82 mg/kg. 

Thus, patients receiving HCQ above 80 mg/kg of HCQ with >1g AZM had 14 times higher survival odds compared to those who did not. If HCQ dosage was fixed at >3g, the odds of survival were 7 times higher, or less than half of that achieved with the weight-adjusted cumulative dosage. 

“The fact that weight-adjusted cumulative dose has an even greater effect on survival than cumulative HCQ dose is strong confirmation of the causal relationship between this treatment and improvement in survival rate.” 

Age was another major factor since those older than 60 were five times more likely to succumb than younger patients. Hyperlipidemia was the single comorbidity linked to approximately four times higher odds of death. 

Interestingly, there was no correlation between the cumulative dose of HCQ (or AZM) and the occurrence of QTc prolongation. In fact, the QT interval began to fall during the period when the cumulative dose of HCQ increased. None of the patients showed torsades de pointes. 

What are the implications?

These findings indicate that a steeply rising ferritin, D-dimer and LDH over time predict poor survival, the rate of rise being several times greater for non-survivors. This should be validated to help provide a better prognosis for COVID-19 patients. 

The extensive range of obesity among critically ill patients indicates that weight-adjusted dosage is critical in achieving the correct therapeutic levels. Moreover, AZM is an independent contributor to improved survival. 

Most importantly, this is the first clinical study to demonstrate the remarkable benefit of using cumulative doses of HCQ>3g/AZM>1g, compared to those not treated with this combination. 

Why did such a large effect miss observation? For one thing, HCQ produces its benefit by cumulative effects on the target cells, which is weight-dependent. The failure to treat patients with weight-adjusted doses leads to ineffective treatment and outcomes biased towards lighter patients. 

HCQ is both safe and tolerable at higher doses, as shown in studies of rheumatoid arthritis or lupus. Such high doses for such long durations have not been used to treat COVID-19. 

The earlier studies claiming prolongation of the QTc duration with HCQ in COVID-19 treatment are shown to be flawed. Indeed, available data suggests that this finding is due to the underlying illness itself. 

The investigators also point out: “On April 24, 2020, the FDA issued a warning about the possible effects of low HCQ on QTc interval (47). Since 2010, the FDA has approved over 150 clinical trials, which include HCQ treatment. The FDA did and does not require monitoring for cardiotoxicity. In each of these trials, the total HCQ dose and expected tissue levels are markedly higher than used or seen in Covid patients. This discrepancy lacks logic or explanation.” 

In this startling study, the investigators carefully re-examined the data, showing that among critically ill COVID-19 patients on IMV, less than 4% “walk out of hospital.” In contrast, the survival benefit of combined HCQ/AZM at a cumulative dosage of >80 mg/kg and >1g, respectively, is shown to be both clear and significant. 

The safety at such doses is obvious, since survival is increased by almost 130% in this very high-risk population. Moreover, it appears that AZM is an important component of this therapy in terms of mortality reduction.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Thursday, June 10, 2021

The effect of ketogenic diet on serum lipid concentrations in children with drug resistant epilepsy

Ünsal Yılmaz, Selvinaz Edizer, Melis Köse, Zeynep Akışin, Yiğithan Güzin, Serdar Pekuz, Hatice Hilal Kırkgöz, Merve Yavuz, Aycan Ünalp.  The effect of ketogenic diet on serum lipid concentrations in children with drug resistant epilepsy, Seizure, 2021.


Olive oil-based ketogenic diet may cause dyslipidemia in children with medication-resistant epilepsy 

Ketogenic diet causes significant increases in cholesterol and triglyceride levels over the 24-month treatment period 

The initial rapid rise in cholesterol and triglyceride levels is followed by a gradually decreasing trend. 

Cholesterol and triglyceride levels do not rise in patients with pre-existing dyslipidemia. 

Ketogenic diet can be safely used even in patients with pre-existing dyslipidemia.




Ketogenic diet (KD) is a valuable treatment option for patients with medication-resistant epilepsy. It is associated with a number of side effects. However limited data are available for the long-term effects of KD on serum lipid levels. 


The aim of this study was to investigate the long-term effects of KD on serum lipid concentrations in children with medication-resistant epilepsy in daily clinical practice. 


A total of 73 children (40 girls) aged 3 to 193 months (median, 53 months) with medication-resistant epilepsy who received a KD treatment for at least 12 months between 2014 and 2019 years were enrolled in the study. All children were started on a KD with 3:1 ratio which was then adjusted between 2:1 to 4:1 after the onset of KD as clinically necessary. Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride concentrations and body mass index-standard deviation scores (BMI-SDS) were measured at onset and at 1, 6 and 12 months of treatment, and also in 40 of these patients they were measured at 18 and 24 months of treatment 


Dyslipidemia was observed in 71.2, 63, 63, 50, and 52.5% of the patients, at 1, 6, 12, 18, and 24 months, respectively. Median total cholesterol and triglyceride concentrations increased significantly at month-1, and although these high levels persisted for 24 months, the increase did not continue and showed a downward trend. However, this increase did not occur in the subset of patients with pre-existing dyslipidemia. Compared to baseline values, total cholesterol and triglyceride concentrations were higher at all time points, except 24-month cholesterol values. During the 24-month treatment period, BMI-SDS increased and the number of antiepileptic drugs decreased significantly.. 


Total cholesterol and triglyceride concentrations appear to increase during the first month of KD treatment, and although these high values persist for 24 months, the increase does not continue, on the contrary, it approaches the normal values by drawing a downward trend. However, cholesterol and triglyceride concentrations do not increase in the subset of patients with pre-existing dyslipidemia.

Courtesy of:

Wednesday, June 9, 2021

Intervention to prevent health officials from disconnecting a Jewish infant from life support

Israel’s President Reuven Rivlin made an impassioned plea to Britain’s Prince Charles, seeking his intervention to prevent health officials from disconnecting a Jewish infant from life support, the president’s office reported Wednesday. 

Two-year-old Alta Fixler has been hospitalized in England since she was born with brain damage. British health authorities petitioned the courts there for permission to switch off life-support equipment, claiming that it was in the child’s best interest. 

Her devoutly religious parents have refused to let her die and asked that they be allowed to transport Alta to Israel, where officials have agreed to accept her for continued medical treatment. 

“Your Royal Highness, I am writing to you today on a matter of grave and urgent humanitarian importance,” Rivlin wrote. “As you may know, a recent High Court ruling in the case of two-year-old Alta Fixler of Manchester has given doctors permission to switch off the life-support treatment that is keeping her alive.” 

“It is the fervent wish of her parents, who are devoutly religious Jews and Israeli citizens, that their daughter be brought to Israel. Their religious beliefs directly oppose ceasing medical treatment that could extend her life and have made arrangements for her safe transfer and continued treatment in Israel,” Rivlin said. 

“I know that representations have been made to Her Majesty’s Government on this matter, but I feel that the unique circumstances warrant a personal intervention on my part to you. It would be a tragedy if these parents’ wishes could not be accommodated in a way that respects both the law and their religious beliefs,” Rivlin concluded. 

Earlier this week Israeli Health Minister Yuli Edelstein also appealed to his British counterpart, Matt Hancock, to intervene and grant the parents’ request to leave England and take their daughter for treatment in Israel. 

“Alta’s parents are Orthodox Jews and Israeli citizens, living their lives according to [Jewish law], and they are interested in transferring Alta to one of the two hospitals in Israel that have expressed a willingness to treat her. I would appreciate if you could help the Fixler family bring Alta for further treatment in Israel,” Edelstein said. 

The family’s lawyer, Barrister Victoria Butler-Cole, told the website WhatsNew2Day that the parents don’t understand why the hospital wants their daughter to die instead of being allowed “to be treated in Israel by doctors who share their religious beliefs and ethical framework.” 

“Hospitals in Israel are willing to accept Alta, the risks of transmission are very low and the costs of safely transporting Alta are covered,” Butler-Cole said, saying the parents are begging the court and the hospital to reconsider their decision.

A fundraising website set up for Alta had raised £275,907 ($391,000) as of Monday.

Hickam's dictum in genetic myopathies

Sanchez-Tejerina, Daniel, Panades-de Oliveira, Luisa, Martin, Miguel, Alvarez-Mora, Maria, Hernandez-Lain, Aurelio, Dominguez-Gonzalez, Cristina. Pearls & Oy-sters: Hickam's Dictum in Genetic Myopathies: When a Proven Pathogenic Mutation Does Not Explain the Phenotype. Neurology. 2021;96(21):1007-1009. doi:10.1212/WNL.0000000000012000.


* Exercise intolerance is the most common phenotype in McArdle disease. Fixed weakness can be present in advanced ages, mainly affecting the shoulder girdle.

* ANO5 patients may present with a wide spectrum phenotype, including limb-girdle dystrophies, distal myopathies, and asymptomatic or mild symptomatic hyperCKemia. A characteristic radiologic pattern, involving the posterior compartment of the thigh, soleus, and medial gastrocnemius muscles in the legs, may assist in the genetic diagnosis of this entity.


* Consider the coexistence of genetic conditions, particularly among patients with a history of consanguinity.

* Although fixed muscle weakness may be present in patients with McArdle disease, in the majority of cases, it is mild to moderate and associated or preceded by a history of exercise-related symptoms.

* The presence of subsarcolemmal vacuoles that may contain periodic acid-Schiff (PAS)-positive glycogen and the absence of histochemical staining for myophosphorylase are hallmarks of McArdle disease on muscle biopsy. However, severe dystrophic changes are rare and should raise the suspicion of an additional concomitant myopathy.

A 67-year-old woman, born to consanguineous parents, was referred to our Neuromuscular National Reference Center with the diagnosis of McArdle disease made at age 58. She first noticed difficulties in climbing stairs and standing up from a sitting position in her 40s, which progressed over 10 years when she lost independent ambulation. She denied any history of exercise intolerance or episodes of rhabdomyolysis or myoglobinuria. She did not have symptoms of bulbar or extraocular musculature weakness, nor did she report cardiac or respiratory issues.

Initial laboratory tests showed elevated creatine kinase (CK) levels (range 1049-1269 U/L) and normal lactate levels. ECG showed a first-degree atrioventricular block, with a normal echocardiogram. Given the progressive proximal weakness and hyperCKemia, a muscle biopsy was performed and showed subsarcolemmal accumulation of glycogen (PAS-positive vacuoles) and myophosphorylase deficiency, but also striking dystrophic changes (figure). Sanger sequencing of the PYGM gene (NM_005609.3) identified the c.13_14del (p.Leu5ValfsTer22) frameshift variant in homozygosity, previously associated with McArdle disease (HGMD accession number: CD066398; ClinVar variation ID: 371064).              

Neurologic examination revealed symmetric proximal muscular weakness and bilateral calf hypertrophy. Manual muscle strength testing revealed the following Medical Research Council scores: shoulder abduction 4/5, elbow flexion 4-/5, elbow extension 4+/5, distal upper limbs musculature 5/5, hip abduction, adduction, and flexion 2/5, knee flexion and extension 4/5, distal lower limbs musculature 5/5. The patient was not able to rise from a chair and independent ambulation was not possible, requiring bilateral support. The rest of the neurologic examination was unremarkable, and reflexes were normal. A nonischemic exercise forearm test showed a flat curve for both venous lactate and ammonia, probably due to insufficient effort during the test.

After review of clinical and paraclinical features, an overlapping muscle dystrophy was suspected. A muscle MRI was performed (figure), confirming extensive muscular fatty infiltration, which involved almost the whole pelvic and thigh musculature, sparing solely gracilis and sartorius muscles. At the leg level, it showed a predominant involvement of medial gastrocnemius and soleus.

Subsequently, next-generation sequencing of a targeted panel of 202 genes related to muscular disorders was performed, and an additional homozygous pathogenic mutation was identified in the ANO5 gene (NM_213599.2: c.191dup, p.Asn64Lysfs*15), associated with limb-girdle muscular dystrophy 12 (LGMDR12),1 formally called LGMD2L. The patient was finally diagnosed with double genetic trouble, harboring proven pathogenic mutations homozygosis in 2 different genes. The latter is probably the main cause that explains the clinical phenotype...

In the case we report, the patient was initially diagnosed with McArdle disease based on the evidence of myophosphorylase deficiency in the muscle biopsy, which prompted the performance of a targeted PYGM genetic analysis. A muscle biopsy was performed prior to a forearm exercise test because the reported symptoms did not suggest a metabolic muscle disorder. Fixed muscle weakness occurs in approximately 20%-30% of affected individuals with McArdle disease, but it is normally preceded by a history of exercise-related symptoms. It is more likely to involve proximal muscles and is more common in individuals of advanced age.4,9 In the literature, there are only a few reports of patients diagnosed in later adulthood with a phenotype of fixed weakness as the sole clinical manifestation.10 The cause of the fixed weakness in McArdle disease and its phenotype heterogeneity remains unclear.4 To date, no genotype-phenotype correlation has been described.5,9

Regarding complementary tests, muscle pathology may show some degenerating or necrotic fibers, accompanied by regeneration, but the most consistent finding is PAS-positive subsarcolemmal vacuoles. The presence, in this case, of intense dystrophic changes in the muscle biopsy led, therefore, to the suspicion of another concomitant myopathy. Muscle MRI showed extensive fatty infiltration. Little is known about radiologic features in McArdle disease, and there are sporadic studies reporting fatty degeneration involving proximal muscles in patients with fixed weakness or advanced age.9 Therefore, it was necessary to rule out an associated limb-girdle muscular dystrophy in this case. A genetic analysis confirmed a concomitant anoctaminopathy, which better correlates with the patient's clinical picture.

We highlight the importance of carefully evaluating the entire clinical picture. The clinical features should outweigh the complementary tests to guide the definitive diagnosis. It is also important to remember that the coexistence of genetic conditions is possible, particularly among patients with a history of consanguinity. If complementary findings, including genetic results, do not explain the patient's clinical manifestations, the investigation should continue until it leads to a proper answer.

Borden N, Linklater D. Hickam's Dictum. West J Emerg Med. 2013;14(2):164. doi:10.5811/westjem.2012.10.12164

This case illustrates the dulling of Ockham’s razor and serves as a reminder that sometimes Hickam’s Dictum (“Patients can have as many diseases as they damn well please”) prevails over diagnostic parsimony.

Tuesday, June 8, 2021

Molecular signaling pathways underlying sudden unexpected death in epilepsy

Dominique F. Leitner, James D. Mills, Geoffrey Pires, Arline Faustin, Eleanor Drummond, Evgeny Kanshin, Shruti Nayak, Manor Askenazi, Chloe Verducci, Bei Jun Chen, Michael Janitz, Jasper J. Anink, Johannes C. Baayen, Sander Idema, Erwin A. van Vliet, Sasha Devore, Daniel Friedman, Beate Diehl, Catherine Scott, Roland Thijs, Thomas Wisniewski, Beatrix Ueberheide, Maria Thom, Eleonora Aronica, Orrin Devinsky. Proteomics and Transcriptomics of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Patients. Neurology May 2021, 96 (21) e2639-e2652; DOI: 10.1212/WNL.0000000000011999

Objective To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to control patients with epilepsy. 

Methods For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected postmortem brain tissue of 12 patients with SUDEP and 14 with non-SUDEP epilepsy. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from patients with mesial temporal lobe epilepsy: 6 low-risk and 8 high-risk SUDEP as determined by a short (<50 seconds) or prolonged (≥50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. 

Results In autopsy hippocampus and cortex, we observed no proteomic differences between patients with SUDEP and those with non-SUDEP epilepsy, contrasting with our previously reported robust differences between epilepsy and controls without epilepsy. Transcriptomics in hippocampus and cortex from patients with surgical epilepsy segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 long noncoding RNAs, 3 pending) in hippocampus. 

Conclusion The SUDEP proteome and high-risk SUDEP transcriptome were similar to those in other patients with epilepsy in hippocampus and cortex, consistent with diverse epilepsy syndromes and comorbid conditions associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions, may identify molecular mechanisms of SUDEP.

Mentorship and sexual harrassment

When a prominent and highly published medical oncologist left the Mayo Clinic in Minnesota in 2018, there were no details as to why. Axel Grothey, MD, a specialist in gastrointestinal cancers, "has decided to leave," the institution told its staff in an email. 

It's only now, 3 years later, that details have emerged of unethical sexual relationships that he had with two women — an oncology fellow and a junior faculty member. 

A timeline of the events was reported in detail by The Cancer Letter, a newsletter for oncologists in academia. 

The inappropriate sexual relationships with mentees only came to light once medical licensure boards in three states reprimanded him last year, events first triggered by additional women at Mayo filing their grievances with the Minnesota Board of Medical Practice, causing related documentation to be made public. 

The Cancer Letter notes that the GI oncologist was reported to Mayo's human resources department, which conducted an internal investigation. This found that Grothey's "pattern of conduct demonstrated a failure on his part to establish and maintain appropriate professional boundaries with people who viewed him as a mentor." 

However, this finding was not made public, and Grothey was given a choice between resigning and being terminated, the newsletter reported. 

Grothey chose to resign, and he moved to the West Cancer Center, which has fellowship and residency programs in Germantown, Tennessee, as director of GI cancer research. He was also appointed medical director of OneOncology Research Network's clinical trial site management organization. 

Until last week, he also retained his position as co-chair of a National Cancer Institute steering committee, which influences which clinical trials in GI oncology get funded. However, he was removed from that position May 27, with NCI director Ned Sharpless, MD, stating: "We cannot and will not tolerate sexual harassment within the agency, at research organizations that receive NIH funding, or anywhere else NIH-funded activities are conducted."

The Oncoalert Network, a global network of oncology professionals, said it has zero tolerance for sexual harassment or abuse and acted immediately after double-checking facts and allegations, removing Grothey from the network on May 1. 

Fight CRC, an advocacy group for colorectal cancer patients, also removed Grothey from its medical advisory board, it announced last week. 

Grothey did not respond to a request for comment. 

Charanjit S. Rihal, MD, chair of Mayo Clinic's personnel committee, said in a statement to Medscape Medical News that "all instances of sexual harassment are reported to the board of medical practice..." and that it also "provides truthful information about corrective action taken when references are requested and credentialing inquiries occur..." 

The revelations triggered a stream of social media responses. 

Some suggested that this behavior is common. Shruti Patel, MD, an incoming oncology fellow at Stanford University and former resident at Mayo Clinic, tweeted: "#MedTwitter If you think this hasn't happened at your institution, you are [probably] wrong." 

Sarah Temkin, MD, an oncologist and executive producer, 1001 Cuts, a forthcoming film about women surgeons, tweeted: "Off the top of my head I can think of a half dozen nearly identical stories. All the perpetrators are still working. Many of the victims are not. If our professional calling is supposed to be 'do no harm,' we ought to clean up the house of medicine." 

Another medical oncologist said rumors about Grothey were longstanding. "Heard from many colleagues that this behavior was known in the field and went on for years. Years," tweeted Charu Aggarwal, MD, MPH, from the University of Pennsylvania in Philadelphia. However, Aggarwal also said she was "shocked" by the news, as did others. 

Estela Rodriguez, MD, of the Sylvester Comprehensive Cancer Center in Miami, Florida, asked oncologists to contemplate harassment and abuse of power in the workplace. "Medical training is so long that you witness a lot of inappropriate abuse of power, sexual harassment, racism, bullying. Mentor-mentee, doctor-nurse, resident-resident. If anything, take this time to reflect on your part," she tweeted. 

Sexual Harassment in Oncology

The public airing of Grothey's story comes at the same time that a new study of sexual harassment in oncology has been released as an abstract as part of the run-up to the 2021 American Society of Clinical Oncology (ASCO) annual meeting, which starts later this week. 

In the previous 12 months, 70% of American oncologists reported sexual harassment from peers and/or supervisors, according to the survey of 271 full-time clinicians. 

Women oncologists had a higher incidence than men (80% vs 56%), a difference that was statistically significant (P < .0001). 

The investigators queried respondents about three types of sexual harassment (gender harassment, unwanted sexual attention, and sexual coercion), as defined in a 2018 report from the National Academies of Sciences, Engineering, and Medicine. 

The survey results are "sobering," lead author Ishwaria Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston, told Medscape Medical News. The full study will be presented as an oral presentation at ASCO. 

"Sadly, both timely and timeless," tweeted medical oncologist Tatiana Prowell, MD, of Johns Hopkins University in Baltimore, Maryland, about the new study. 

The Grothey news triggered multiple examples of public storytelling by women who have endured harassment. 

Martina Murphy, MD, a medical gynecological oncologist at the University of Florida in Gainesville, posted on Twitter a germane story: "I was sexually harassed as a resident by an attending, something I learned was repeated behavior. I complained despite fearing jeopardizing my chance to match in fellowship. He was ultimately fired — when another man revealed his research misconduct." 

Sangeetha Kolluri, DO, a breast surgeon at Austin Cancer Centers in Texas, responded to Murphy. "You were braver than I was. I did not report sexually harassing behavior by a prominent surgical oncologist until after I completed my breast surgery match and my program director was…unsupportive. I was labeled manipulative at my exit interview."


Friday, June 4, 2021

Wrong brain surgery

An Alabama neurosurgeon who was charged with manslaughter in the death of a third-year medical student is now facing a malpractice suit alleging he performed the wrong brain surgery. 

The brain surgery patient's widow, Christine Metzger, is suing Jonathan Nakhla, MD, and his former employer, Infirmary Health System, for negligence and wrongful death, according to Mobile, Alabama-based television station WKRG. 

Dennis Metzger was admitted to Mobile Infirmary Medical Center in December 2018 with a left frontal lobe brain tumor that had been confirmed on MRI. A cerebral angiogram, ordered by Nakhla, showed that a preliminary embolization was not possible, so Nakhla took Metzger to the operating room 5 days after he was first admitted. 

The patient consented to "biopsy and debulking brain tumor," but, according to the lawsuit, Nakhla instead performed a bifrontal craniotomy and resected the tumor. 

The surgeon documented that the tumor came out easily but that "the mass was extremely vascular and hemorrhagic." The suit alleges that Nakhla later "realized he performed the wrong surgery and either he himself crossed through the original disclosure to alter it...or directed someone else to do so." 

Later that evening, Nakhla reportedly took the patient, who had become lethargic and nonresponsive, back to the operating room for emergency evacuation of a subdural hematoma. Metzger never regained consciousness and died within 4 days of the initial procedure.

Nakhla has had a rapid fall from grace since August 2020, when he was charged with manslaughter.

According to WKRG reporting, prosecutors said the neurosurgeon — who was 26 years old at the time — was driving more than 130 miles per hour in a 45 MPH zone and had a blood alcohol content above the legal limit when he swerved to avoid another car. He rolled his sports car multiple times, and the impact killed Nakhla's passenger, third-year medical student Samantha Thomas, who was 24.

Thomas' father sued Nakhla a few weeks after the accident, seeking punitive damages.

Nakhla, a graduate of Duke University School of Medicine, was first licensed in Alabama in 2018. He interned in neurologic surgery at Albert Einstein College of Medicine/Montefiore Health System in New York City and participated in fellowships at both Einstein and Weill Cornell Medical College/New York–Presbyterian Hospital. Nakhla was a junior attending neurosurgeon at Brown University's Lifespan Health System, according to his curriculum vitae. 

Soon after the manslaughter charge, Nakhla was fired from Mobile Infirmary, according to WKRG. He voluntarily surrendered his medical license in September 2020, according to the Alabama State Board of Medical Examiners.