Friday, September 27, 2019

POTS story

A British woman who claims she once fainted up to six times a day and would often wake up in the hospital without knowing how she got there says she has finally received a diagnosis that explains her symptoms.

Beth Joyce, 27, told South West News Service (SWNS), a British news agency, that she has postural orthostatic tachycardia syndrome (POTS). The condition is “characterized by too little blood returning to the heart when moving from a lying down to a standing up position (orthostatic intolerance),” according to Genetic and Rare Diseases Information Center (GARD).

Fainting, blurred vision, headaches, heart palpitations, weakness, tiredness and sleep disorders are common signs. 

“It was really scary because I never knew when it was going to happen and I'd end up banging into things or knocking my head,” Joyce told SWNS. "I didn't want to be out and about in case it happened and I shut myself off completely.”

"On a couple of occasions I fainted in the street and woke up in hospital covered in wires not knowing what was going on,” she added. "That was the scariest thing that has ever happened in my life.”

Joyce, who said she first noticed symptoms of POTS when she was 19, said she went to multiple doctors in the hopes of receiving a diagnosis — but many wrote off her symptoms, she claimed. One reportedly told her that the symptoms were “all in [her] head.”

What’s more, Joyce said she struggled to work due to the condition and was hesitant to leave the house without someone by her side.

“I used to work part-time in an office and I would get home from work and literally go straight to sleep for a few hours, I was completely wiped out,” she said. "I'd only go to places close by with a friend. I couldn't even go to university and missed out on a huge part of my education.” (Joyce later completed her degree, SWNS reported.)

"I started to suffer from depression because it was upsetting," she said, adding that she felt lonely at the time.

At its worst, Joyce said she would sometimes faint up to six times a day, often waking with bruises or suffering a black eye.

Eventually, she was referred to a specialist who, after conducting a series of tests, confirmed she has POTS.

"Being diagnosed with and coming to terms with POTS has been one of the hardest, life-altering things I have ever had to deal with,” she said. "However, it has shown me just how strong I am as a person to come as far as I have despite the daily difficulties that I continue to face.”

Joyce added: "It was a big relief to know it wasn't all in my head and something could be done about it. But it was also terrifying because it was life-altering.”

The cause of POTS is not well understood, and women — typically those between 15 and 50 years of age — are more prone to the condition, though men can also be affected. POTS most commonly occurs “after major surgery, trauma, or a viral illness,” according to GARD.  In women, “episodes may also begin after pregnancy and the symptoms may worsen or the number of episodes may increase right before menstruation,” it noted.

It’s not clear what spurred Joyce’s condition.

Joyce has been unable to drive due to POTS because of the chance she could faint while behind the wheel. But, as she continues treatment, she hopes to one day receive her license.

"It would be a huge difference,” she said. "I'd also be able to get to work or to appointments without having to rely on public transport or lifts from my boyfriend.”

Wednesday, September 25, 2019

The role of EEG in the erroneous diagnosis of epilepsy

Amin U, Benbadis SR. The Role of EEG in the Erroneous Diagnosis of Epilepsy. J Clin Neurophysiol. 2019 Jul;36(4):294-297.

Errors in diagnosis are relatively common in medicine and occur in all specialties. The consequences can be serious for both patients and physicians. Errors in neurology are often because of the overemphasis on 'tests' over the clinical picture. The diagnosis of epilepsy in general is a clinical one and is typically based on history. Epilepsy is more commonly overdiagnosed than underdiagnosed. An erroneous diagnosis of epilepsy is often the result of weak history and an 'abnormal' EEG. Twenty-five to 30% of patients previously diagnosed with epilepsy who did not respond to initial antiepileptic drug treatment do not have epilepsy. Most patients misdiagnosed with epilepsy turn out to have either psychogenic nonepileptic attacks or syncope. Reasons for reading a normal EEG as an abnormal one include over-reading normal variants or simple fluctuations of background rhythms. Reversing the diagnosis of epilepsy is challenging and requires reviewing the 'abnormal' EEG, which can be difficult. The lack of mandatory training in neurology residency programs is one of the main reasons for normal EEGs being over-read as abnormal. Tests (including EEG) should not be overemphasized over clinical judgment. The diagnosis of epilepsy can be challenging, and some seizure types may be underdiagnosed. Frontal lobe hypermotor seizures may be misdiagnosed as psychogenic events. Focal unaware cognitive seizures in elderly maybe be blamed on dementia, and ictal or interictal psychosis in frontal and temporal lobe epilepsies may be mistaken for a primary psychiatric disorder.

From the srticle

Errors in diagnosis are relatively common in medicine and occur in all specialties. The rate of diagnostic error is estimated at 10% to 15%. The consequences can be serious for both patients and physicians. Diagnostic errors, including incorrect or delayed diagnosis, can result in harm to patients and also increase cost. Factors that can cause or contribute to diagnostic errors fall into two categories: system-related errors or cognitive factors. Examples of system-related errors include problems with policies and procedures, inefficient communication and teamwork, and increasing time constraints for clinicians. Examples of cognitive errors include premature diagnostic closure (failure to continue considering alternative diagnoses after the initial diagnosis was made), faulty perception, using standardized algorithms, and erroneous “context generation” (overemphasis on tests and errors in interpreting the results of the test). Failure by the patient or family to provide an accurate medical history or an atypical or masked presentation of a disease are also important factors...

The diagnosis of epilepsy in general is a clinical one and is typically based on the history. Most epilepsy patients have normal brain MRIs and normal routine EEGs, so obtaining a detailed history is the key. It not only can lead to the correct diagnosis of epilepsy but may even help characterize the type of epilepsy. Seizure history has to include the following:

A detailed semiology of the events including preictal warning signs and symptoms, ictal phase (from both the patient and observers who have witnessed the event), and postictal phase

Frequency of events


Seizure risk factors including history of febrile or childhood seizures, family history of epilepsy, history of central nervous system infections and history of traumatic brain injury

Prior work-up including brain MRIs and EEGs

Previous and current antiepileptic medications, reason for discontinuation and possible side effects
Review home (cell phone) videos, which can provide an extension of the history with a more objective lens and may help the neurologist reach a correct diagnosis quickly.

An appropriate suggestive history of epilepsy even with a normal interictal EEG is enough for correct diagnosis and is probably the most common scenario in general neurology practices. A good history plus a strong interictal EEG abnormalities allow for a diagnosis with a high degree of confidence. An erroneous diagnosis of epilepsy is often the result of a weak history and a weak (“overread”) EEG. A definite diagnosis usually requires capturing a seizure with EEG-video monitoring and having both a clinical (video) and an EEG seizure. Unfortunately, simultaneous EEG and video recordings are only practical for patients with frequent (“intractable”) seizures...

This [the overdiagnosis of epilepsy] is by far the most common scenario encountered at referral epilepsy centers. Approximately 25% to 30% of patients previously diagnosed with epilepsy who do not respond to initial antiepileptic drug (AED) treatment do not have epilepsy. This number has been consistent across continents and different age groups. The erroneous diagnosis is often a result of the “dangerous formula” of a weak history plus an overread EEG, with overemphasis of the EEG. Clinicians perceive missing an epilepsy diagnosis as riskier than overdiagnosing it, which is somewhat understandable. This can result in unnecessary treatments and side effects, driving restrictions, employment difficulties, psychological and socioeconomic consequences, and the stigma associated with the diagnosis of epilepsy. Some patients have an incorrect diagnosis for >10 years...

Sometimes reaching the correct diagnosis can be challenging. It should start with a thorough history, a good eye-witness account, a detailed physician examination, and selecting and interpreting the necessary laboratory and imaging studies correctly. When in doubt, referring patients to subspecialists and having multidisciplinary team approaches to discuss individual cases are key. After reaching the correct diagnosis, optimizing communication between healthcare providers is crucial. Very importantly, EEG should not be over-emphasized with respect to the history...

Reversing the diagnosis of epilepsy is difficult. An EEG that was overread as epileptiform will not be canceled by multiple subsequent normal EEGs because EEG is a test of cerebral activity during a specific period, and it can vary from time to time. The only way in undoing the erroneous diagnosis is to rereview the “abnormal EEG.” This can be difficult as previous records are not always available or accessible and not all digital EEG systems are compatible.

Lack of mandatory training in EEGs and the erroneous assumption that all neurologists are competent electroencephalographers are the main reasons for an “abnormal EEG” overread. Taking an accurate and thorough history and performing a detailed neurologic examination are by far the best and most valuable tools for any physician, including neurologists, to establish a correct diagnosis. Complementing history with home (cell phone) videos of the seizure-like episodes can be very helpful. Also, clinicians should always be mindful that the diagnoses may be wrong and routinely question and review diagnoses. It has been shown that experts are more likely to admit to diagnostic uncertainty than nonspecialists. Finally, EEG and other tests should not be overemphasized over the clinical picture and clinical judgment.

Tuesday, September 24, 2019

Wasabi inducing "broken heart syndrome"

[Whether the sushi is spicy tuna or California roll, it all tastes like wasabi to me.]

An Isreali woman was hospitalized with so-called “broken heart syndrome” after mistaking wasabi for avocado, according to a report recently detailed in a medical journal.

The unusual story begins with a woman in her late 60s who attended a wedding. At the nuptials, the woman, who was not identified in the report published in BMJ Case Reports, ate a “large amount” of what she thought was avocado dip — only to very quickly realize it was actually wasabi paste, a Japanese horseradish.

The woman then felt a “sudden pressure” in her chest before the feeling moved down to her arms, according to IFL Science, which cited the report. The sensation lasted for the next few hours, though the woman chose to stay at the wedding.

By the next morning, however, she awoke feeling “uncomfortable and weak” and decided to see a doctor, reported IFL Science.

Doctors performed an electrocardiogram (ECG), which revealed the woman was suffering from takotsubo cardiomyopathy, colloquially known as “broken heart syndrome." The Mayo Clinic defines the condition as a "temporary disruption of [the] heart's normal pumping function in one area of the heart."

It's typically triggered by extreme emotional or physical stress, such as the death of a loved one or a car accident. Most people who experience broken heart syndrome are 50 years old or older.
In the report, the researchers claim the woman’s broken heart syndrome case is the first to be spurred by “food consumption alone,” IFL Science reports. In the past, other food-related cases of broken heart syndrome were linked to anaphylaxis, a severe allergic reaction.

"To the best of our knowledge, this is the first report of takotsubo cardiomyopathy triggered by wasabi consumption," the researchers wrote, according to IFL Science, which added the woman recovered after she was treated with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers.

Finkel-Oron A, Olchowski J, Jotkowitz A, et al.  Takotsubo cardiomyopathy triggered by wasabi consumption: can sushi break your heart?  BMJ Case Reports CP 2019;12:e230065.


Takotsubo cardiomyopathy is a left ventricular dysfunction that typically occurs after sudden intense emotional or physical stress and mimics myocardial infarction. We describe a case of a 60-year-old woman that presented to the emergency department with chest pain after she attended a wedding and ate a large amount of wasabi, assuming it to be an avocado. To the best of our knowledge, this is the first report of takotsubo cardiomyopathy triggered by wasabi consumption.

Cerebral arteriovenous malformation

The high school football player in Florida who collapsed during a game on Friday was “completely brain dead” and was taken off life support on Monday, according to local reports.

Jacquez Welch’s organs will be donated, The Tampa Bay Times reported, adding that his mother said doctors told her seven lives would be saved by her son.

Bay News 9 reported that Welch’s mother, Marcia Nelson, provided the update that her son was "completely brain dead" at a gathering on Monday evening.

Welch, a senior football captain at Northeast High School in St. Petersburg, didn’t get up after a tackle during Friday night’s game against Seminole Osceola High School. His mom was at the game.
"It was a group tackle. Everybody got up. He got up a little slow and he didn't get back up," she told the television station.

Paramedics rushed an unresponsive Welch to the hospital. Once there, doctors discovered the 17-year-old was suffering from severe bleeding on the brain from a preexisting condition, coach Jeremy Frioud said, according to the newspaper.

Doctors reportedly said Welch had a brain arteriovenous malformation, a rare tangle of abnormal blood vessels connecting arteries and veins, according to the Mayo Clinic.

A brain AVM may not cause any symptoms until it ruptures, but some signs can include seizures, headache or pain in one area of the head, muscle weakness or numbness in one part of the body, vision loss, severe unsteadiness and difficulty speaking.

Frioud described Welch as “an incredible kid.” He was a star athlete and a good student, and had already been recruited, receiving his first offer from Concordia University in St. Paul, Minn., the newspaper reported.

Coach Jeremy Frioud: “He left this world doing what he loved more than anything else."


[One day I will see one.]

A 15-year-old British teen who suffered from strep throat in June has since developed a rare psychiatric condition that causes involuntary outbursts and tics.

“When it happens it’s like he’s been imprisoned. I’m scared to take him out or let him go anywhere in case it happens in public,” Lee Wilson’s mother, Lisa Bullen, said of her son. “It comes out of nowhere. His eyes roll back and it’s really shocking to see.”

Lee has been diagnosed with PANDAS, or pediatric autoimmune neuropsychiatric disorders, associated with Streptococcus infections. The neurological condition, which is a subtype of PANS (pediatric acute-onset neuropsychiatric syndrome), can bring on or worsen symptoms of obsessive-compulsive disorder (OCD) and tics, according to the National Institute of Mental Health.

Those who develop the condition following a strep infection are said to often show signs “overnight and out of the blue,” says the institute.

“It’s incredibly disturbing. There’s nothing I can do to help him. He just sits there dribbling and drooling and making these awful noises,” Bullen, 36, told South West News Service (SWNS), a British news agency. “It’s like he’s been possessed by a ghost or something and to be honest it scares the life out of me.”

“He’s imprisoned in his own mind.”

PANDAS can occur when a strep infection “causes an abnormal immune response resulting in neuropsychiatric symptoms,” according to the Genetic and Rare Diseases Information Center (GARD)....

Bullen said her son’s condition developed just days after he suffered a strep infection. Though he was treated with antibiotics, his symptoms persisted. She has since taken him to numerous doctors in an attempt to understand, as Bullen put it, Lee’s “personality change.”

Before Lee was formally diagnosed with the condition, Bullen said, many doctors told her that he needed to be admitted to a psychiatric institute.

“I felt like I had to constantly fight to prove my son wasn’t mental," said Bullen. "I knew he was really, really ill and not crazy. I was devastated by it all. My son just wasn’t the same person anymore.”

Lee continues to suffer from tics and fits. When they occur, the teen’s body becomes rigid. He laughs and cries uncontrollably.

Treatment for PANDAS typically includes medication and cognitive behavioral therapy. In severe cases, intravenous immunoglobulin therapy and plasmapheresis — or plasma exchange — are sometimes considered. Most people with PANDAS can recover with treatment, though they can redevelop the condition if another strep infection occurs.

Lee will soon see neurologists at the Evelina Children's Hospital in London for further treatment, his mother said.

"I’m so worried for his future,” she said. “My son isn’t the person I remember him to be. It is heartbreaking for me.”

Benign external hydrocephalus mistaken for child abuse

Wester K. Two Infant Boys Misdiagnosed as "Shaken Baby" and Their Twin Sisters: A Cautionary Tale. Pediatr Neurol. 2019 Aug;97:3-11.

BEH [benign external hydrocephalus] may, however, be associated with cognitive problems 319 or have considerably more severe consequences, including a predisposition for subdural hematomas (SDHs). This predisposition for SDH does not appear to be well-understood by many of the physicians who deal with child abuse. Moreover, the scientific evidence supporting a causal connection between nonaccidental trauma and SDH in infants is at best scant.

This article describes two pairs of dizygotic twins with nearly identical histories. Both twin pairs were born preterm just three weeks apart; each pair consisted of a boy and a girl, and most importantly, the boys, but not the girls, developed symptoms of increased intracranial pressure (ICP). All the children were diagnosed with wide subdural-blood-containing fluid collections, mainly over the frontal lobes, and medical expert witnesses told the court that all four children had been subjected to violent shaking. As a consequence one parent was sentenced to 1.5 years in jail and all four children were taken from their biological parents and raised in foster homes for more than three years until appeal courts decided in favor of the parents.

These children are by no means unique, but they may serve to illustrate some important points concerning BEH and “shaken baby syndrome" or abusive head trauma, including some striking epidemiologic similarities. In addition to documenting these four children, this contribution reviews the literature on the shaken baby syndrome or abusive head trauma with an emphasis on the possibility that some infants with BEH might be mistaken for shaken baby syndrome....


Computed tomography (CT) the next day showed fluid collections in widely enlarged subdural spaces, especially in the frontal region, with higher density than cerebrospinal fluid (CSF), but only a few, minor acute blood clots. The initial radiological description listed external hydrocephalus as a diagnosis; this was later abandoned, and the CT was finally described as showing a “large subdural hematoma,” SDH.

Child abuse was suspected. A total skeleton x-ray evaluation revealed no fractures; he had no bruises or subcutaneous hematomas. Ophthalmoscopy showed bilateral, extensive retinal hemorrhages (RH)...

Based on the radiological description of “a large subdural hematoma” and bilateral retinal hemorrhages (RH), the case was reported to the child protection team and the police, followed by a charge of child abuse against his father. The medical experts in the lower court (forensic medicine, ophthalmology, and pediatrics) testified in favor of child abuse, disregarding the perioperative finding of only clear fluid without visible blood. The father was sentenced to 1.5 years in jail but appealed the verdict. Both twins were taken from the parents and raised in foster homes for the next three years.

The boy had sustained severe brain injury; the follow-up MRI was described as follows: “ The restricted diffusion as seen here is a finding that in nearly all cases can be taken as a sign of severe lack of oxygen and an early permanent brain damage ” (the author's translation from Norwegian). The boy is permanently vegetative...

The appeal court

In the appeal court, the author was appointed expert witness in addition to those from the primary court, who still favored the abuse explanation. The father was found not guilty, as the court accepted BEH and associated complications as a more likely cause of the condition than physical abuse...

Boy 2

He had no bruises or other external indications of injury. On the third day, MRI and CT scans were performed. The CT scan showed “ a subdural haematoma/fluid collection with a definitely higher density than CSF, but lower density than cerebral cortex (hypodense/isodense) with hyperdense stripes in the frontal subdural space, probably representing fresh blood in the subdural space ” (the author's translation). The MRI scan was interpreted as showing the same, with the age of the hematomas estimated as two to three days to a few weeks. Twelve plain skeleton X-rays revealed no fractures.

Fundoscopy disclosed multiple RH in several layers of retina in one eye but only two minor peripheral bleedings in the other, the conclusion being “ findings compatible with retinal haemorrhages as seen in the shaken-baby syndrome, although it is atypical that the extent of bleedings is so different in the two eyes ” (the author's translation).

Child protection authorities and police were notified, and both infants were routinely placed in a foster home, where they remained for the next three years.

The appeal court

The police found it difficult to prove physical abuse and rested the case. The child protection authorities, however, insisted on keeping the children separated from their parents. A lower court had decided in favor of the parents, but the child protection authorities appealed that decision and delayed the transfer of the children back to their parents for another 16 months. The appeal trial was almost identical to the one described above, with almost the same set of expert witnesses, including the present author. The court decided in favor of the biological parents, and after more than three years, the children were reunited with their parents.

This report describes two pairs of three-month-old premature dizygotic twins who were separated from their biological parents for three years under the assumption that they had been subjected to vigorous shaking. This assumption was based solely on neuroimaging findings of extracerebral or subdural fluid collections described as containing chronic hematomas and small amounts of fresh blood. In addition, the boys, but not the girls, had dramatic symptom debuts and were found to have RH described as compatible with nonaccidental head injury caused by shaking. None of the twins had any sign of impact to the head or any extracranial finding indicating violence. Duhaime et al. stated in 1987 that impact is required to cause the findings of the triad.

In the author's opinion, all four infants exhibited extracerebral fluid collections compatible with external hydrocephalus, as defined by several authors. Most likely, their BEH condition had been complicated by spontaneous bleeding or oozing of blood products into the subdural space; BEH is known to predispose for spontaneous subdural bleedings in infants, and this predisposition can be a pitfall in the diagnosis of abusive head trauma.

Shaken baby syndrome and lack of medical evidence

These infants were diagnosed as having been shaken with the most serious consequences for their families. It therefore seems appropriate to analyze the quality of medical evidence behind the widely accepted notion that a triad consisting of SDH(s), RH, and encephalopathy can be used to prove a criminal act—shaking. As in other countries, in Norway guilt has to be proven beyond reasonable doubt. The solidity of the triad as proof of a criminal act must therefore not be doubted.

It is difficult to find scientific evidence above level 3 for a causal relationship between the triad and violent shaking, as also concluded after an extensive earlier review. 41 A more recent review, based on thousands of articles, concluded as follows: “ There is limited scientific evidence that the triad and therefore its components can be associated with traumatic shaking (low quality evidence). There is insufficient scientific evidence on which to assess the diagnostic accuracy of the triad in identifying traumatic shaking (very low quality evidence) ”. No study based on observed shaking could be identified. Only two studies in the literature were found to be based on confessed shaking; these confessions came during police custody or judicial investigations, weeks to months after the diagnosis. Confessions obtained under such circumstances are known to be encumbered with uncertainties.  These conclusions underline the importance of considering alternative etiologies for the triad and its findings.

Subdural hematomas will inevitably raise suspicion of child abuse; SDH may, however, also appear spontaneously in infants, often precipitated by one of two congenital conditions, namely, arachnoid cysts or BEH. Several mechanisms may explain why external hydrocephalus predisposes for SDH. To me as a neurosurgeon, the most likely is leakage of small amounts of blood from where the bridging veins enter the dura. It is a common intraoperative observation that even minor manipulations of normal bridging veins during a craniotomy may cause such leakage. In external hydrocephalus, these veins may ooze blood spontaneously just because they are stretched.

Subdural hematomas also occur in newborns, especially in preterm deliveries and twins; our twins were born four to five weeks preterm. Subdural hematomas occur more frequently after vaginal delivery than after a planned Caesarean section and even more frequently after emergency Caesarean sections and forceps or vacuum-assisted deliveries. These subdural blood collections may gradually develop into larger hematomas over time. There are factors in old hematomas that may induce neovascularization in the parietal hematoma membrane, and these pathologic vessels bleed easily. Other factors disturb normal coagulation in subdural blood collections. 

Male preponderance: Our group has recently found a male preponderance of 86% in a population-based epidemiologic study of BEH. Others have documnted a similarly high male preponderance, even as early as in 1944 by Ingraham and Matson.

Adamsbaum et al. and Vinchon et al. also reported male preponderance in their abuse cases, 76% and 64%, respectively. Pooled together, these two studies show a male preponderance of 73%. A male preponderance has also been demonstrated in most published series on shaken baby syndrome or abusive head trauma. The large number (157) of infants in the two studies above renders it unlikely that this male dominance is coincidental. Moreover, in a national register study comprising 306 infants with SDHs, we have recently demonstrated that even in this cohort, there was a clear overrepresentation of males...

To the present author, the twins' MRI and CT scans carry no resemblance to an acutely acquired traumatic hematoma. In this context, it is of interest that the Adamsbaum et al. 44 report included a CT scan (see their Fig 1) of an allegedly shaken infant; the scan appears to show the exact features of external hydrocephalus, as defined by Maytal et al.: slightly widened lateral ventricles, a large extracerebral space, and widening of the frontal interhemispheric fissure. Girard et al. provided a detailed discussion of external hydrocephalus as a differential diagnosis to abusive head trauma.
The only plausible explanation of the combination of an increased or rapidly growing HC, increased extracerebral fluid, and enlarged ventricles is that there is an increased ICP equally distributed within the intracranial compartments, in both the extracerebral space and the ventricles. A traumatic acute or chronic SDH would normally compress the brain, including the ventricles, and if unilateral, would cause asymmetry of the ventricles and a midline shift. These characteristic features were absent in our twins and surprisingly, also in other children published as victims of shaking...

 Bilateral, extensive bleeding in several retinal layers has been regarded as a key feature of abusive head trauma. However, RH may not be pathognomonic for abusive head traumas; they can also be seen in infants not related to abuse, e.g., in a large number of healthy newborns, in infants with “macrocephaly,” after “high-risk” deliveries, following acute life-threatening events, and after cardiopulmonary resuscitation. RHs have also been documented in premature infants; contrary to the rapid resolution of the bleeding one usually sees in most newborns, the bleeding in preterms tend to be long lasting.

As for the rest of the triad, there is no high-quality evidence that proves a causal relationship between retinal bleedings and violent shaking. The problem lies again in the lack of objective proofs of shaking...

My concern in this report is that many infants appear to be diagnosed as shaken babies without any clear signs of an inflicted trauma (impact). The scientifically weak documentation of a causal relationship between the triad and the criminal act of violent shaking without impact cannot be used as judicial evidence for child abuse, beyond reasonable doubt.

When suspecting the shaken baby syndrome or abusive head trauma, external hydrocephalus should always be ruled out as a possible alternative diagnosis, as this condition may have medical findings compatible with those claimed to prove violent shaking. Unfortunately, many physicians who deal with child abuse seem unfamiliar with the manifestations of benign external hydrocephalus in children.

Monday, September 23, 2019

The risk for developing multiple sclerosis over time nearly doubles following concussion in adolescence

People who experience a concussion during adolescence are at significantly elevated risk for multiple sclerosis (MS) later in life, especially 15 years or more following their head trauma, a large retrospective study suggests.

This risk for developing MS over time nearly doubled in this population compared with people without a history of concussion.

"We also found a significantly increased risk among males and not females" starting at about 8 years post-concussion in a secondary analysis, lead study author Christopher Povolo, BSc, of the Department of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry at Western University in London, Ontario, Canada, told Medscape Medical News.

The findings were presented during a poster session here at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019. 

Previously, other investigators linked head trauma, including concussion, with MS.

For example, a Swedish case control study presented at ECTRIMS in 2017 showed adolescents with one concussion diagnosis were at elevated risk to develop MS (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.05 - 1.42; P = .008).

The study, published the same year in Annals of Neurology, revealed the risk was even greater among those with two or more concussion diagnoses (OR, 2.33; 95% CI, 1.35 - 4.04; P = .002).

In the current research, Povolo and colleagues studied the correlation between concussions in adolescents age 11 to 18 years and future MS using information from several linked Canadian databases. They assessed 391,860 people, including 97,965 diagnosed with a concussion as adolescents.sed risk of MS within 15 years of follow-up among those with a history of adolescent concussion.

In contrast, the same group had a significantly elevated risk of developing MS at 15 years or longer (hazard ratio [HR], 1.85; P = .005), according to a stratified Cox regression analysis.

A secondary analysis showed a difference by sex. Males exposed to concussion as teenagers had an increased risk for MS earlier, at 8 or more years of follow-up (HR, 1.58; P = .02). Females showed no such significantly increased risk.

Povolo and colleagues also tried a more sensitive definition for developing MS: three or more hospital or physician claims using all available years of data. In this case, all participants regardless of sex had an increased risk of MS (HR, 1.37; P = .008) if they had at least 8 years of follow-up since their concussion.

The investigators would like to expand their research in this area. "In the future, we could make it longer, or use a countrywide database," Povolo said.

"All Is Fine With Their Data" 

A main message of the research is "prevention and the risk during adolescence," Tomas Olsson, MD, PhD, a professor of neurology affiliated with the Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Hospital in Stockholm, told Medscape Medical News when asked to comment.

"So tough sports like boxing, ice hockey, American football may not be good in relation to MS, probably mainly for those having parents with MS," he added.

Olsson was coauthor of the 2017 study in Sweden that reported similar associations between adolescent concussion and risk of future MS. "Basically their findings replicate our own, which were published a couple of years ago. So I think all is fine with their data."

Support for the study was provided by a Roche Canada unrestricted, investigator-initiated trial grant and research funding from the Swedish Research Council, Knut and Alice Wallenberg foundation, and the Swedish Brain Foundation. Povolo has disclosed no relevant financial relationships. Olsson reported unrestricted MS research grants and compensation for advisory boards and/or lectures from Biogen, Genzyme, Novartis, AstraZeneca, and Allmiral.

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019: Abstract P396. Presented September 11, 2019.

Continued clinical gains in spinal muscular atrophy treated with single dose gene therapy

Children treated with single-dose gene replacement therapy (Zolgensma; Avexis, Bannockburn, IL) for spinal muscular atrophy (SMA) continue meeting development milestones in the phase 3 SPR1NT clinical trial (NCT03505099). Treatment was administered intravenously to presymptomatic children with genetically confirmed SMA  intravenously when they were age 6 weeks or less.

The SPR1NT trial showed ageappropriate major milestone gains with treatment, and prolonged event-free survival in patients with SMA Type 1. At the last follow up assessment, participants mean age was 6.6 months for a cohort of 10 children and 4.6 months for a cohort of 12 individuals. Of those who had a 6-month swallow evaluation, all had normal swallow function and were fed exclusively by mouth. Of the 22 patients being evaluated overall, all were alive and none required permanent ventilation.

All participants in the cohort of 10 children achieved or maintained a Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of more than 50; 7 had a score 60 or more and 5 had the maximum score of 64.

Of those in the cohort of 10 children, 6 were able to sit without support for at least 30 seconds at an average age of 7.6 months. Of those children, 3 (30%) were able to stand with assistance at an average age of 10.1 months.

"These updated data reinforce what we have seen in other Zolgensma studies, including survival of children with SMA Type 1 who would have in the past died or required permanent ventilation before the age of 2," said Eugenio Mercuri, MD, PhD, Department of Pediatric Neurology, Catholic University. "We are seeing further robust evidence of the potential of gene therapy to effectively halt motor neuron loss, help patients achieve motor milestones and alter the course of SMA with a 1-time treatment."

Gene therapy for cerebral adrenoleukodystrophy successful in phase 2/3 clinical trial

In a phase 2/3 study (NCT01896102) assessing efficacy and safety  of autologous CD34+ hematopoietic stem cell transplants genetically modified with a lentiviral vector encoding human adrenoleukodystrophy protein (ALDP) (Lenti-D; Bluebird Bio, Cambrige, MA), 32 boys less than age 17 years with cerebral adrenoleukodystropy (CALD) have been treated. Median follow-up time has been 21.2 months, and 15 children have completed the study and been enrolled in long-term follow-up.

Of participants who have had 24 months of follow-up after 1-time treatment, 88% (15/17) are alive and free of major functional disabilities (MFD). Most children with CALD develop MFDs, including loss of ability to communicate, cortical blindness, need for tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement.

“With the longest follow-up from the phase 2/3 starbeam study now up to 5 years, the data show that all boys with CALD who were treated with Lenti-D and were free of MFDs at 24 months continued to be MFD-free,” said David Davidson, MD, chief medical officer, Bluebird Bio. “Importantly, there were no reports of graft failure or treatment-related mortality, and adverse events were generally consistent with myeloablative conditioning. These results support the potential of Lenti-D as a treatment for CALD, which we hope may become an option for the boys and their families affected by this devastating disease.”

Cerebral adrenoleukodystrophy (CALD) is an X-linked metabolic disorder affecting 1 in 21,000 male newborns globally and causes cognitive deficits and other MFD. Caused by ABCD1 mutations, CALD alters adrenoleukodystrophy protein (ALDP) production causing very long-chain fatty acid (VLCFAs) deposits primarily in white matter and adrenal cortex.

Secondary and exploratory efficacy outcomes included changes in neurologic function score (NFS), resolution of gadolinium enhancement (GdE), and change in Loes score (an MRI measurement of white matter changes in CALD). Of the 32 patients treated, 30 had a stable NFS following treatment with Lenti-D, defined as NFS <4, without a change of >3 from baseline.

No events of acute or chronic graft vs host disease have been reported after Lenti-D treatment and there have been no reports of graft failure, cases of insertional oncogenesis, or replication competent lentivirus.

These results were announced at the 13th European Pediatric Neurology Society Congress in Athens, Greece.

Sunday, September 22, 2019

Sirolimus for Castleman disease

An otherwise healthy medical student wasn’t going to let a rare disease stop him from living life to the fullest.

Dr. David Fajgenbaum was in his third year of medical school when he got so sick he had to be hospitalized for five months. Doctors told him his liver, kidney and other organs were shutting down.

At 25 years old, Fajgenbaum was diagnosed with Castleman disease, a condition that acts like a cross between cancer and an autoimmune disorder. According to the National Organization for Rare Disorders (NORD) there are about 5,000 people diagnosed with Castleman disease in the U.S. each year, making it roughly as common as Lou Gehrig’s disease, also known as ALS.

People who have Castleman disease can experience such things as flu-like symptoms and abdominal pain to the complete failure of multiple organ systems.

“The diagnosis took about 11 weeks, and most of that time I was in the intensive care unit,” 
Fajgenbaum told Fox News. “I had a retinal hemorrhage and went blind in my left eye. I gained about 70 pounds of fluid and I was so sick that I had my last rites read to me right around the time the diagnosis was made.”...

When Fajgenbaum was diagnosed with Castleman disease there was only one drug currently approved by the U.S. Food and Drug Administration (FDA), but that he relapsed on, leaving him with no other therapy choices.

 “When I relapsed on the only drug in development and my doctor told me that there was nothing coming down the pipeline and there were no promising leads, that's when I promised my dad, my sisters, and my now wife that I would dedicate the rest of my life, however long that may be, to trying to cure this disease,” Fajgenbaum said.

In a little more than three years, Fajgenbaum relapsed four times, nearly missing death each time.

Yet with the help of chemotherapy keeping his disease at bay, Fajgenbaum was able to finish medical school and propose to his college sweetheart. But instead of starting a residency, he founded the Castleman Disease Collaborative Network (CDCN), to “drive forward research internationally but also to begin conducting laboratory work.”

“We've made a lot of progress in the last seven years since I started the CDCN and we've invested about $1 million into research, which has led to an additional $7 million in external funding from the government and from non-profits,” Fajgenbaum said.

With experts collaborating together from around the globe and a “relatively limited amount of funding” Fajgenbaum and his organization identified the first novel drug target in 25 years.

“That drug target that we identified, I actually identified it in my lab using my own samples,” said Fajgenbaum, who is also an assistant professor of medicine in the division of Translational Medicine & Human Genetics at the University of Pennsylvania. “I started myself on this drug Sirolimus about five and a half years ago and I've been in remission ever since.”

Fajgenbaum was the first patient to try Sirolimus as a treatment for Castleman disease, but he and his team will test the treatment in a clinical trial scheduled to begin at the University of Pennsylvania later this year.

Fajgenbaum, now 34 years old, with a wife and 1-year-old daughter, chronicled his journey to a cure in a new book, “Chasing My Cure: A Doctor’s Race to Turn Hope into Action.”

“I wrote this book because there's lessons that I've learned about life, lessons about living from nearly dying five times, lessons that hopefully will inspire people to turn their hopes into action and create silver linings in the midst of tough times,” Fajgenbaum said.

Wednesday, September 18, 2019

Eastern equine encephalitis

A man from Michigan went from “perfectly healthy to brain dead” in nine days after contracting a rare-mosquito-borne disease, according to a local report.

Gregg McChesney, 64, died last month after a “nine-day illness,” according to his obituary. McChesney, of Kalamazoo County, reportedly died from Eastern equine encephalitis (EEE). The disease is sometimes called Triple E, or sleeping sickness.

 “Late July, he was here at the farm helping me put docks in at the pond,” WOOD-TV reported McChesney's brother Mark as saying on Tuesday. “He was perfectly healthy, happy human being and within a matter of nine days he went from perfectly healthy to brain dead.”

He told the station that his brother had a seizure and “next thing you know, he’s in the ER and he just never came out of it.”

Several days after Gregg McChesney had died, doctors reportedly confirmed that he had the mosquito-borne illness EEE.

“Right off the bat, we were like: ‘How could this happen? What did happen?'” Mark McChesney reportedly said. “We just didn’t know and the doctors were just doing everything they could to try to say it was this or that, and they just couldn’t figure it out.”

The Michigan Department of Health and Human Services (MDHHS) tweeted on Tuesday that four additional cases of EEE have been confirmed in southwest Michigan, including two that were fatal.

Vitamin D3 supplementation treating children with chronic tic disorders

Li HH, Xu ZD, Wang B, Feng JY, Dong HY, Jia FY.  Clinical improvement following vitamin D3 supplementation in children with chronic tic disorders.  Neuropsychiatric Disease and Treatment. 2019:15 Pages 2443—2450.

Purpose: Vitamin D deficiency has been found in children with chronic tic disorders (CTDs). Our previous data showed that serum 25-hydroxyvitamin D [25(OH)D] level in children with CTDs was lower than that of the healthy controls and lower serum 25(OH)D level was associated with increased severity of the tic disorder. Thus, we intend to further verify this phenomenon and examine the effect of vitamin D3 on CTDs.

Patients and methods: In total, 120 children with CTDs and 140 normal controls were enrolled in this study, with 36/120 of those in the CTD group receiving vitamin D3 treatment for 3 months. The Yale Global Tic Severity Scale (YGTSS) and Clinical Global Impression of Severity of Illness (CGI-SI) were, respectively, used to evaluate the tic severity. High-performance liquid chromatography and tandem mass spectrometry were used to measure serum 25(OH)D level.

Results: Those children with CTDs exhibited significantly lower 25(OH)D levels than did healthy controls, and these reduced 25(OH)D levels were linked to increasing severity of tic symptoms. After treatment with supplemental vitamin D3, serum 25(OH)D level and scores of YGTSS total, motor tics, phonic tics, total tic, impairment, and CGI-SI improved significantly in children with CTDs without any adverse reactions.

Conclusion: Supplementation vitamin D3, given its low cost and excellent safety, may be an effective means of improving symptoms in certain children with CTDs.


Congenital myotonic dystrophy

Stokes M, Varughese N, Iannaccone S, Castro D. Clinical and Genetic Characteristics of Childhood-onset Myotonic Dystrophy. Muscle Nerve. 2019 Sep 14. doi: 10.1002/mus.26716. [Epub ahead of print] PubMed PMID: 31520483.


Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion. Congenital DM (CDM) presents in the first month of life, whereas individuals with infantile and juvenile DM1 have later onset of symptoms.

We performed a retrospective chart review of patients with childhood-onset DM1 seen at one of three locations in Dallas, TX between 1990 and 2018. Symptoms, disease course, cognitive features and family history were reviewed.

There were 74 patients included; CDM was diagnosed in 52. There was maternal inheritance in 74% of patients. CTG repeat number ranged from 143 to 2300. Neuropsychiatric and cognitive deficits were common. Over half of patients had GI disturbances; orthopedic complications were also common.

DM1 in children requires a multidisciplinary approach to management. Presenting symptoms vary, and repeat expansion size does not necessarily directly relate to severity of symptoms. A consensus for outcome measures is needed.

Courtesy of:

Monday, September 16, 2019

Don't laugh too loudly

Laughter may not always be the best medicine - at least not for this woman who was left with her mouth stuck open after laughing too loudly.

In a strange incident in China, a woman on a train laughed so loudly that she dislocated her jaw. According to Guancha News, the incident occurred on a train to Guangzhou South Railway Station in China's Guangdong province. Last Sunday, the woman, while travelling on the train, dislocated her jaw after laughing too loudly.

Luckily for her, there was a doctor on the train to help her out.

Ladbible reports that Doctor Luo Wensheng of Liwan Hospital responded to the appeal for medical assistance that was broadcast through the train's carriages.

"I rushed over and found the passenger unable to speak or close her mouth," said Dr Wensheng.

"She was drooling, so I initially thought she had had a stroke.

"But I took her blood pressure, then asked her some questions, and learned that she had actually dislocated her jaw."

The doctor was able to reset her jaw on his second try. "I did it while she was distracted, and luckily it went back in place," he said, according to Ladbible.

The unnamed passenger also revealed that she had earlier dislocated her jaw while vomiting during pregnancy.

Sunday, September 15, 2019

Why doctors kill themselves

TEDMED talk by Pamela Wible, MD, on the need to heal the medical profession

I love the three things that people fear the most: death, disease, and public speaking. Here's how it all started. At four, I was so talkative and bossy no babysitter would stay with me, so I tagged along with mom, a hospital psychiatrist, interviewing suicidal patients. Then she'd drop me off at the morgue with dad, a pathologist. He'd open up these big cooler doors and say, "Good morning. Is anyone home?" Then he'd introduce me to his patients as a doctor in training and leave me there talking. My first captive audience. Now, I'm a doctor and I'm speaking on behalf of thousands of doctors who couldn't be with us, but they're here in spirit. I simply ask that you open your heart to their words.

"Dear Mama and Daddy. I know you may not understand why I didn't seek help, but this choice makes sense to me. I know I would have been such a successful doctor and wife and mother. I love you so much. Your daughter, Kaitlyn." Date of death: April 11th, 2013. Cause of death: asphyxiation by helium inhalation due to untreated depression in medical school.

Each year, more than 1 million Americans lose their doctors to suicide. Across the country, our doctors are jumping from hospital rooftops, overdosing in call rooms, found hanging in hospital chapels. It's medicine's dirty secret and it's covered up by our hospitals, clinics, and medical schools.

No medical school wants to be known as the "suicide school." No hospital wants to be #1 for interns jumping from rooftops. No one wants to become a doctor to kill themselves. It's the ultimate oxymoron, the barefoot shoemaker, the starving chef, the suicidal doctor. Why? What the hell is going on and why is it such a secret? Why am I piecing this together between patients? I'm a solo family doc, yet somehow I've become an investigative reporter, a specialist in physician suicide. Why? Mostly because I can't stop asking why. Why both doctors I dated in med school died by suicide and why eight doctors killed themselves just in my sweet little town. I keep talking and writing and listening for the truth. Because I'm listening with my heart and soul 24/7, my cellphone has turned into a suicide hotline and I've received hundreds of letters from suicidal physicians.

You may be wondering why do so many people who want to help people kill themselves? Anna, a retired surgeon, writes, "Dear Pamela, I was happy, secure, and mostly unafraid until med school. I recall in vivid detail the first orientation day. Our anatomy professor stood before an auditorium filled with 125 eager, nervous, idealistic, would-be healers and said these words, 'If you decide to commit suicide, do it right so you do not become a burden to society.' He then described in anatomical detail how to commit suicide." What better way to bring shame to your alma mater than with a failed suicide? Alma mater means "kind mother," yet doctors describe med school as a soul-crushing bootcamp, a dehumanizing nightmare, my own personal Vietnam. Medical training is neither motherly nor kind.

"I love you, Mom. I'm sorry. Vincent." Date of death: August 25th, 1998. Cause of death: asphyxiation by hanging due to bullying, hazing, and sleep deprivation as an intern at a New York Hospital. Sleep deprivation is a torture technique. Fear as a teaching tool just teaches us to be afraid. I can help doctors, though there's one group I can't help: patients. From all over the country, they write me, begging me to find them caring doctors. How can we give them the care we've never received? "Dear Pamela, I definitely graduated med school with PTSD. It has changed me forever. I will never be the same again. We had two suicides and one murder, skull crushed with a bat and another serving life in prison for murdering a classmate after a delusional episode after not sleeping for a month. Please change medical education. We were so beaten down. It takes a lot for me to cry, but I cried all the time, along with everyone else, but we hid it from each other, of course."

Fact: We enter medicine with our mental health on par with or better than our peers. Suicide is an occupational hazard of our profession. "Dear Some, my family, I love you. To others who have been good friends, I love you too. This is just the end of the line for my particular train. Earth wasn't a great place for me. We'll see what else is out there. We'll miss you all. I'm sorry, for what it's worth. Love, Greg." Date of death: June 22nd, 2012. Cause of death: hemorrhage by transection of the major arteries to his wrists and ankles.

Okay, what happened here? Greg died just a few hours after being told not to follow his psychiatrist's safety plan. By who? By an agency with no physician oversight that controlled his medical license. Our medical schools, clinics, hospitals, and related agencies actually cause mental health conditions in doctors. Then they blame us and force us to release our confidential medical records, and in the end, they take our license, but it gets worse. "Dear Pamela, do you know what really hurts? The fact that anyone can look me up on the Internet and read my dirty laundry. I'm publicly shamed, punished for being ill. I will only know peace when I am gone. Maybe that's why my friend, an excellent psychiatrist, drives 200 miles out of town, pays cash, and uses a fake name to get mental health care." "Dear Pamela, you don't know how thankful I am for your article on physician suicide. I wanted to hug you after reading it. I had a really rough day. 130 outpatients, 60 emergency admissions, and a 12-hour shift. I'm a final-year internal medicine resident in one of the busiest hospitals in India. Two patients on each bed, two lying together on the floor, poverty, misery, pain all around. I've declared 12 patients dead in a day. I just don't feel death anymore. I just don't feel human. My uncle died recently. I felt nothing. This profession demands too much from us. I've thought of suicide a thousand times. The misery is too much for me."

I'm a perpetual optimist, yet after a decade of seven-minute visits at assembly line clinics, even I felt suicidal. I thought I was the only one. Then I got this crazy idea. What if I ask for help? Not from the profession that wounded me, so I asked patients. What is ideal health care? What kind of doctor do you want? They told me an ideal doctor is happy, has a big heart, and a great love for people and service. An ideal clinic is a sanctuary, a safe place, a place of wisdom with fun flannel gowns, complementary massage while waiting, where nobody is turned away for lack of money. I followed their instructions and opened their ideal clinic, the first clinic designed entirely by patients. My life is like a love fest now. My patients and I have inspired hundreds of doctors all across the country to open ideal clinics. At times, I feel like the happiest doctor in America until I get yet another call about a suicide or I read a letter like this.

"Dear Dr. Wible, I'm a patient who just got home from another insulting, degrading appointment with my doctor. I'm literally crying as I write to you." I call her. She shares her horror story. I share mine. She never knew doctors could be suicidal. She never knew she could be the victim in a cycle of abuse that began on day one of med school when her insulting doctor was still an idealistic student. How could she know that abused medical students become abused doctors who may one day abuse patients? How do we stop institutional abuse? Physician suicide hotlines inside our hospitals? Resilience training for our wiped out doctors? Meditation classes for medical students? Wait, is our goal to help victims cope with abuse or to end the abuse?

It's not costly or complicated to stop bullying, hazing, and abuse. It's been outlawed from elementary schools to fraternities. Why not health care? Medical culture and education must change, yet cultures and institutions don't change because we ask them to change, even when it's in their self-interest. They change when they're forced to change. I favor the honor system. What if those in charge are not behaving honorably? What if our medical system continues to blame, shame, and publicly humiliate its victims? Maybe it's time for us to give them a dose of their own medicine. How? By shining an embarrassing public spotlight on physician suicide.

On behalf of those we've lost and those who are barely hanging on, I want to thank you for shining your light into the darkness. Because if we all shine our lights together, there is no darkness to fear. But mostly I want to thank you for your courage, for following a fearless little four-year-old through the morgue and into the coolers to meet a few of her friends.

Inebilizumab and eculizumab for treatment of neuromyelitis optica

A new drug for the treatment of neuromyelitis optica (NMO) — an aggressive inflammatory, immune-mediated disorder of the central nervous system often confused with a severe form of multiple sclerosis, reduced clinical relapses by 73% in a phase 3 study that was stopped early for benefit.

In the N-MOmentum study, the anti-CD19 monoclonal antibody inebilizumab (Viela Bio), which works by depleting B cells, was also associated with a 63% reduction in worsening of clinical disability, and a 44% reduction in active MRI lesions.

The trial was presented this week at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019. It was also published online September 5 in The Lancet.

"Inebilizumab is one of three new agents — all with different mechanisms of action — for the treatment of NMO, all of which show very high efficacy in the condition," Bruce Cree, MD, lead N-MOmentum investigator and clinical research director at the University of California San Francisco Multiple Sclerosis Center, told Medscape Medical News. 

"All these new agents have striking degrees of efficacy, with disease activity being reduced by more than 70% — a stunning feature for any drug in medicine," he added.

"We are going to go in just a year or so from having no approved therapies for NMO to potentially having three approved therapies, each with a different mechanism of action. This is an extremely exciting time for NMO patients and those caring for them," Cree said.

The greatest issue with these new drugs likely will be their cost.

The first of the three new agents, eculizumab (Soliris, Alexion), which recently became available in the US and Europe, has been priced at around $500,000 per year, making it one of the world's most expensive pharmaceutical products.

Commenting for Medscape Medical News, ECTRIMS president Bernhard Hemmer, MD, Technical University of Munich, Germany, said: "The new NMO drugs are certainly very exciting. We will soon have three approved therapies for this condition, which is a great step forward. But we already have a drug — rituximab [Rituxan, Genentech] — which, although not specifically indicated for NMO, is widely used and appears to be effective.

"The big question is whether these new drugs, which are all likely to be very expensive, will be any better than rituximab," Hemmer said. 

"We may have patients that are stable and happy on rituximab but as it is not formally approved for NMO, we may be forced to stop a $5000-a-year drug and switch to one that costs maybe 80 or 100 times more," he added. "But we don't know if these more expensive drugs are actually any more effective."

How NMO Differs From MS

Cree explained that NMO can appear similar to multiple sclerosis in that both can cause optic neuritis and spinal cord inflammation.

"The two disorders have been confused for many years because of the clinical overlap. But the discovery of the AQP4 antibody only in patients with NMO now allows us to distinguish the two conditions," he said. "This antibody is pathogenic and NMO is thought of as an antibody-specific autoimmune disease whereas a specific pathogenic antigen for MS has not been identified."

The AQP4 antibodies target astroglial cells and this distinguishes NMO from being a classic demyelinating disorder, Cree noted. "Demyelination does occur in NMO, but this appears to be secondary to astroglial injury and complement fixation that occurs."

NMO is a rare disorder occurring in 0.5-4.4 per 100,000 people. In the US, roughly 15,000 to 16,000 individuals are estimated to be living with NMO.

"Patients are often initially diagnosed with MS, but generally don't do well on MS therapies, and progress quickly. Most can now be easily identified with the AQP4 antibody test," Cree said. 

While NMO is a severe disease, the prognosis has evolved in recent years. "Before we knew what to do with these patients, their 5-year survival was only about 68%," Cree noted. "Lesions in the cervical spinal cord interrupted the ability to breathe and patients died from respiratory failure."

More recently, off-label use of immunosuppressive drugs have had a major impact on the disease.

"The anti-CD20 antibody rituximab is now widely used for NMO, and many patients have now been spared from having such a severe disease course. Patients still die from the disease, and attacks are still associated with irreversible neurological damage, but the face of the disease has been changed by off-label use of rituximab firstly, and then later mycophenolate and azathioprine," Cree reported.  

The new crop of drugs now being reported on have been developed specifically for NMO.

N-MOmentum study

Inebilizumab, an anti-CD19 antibody, targets a wider range of B cells — thought to be the key cells in the pathogenesis of NMO — than anti-CD20 drugs, Cree said.

The N-MOmentum study enrolled 230 NMO patients (94% positive for AQP4 antibody) with an Expanded Disability Status Scale score of 8.0 or less, 174 of whom were randomly assigned to inebilizumab (two doses of 300 mg given by IV infusion on days 1 and 15) and 56 to placebo. Further doses every 6 months were planned to maintain B-cell depletion. 

The study was stopped before complete enrollment because of a clear demonstration of efficacy, and all patients were then switched to open-label active treatment. 

Results showed that 12% of those on inebilizumab had an attack vs 39% of the placebo group (hazard ratio 0.27; P < .0001). The number needed to treat was 3.73.

Worsening of disability on the EDSS score occurred in 16% of inebilizumab patients vs 34% of placebo (odds ratio 0.37; P = .0049). Inebilizumab was also associated with reductions in active MRI lesions (rate ratio], 0.56; P = .0034) and hospitalizations (RR, 0.28; P = .01).

Adverse events occurred in 72% of inebilizumab patients and 73% of placebo patients, whereas serious adverse events occurred in only 5% of the inebilizumab group and 9% of the placebo group.

Two deaths occurred in the treatment group, which the investigators believe were not related to the drug.

In The Lancet article, the investigators report that although treatment with inebilizumab reduced the risk of optic neuritis attacks (6% vs 18% with placebo), this did not result in a benefit to low-contrast binocular vision (the key secondary endpoint related to vision).

"This observation suggests that inebilizumab treatment might not reduce optic neuritis attack severity or facilitate recovery," the authors say.
Also, because the study included few AQP4 seronegative participants, the efficacy of inebilizumab in this subgroup could not be determined, they report.

"Although longer-term efficacy and safety data are needed, the positive results seen with inebilizumab and the emergence of other developmental therapies have the potential to provide a useful range of treatment options and to establish a new therapeutic landscape for NMO," the researchers conclude.

In an accompanying commentary , Elizabeth Silbermann, MD, and Dennis Bourdette, MD, Oregon Health & Science University, Portland, point out some limitations of the N-MOmentum study.

The editorialists say the follow-up safety period of 12 months is too short to adequately assess for long-term risks of opportunistic infections, secondary malignancies, or prolonged hypogammaglobinemia. "Long-term monitoring is crucial, especially in light of the two deaths reported in the study," they write.

Silbermann and Bourdette also point out that clinicians will question whether inebilizumab offers therapeutic benefit over rituximab, which is a mainstay therapy for NMO and available at a much cheaper price. But they suggest that by targeting CD19, inebilizumab might provide a more targeted attack on pathological autoantibodies while preserving overall humoral immunity.

Inebilizumab is just one of several new drugs for NMO. The others are eculizumab, a complement inhibitor; and two IL-6 antibodies — satralizumab and tocilizumab. New data on all these agents, showing high levels of efficacy against NMO, were also presented here at the ECTRIMS meeting.

"So far, eculizumab seems to have perhaps slightly better efficacy, with 90% suppression in attacks, but we have to be very cautious about cross-trial comparisons," Cree commented.

Eculizumab has recently been approved for use in NMO in both the US and Europe. Inebilizumab and satralizumab are nearing the market, and tocilizumab is already commercially available for other indications but is not licensed for NMO.

Saturday, September 14, 2019

Primary amoebic meningoencephalitis 3

A 10-year-old girl in Texas is fighting for her life after contracting a brain-eating amoeba and rare illness.

Lily Avant has been in the hospital for several days and is currently in a medically-induced coma while doctors treat swelling in her brain.

Avant first contracted Naegleria fowleri, commonly referred to as brain-eating amoeba. The amoeba is typically found in warm fresh water and soil and Avant's family believes she contracted it while swimming in a river over Labor Day weekend. On Sunday, Sept. 8, she contracted a fever, and Wendy Scott, Avant's first cousin once removed, told KXAS-TV, the NBC affiliate in Dallas, that she was seen by a doctor that night.

"They got it checked out," she said. "There were several viruses going around the school. It was assumed it's a virus because the symptoms are exactly the same, so she was sent home."

Scott said that over the course of a few days, Avant's condition deteriorated.

"She was brought into the emergency room on Tuesday when she woke up unresponsive," Scott explained. "She was eyes open, she was there, but she wasn't speaking. Nothing."

The amoeba, which enters the body through the nose and cannot be swallowed, is known to cause a brain infection called primary amebic meningoencephalitis (PAM), according to the CDC. While the amoeba itself is common, according to the Texas Department of State Health Services, PAM is rare and almost always fatal. There have only been five documented cases of survival.

"We average less than one per year in Texas. However, it is extremely serious and almost always fatal. Since it's so rare, we don't know why a few people get sick while millions who swim in natural bodies of water don't," an agency spokesperson for the Texas Department of State Health Services explained. "Because the organism is common in lakes and rivers, we don't recommend people specifically avoid bodies of water where people have contracted the illness."

Scott added that the family is doing everything they can to spread awareness about the amoeba and the potential infection.


Friday, September 13, 2019

TBCK mutations

Inspired by a colleague's patient

Zapata-Aldana E, Kim DD, Remtulla S, Prasad C, Nguyen CT, Campbell C. Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3. Eur J Med Genet. 2019 Apr;62(4):273-277.

Deleterious homozygous or compound heterozygous mutations in the TBCK (TBC1-domain-containing kinase) gene (implicated in the MTOR pathway) produce profound hypotonia, global developmental delay, facial dysmorphic features, and brain abnormalities. The disorder has been named "infantile hypotonia with psychomotor retardation and characteristic facies-3" (IHPRF3). Here we present two sisters with a novel mutation in TBCK (NM_001163435.2: c.753dup; p.(Lys252*)) who have this ultrarare disorder. We have reviewed the literature on the 33 previously reported cases to provide a characterization of this emerging phenotype. Pathogenic mutations in TBCK have a predominant involvement of the Central Nervous System with a progressive pattern, leading to the conclusion where pathogenic mutations of the said gene lead to a progressive neurodegenerative disease. This report adds novel mutation and features to this complex phenotype. Further investigation is required to understand the pathogenesis of TBCK.

Mandel H, Khayat M, Chervinsky E, Elpeleg O, Shalev S. TBCK-related intellectual disability syndrome: Case study of two patients. Am J Med Genet A. 2017 Feb;173(2):491-494.

There is a significant level of genetic heterogeneity underlying the phenotype of nonspecific hypotonia with severe intellectual disability. Exome sequencing has proven to be a powerful tool for identifying the underlying molecular basis of such nonspecific, abnormal neurological phenotypes. Mutations in the TBCK gene have been reported associated with very poor, if any, psychomotor development, poor speech, and inability to walk independently. We describe the long-term phenotypic evolution of a severe nonspecific neurodevelopmental disorder in two siblings born to an Arab-Moslem family living in northern Israel. Exome sequencing led to identification of a novel homozygous mutation: c.1854delT in the TBCK gene. Abnormal elevated β-HCG was found in the maternal serum during the two pregnancies, a finding that has not been reported before. These individuals present with severe intellectual disability, no speech, hypotonia, convulsions, and lack of any independent daily skills.

Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, Nguyen A, Leuzzi V, Webster R, Pizzuti A, Marvin CT, Ishak GE, Ardern-Holmes S, Richmond Z; University of Washington Center for Mendelian Genomics, Bamshad MJ, Ortiz-Gonzalez XR, Tartaglia M, Chopra M, Doherty D. Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. Am J Hum Genet. 2016 Apr 7;98(4):772-81.

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126()] and c.1363A>T [p.Lys455()]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

Thursday, September 12, 2019

Psychopathy self-discovery

No one told James Fallon he was a psychopath.

Or maybe they had. When he was young, he'd heard again and again from people in positions of authority – a priest, a professor, a friend's father – that there was something off about him. Something dark that they couldn't quite name. But Fallon brushed it off each time.

Many years later, as a professor of psychiatry at the medical school of the University of California, Irvine, Fallon discovered his psychopathic mind for himself.

"I'm a little bit of a snake, but I'm not really a bad guy," Fallon told Out in the Open host Piya Chattopadhyay. "But you don't want to be close to me."

Fallon made the discovery by accident.

In the late 1980s, the university got a PET scanner. Accused murderers were coming into the school to get brain scans done as part of their defences. "They'd come in tied up in manacles," Fallon said. "We'd have these SWAT teams all over the roofs of the medical school."

Over the decades that followed, the school accumulated these brain scans. And as Fallon studied them, he was noticing patterns. Certain areas that light up in normal brains were dark.

"So I said, my god, there's something here." He gave talks on his findings.

Bizarre coincidences

Meanwhile, two other events in his life were converging. "All this happened at the same time," he said. "It was very bizarre." 

The first coincidence came when his mother told Fallon about a historical book on his father's family. "And there's all these nasty guys in there," he said. People who weren't so different from the murderers he'd been studying.

Thomas Cornell Jr., an early colonial settler who was convicted and hanged for killing his mother, was a direct ancestor. And Lizzie Borden, who was famously tried for the axe murders of her father and stepmother in the late 19th century, was a distant cousin.

The second coincidence came through Alzheimer's research Fallon was conducting. The team had completed brain scans of patients. But they needed a control group. So Fallon put his family members, including himself, under the machines.

And as he was flipping through the pile of his family's scans, he saw one that looked identical to the killers he'd been studying.

"I said, okay guys, really funny. Ha ha." He thought the lab technicians had played a joke on him, slipping a psychopath's scan into the pile with his family. They assured him that this was no joke.

"I said, whoever this person is shouldn't be walking around in society." The psychopathic markers were all there. The parts of the brain that regulate conscience, emotional empathy and inhibition were turned off. "This is probably a very dangerous person."

"Well, I peeled back the tape over the name, and there it was. It was my name."

He laughed it off. He still didn't believe it. He'd never been a violent guy. He was married with kids. He had plenty of friends, and a successful career.

But when he got home and told his wife about it, she said to him: "It doesn't surprise me." 

He came around to the idea gradually.

"I just started asking everybody, what do you think of me? I started with my wife, my sister, my brothers, my parents. On and on. All the people close to me, including psychiatrists who I'd worked with for years who really knew me well. They all said – except for my mother, who said 'No, you're a nice boy' – everybody else said, we've been telling you for decades, for years, that you do psychopathic things."

He'd been emotionally unavailable. Reckless. Manipulative. Getting by on charm and what he calls "cognitive empathy" – the ability to understand what others are feeling, without actually feeling it himself.

Assessments by his colleagues were what really convinced him. His brain scans, genetic markers and behaviours all pointed toward borderline psychopathy. If a cold-blooded killer is formed through both nature and nurture, Fallon's nature suggested he was capable of terrible things. Perhaps a lack of childhood trauma had prevented him from acting on his violent instincts, he thought.

'What would a good guy do?'

Fallon now describes himself as a "pro-social" psychopath. He's not out to prey on people. And his psychopathic tendencies are relatively benign.

Driven by what he describes as ego, Fallon put a challenge to himself: try pretending to be a nice, normal, emotionally connected guy. He'd start with his wife.

"Every time something came up where I was interacting with her socially, I just asked myself, 'What would a good guy do?'" Whereas in the past he might have made up an excuse to, for example, ditch her uncle's funeral and head down to the beach bar, he was now going to try doing right by her, despite his nature.

When she caught on that a sudden kindness had come over him, he assured her: "Don't take it seriously. It's just an experiment." But nice is nice. She didn't seem to mind.

"Strangers are very safe around me," he said. "It's when you get close to me that it's a little more dangerous, because I'm going to get you to do something you don't want to do.

"So, I'm trying to control that. I figure if I tell everybody I have this, then I can't get away with anything any more."