Friday, October 18, 2019

Cortical stimulation-induced seizures versus spontaneous seizures for epilepsy surgery planning


Cuello Oderiz C, von Ellenrieder N, Dubeau F, Eisenberg A, Gotman J, Hall J, Hincapié AS, Hoffmann D, Job AS, Khoo HM, Minotti L, Olivier A, Kahane P, Frauscher B. Association of Cortical Stimulation-Induced Seizure With Surgical Outcome in Patients With Focal Drug-Resistant Epilepsy. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464. [Epub ahead of print]

Abstract

IMPORTANCE:
Cortical stimulation is used during presurgical epilepsy evaluation for functional mapping and for defining the cortical area responsible for seizure generation. Despite wide use of cortical stimulation, the association between cortical stimulation-induced seizures and surgical outcome remains unknown.

OBJECTIVE:
To assess whether removal of the seizure-onset zone resulting from cortical stimulation is associated with a good surgical outcome.

DESIGN, SETTING, AND PARTICIPANTS:
This cohort study used data from 2 tertiary epilepsy centers: Montreal Neurological Institute in Montreal, Quebec, Canada, and Grenoble-Alpes University Hospital in Grenoble, France. Participants included consecutive patients (n = 103) with focal drug-resistant epilepsy who underwent stereoelectroencephalography between January 1, 2007, and January 1, 2017. Participant selection criteria were cortical stimulation during implantation, subsequent open surgical procedure with a follow-up of 1 or more years, and complete neuroimaging data sets for superimposition between intracranial electrodes and the resection.

MAIN OUTCOMES AND MEASURES:
Cortical stimulation-induced typical electroclinical seizures, the volume of the surgical resection, and the percentage of resected electrode contacts inducing a seizure or encompassing the cortical stimulation-informed and spontaneous seizure-onset zones were identified. These measures were correlated with good (Engel class I) and poor (Engel classes II-IV) surgical outcomes. Electroclinical characteristics associated with cortical stimulation-induced seizures were analyzed.

RESULTS:
In total, 103 patients were included, of whom 54 (52.4%) were female, and the mean (SD) age was 31 (11) years. Fifty-nine patients (57.3%) had cortical stimulation-induced seizures. The percentage of patients with cortical stimulation-induced electroclinical seizures was higher in the good outcome group than in the poor outcome group (31 of 44 [70.5%] vs 28 of 59 [47.5%]; P = .02). The percentage of the resected contacts encompassing the cortical stimulation-informed seizure-onset zone correlated with surgical outcome (median [range] percentage in good vs poor outcome: 63.2% [0%-100%] vs 33.3% [0%-84.6%]; Spearman ρ = 0.38; P = .003). A similar result was observed for spontaneous seizures (median [range] percentage in good vs poor outcome: 57.1% [0%-100%] vs 32.7% [0%-100%]; Spearman ρ = 0.32; P = .002). Longer elapsed time since the most recent seizure was associated with a higher likelihood of inducing seizures (>24 hours: 64.7% vs <24 hours: 27.3%; P = .04).

CONCLUSIONS AND RELEVANCE:
Seizure induction by cortical stimulation appears to identify the epileptic generator as reliably as spontaneous seizures do; this finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy as the need to record spontaneous seizures is reduced.
_________________________________________________________________________

Some epileptologists already use cortical stimulation to help define the focal point for surgery, Dr. Frauscher told Neurology Today, but typically patients are put in an EEG monitoring unit to wait for spontaneous seizures to happen so that doctors can pinpoint the seizure-onset zone. She said it may take days, or even weeks, for patients to have a spontaneous seizure, an approach that may be costlier due to lengthy hospital stays and riskier because the implanted electrodes need to remain in place longer.

“These long stays can be inconvenient for patients and expensive for health care systems,” said Dr. Frauscher. “Using induced seizures in this way could reduce the length of hospital stays to just 48-72 hours, which is a game-changer for patients and health care providers.”

The new study was not a randomized trial involving a head-to-head comparison of the two approaches, but it involved a fairly large cohort and produced encouraging results.

Several independent epilepsy experts interviewed by Neurology Today said the new results could cause a shift in the way candidates for epilepsy surgery are evaluated, though they cautioned that the new study included only patients with focal drug-resistant epilepsy and among that group, only those who met the study's strict inclusion criteria. Whether the findings would apply to a broader patient population remains a question.

“I think it is an intriguing study, and it is an area that is relatively understudied despite the fact that intracranial monitoring has been done for years,” said David C. Spencer, MD, FAAN, professor of neurology at Oregon Health & Science University (OHSU) and director of the OHSU Epilepsy Center. “If it is further validated, I think that localization by cortical stimulation could be a very helpful complement to standard assessments. If we could get the same quality of data in a shorter period, it could be positive for both the patient and for medical costs and medical care in general.”…
Seven patients in the total cohort had cortical stimulation-induced seizures but no spontaneous seizures during their presurgical workup.

“That surgical outcomes in this group did not differ from the outcome of the total group suggested that cortical stimulation might be extremely valuable to obtain induced electroclinical seizures and might be used as a substitute for the recording of spontaneous seizures,” the researchers said…
They said that the failure to stimulate seizures in a sizable portion of the 103 patients may be attributed to the fact that “the electrodes were probably placed in a cortical area of high neuronal threshold incapable of sufficiently activating the epileptic network to induce seizures.”

“The absence of cortical-induced seizure might represent a red flag, suggesting the true epileptic zone was missed or only partially sampled,” the study authors said…

Joon-Yi Kang, MD, assistant professor of neurology in the epilepsy center at Johns Hopkins Hospital, said the new report is “very exciting” because “there has always been this question, ‘Can we incorporate information about stimulation induced seizures into our surgical plan?” She said that epilepsy doctors in European epilepsy centers have traditionally been using the approach longer than doctors in the US, who consider spontaneous seizure monitoring the gold standard.

Dr. Kang said that while cortical stimulation is frequently used for functional mapping in epilepsy pre-surgical evaluations, “it hasn't been clear whether stimulation is as good as monitoring for spontaneous seizures, when it comes to pre-surgically defining the target for resection. This paper shows that, yes, it may be as good as passively monitoring patients for seizures in some cases.”

Chrystal M. Reed, MD, PhD, assistant professor of neurology at Cedars-Sinai Medical Center in Los Angeles, said a downside to spontaneous seizure monitoring in an EEG unit is that it may take considerable time for a seizure to occur and show changes on an EEG, even though the patients has been tapered off their antiseizure medication.

“A prolonged period of waiting in an EEG monitoring unit is both time consuming and costly and may increase the risk of infection from having electrodes implanted in the brain for a long time,” she said.

While most patients tend to have spontaneous seizures rather quickly, “some patients are in the monitoring unit for weeks or months,” until a seizure occurs, Dr. Reed said. She said merely taking a patient out of their normal environment may diminish the likelihood of a seizure because the everyday stress that can make patients vulnerable to seizures is absent.

https://journals.lww.com/neurotodayonline/Fulltext/2019/10170/Cortical_Stimulation_Induced_Seizures_May_Be_as.8.aspx

Mosaic trisomy 9


It's true: Not all heroes wear capes. Some are just 3 months old and are already in the fight of their lifetimes. That's the case for Randy James Ahlers - "RJ" - and his parents, Angel and KC Ahlers of Toledo.

By all accounts, Angel's pregnancy was fairly routine and there were no signs that the Ahlers' baby would be anything but healthy. So, it was a shock when RJ was born and doctors discovered he had not one, but two very rare conditions.

The Ahlers' son has Agenesis of the Corpus Callosum or AgCC, and Mosaic trisomy 9. With AgCC, the center of the brain that facilitates communication of the two hemispheres is underdeveloped. About 1 in 4,000 people are born with this. Mosaic trisomy 9 is a rare chromosomal anomaly syndrome. This happens to 1 in 4 million babies.

"Twenty minutes after he was born, the doctors came in and said they wanted an emergency neurological team to look at our son," KC Ahlers said. "They took him from us, and my wife and I were terrified. About an hour and a half later they brought RJ back to us and said the doctor would be in soon to talk with us.

"We were informed that this could mean RJ could have issues seeing, seizures, and mild to severe mental disabilities, and the potential for intellectual disabilities, facial dysmorphism, congenital heart defects, urogenital defects, skeletal defects, and central nervous system defects," KC Ahlers said.

The Ahlers were faced with some very hard to hear facts. Only 50% of children born with the conditions RJ has reach the age of 2. But, the Ahlerses are undaunted - they are exploring every possible option to help their rare son beat the odds. This comes at a steep cost, however. They already have more than $3,000 in accumulative medical bills for his condition from six different specialists, none of whom has ever worked with a Trisomy 9 Mosaic patient. 

"He has medical tests he needs that we have not done yet because we cannot afford them. A DNA/RNA genetic testing of all major organs could locate the areas he has the mutated Trisomy 9. This will let us know what to expect," KC Ahlers said. "This test alone is $10,000 and insurance claims it's not medically necessary. Plus, we have the cost of any future tests and therapy he will need, which is a lot.

"Every day we wake up terrified that this is the day our child will have a hole present itself in one of his organs and bleed out and die. Every cry he makes, we have to worry, 'Is this that moment?' It's like walking in a minefield."

Angel Ahlers says they are willing to do anything for their son, even as medical bills are bankrupting them. They do have medical insurance, and she is a nursing assistant at St. Anne's, but many of RJ's medical tests are being said to be not medically necessary.  

"Just because he is different does not detract our love for him. He has a condition that is rare, and add the AgCC and now he is the rarest of the rare," she said. "We love him so much as the precious, one-of-a-kind treasure that he is, like a 25-carat diamond. How many of those are out there? Same as our son."

The Ahlers family absolutely loves comic books and Halloween - KC and Angel were married on Halloween - and they are combining the two in an effort to raise money to hopefully afford the tests that could extend RJ's odds.

This Saturday, the family and friends will don superhero costumes in honor of their tiny hero, and are asking the community to help fill the buckets for RJ's tests and treatments. They'll be unmistakable in their Marvel and DC Universe costumes at the intersection of Laskey, Tremainsville and Douglas roads in Toledo from 9 a.m. to 5 p.m. If you would like to help, but won't be out and about Saturday, a Go Fund Me has also been established and can be accessed here. 

"He's our fighter," Angel said. "He's our miracle and our gift from God."

Tuesday, October 15, 2019

The first drug developed for just one person


Eight-year-old Mila Makovec was diagnosed with a rare, usually fatal neurological disorder in 2016, but now—thanks to a "custom" drug that researchers developed specifically for her—many of Mila's symptoms have been halted or reversed, according to a report published Wednesday in the New England Journal of Medicine.

Mila's condition

Mila's symptoms began when she was three years old. Previously a healthy young girl, she began to suffer from frequent seizures—as many as 30 per day, lasting up to a few minutes each. As the disease progressed, she lost her eyesight, became unable to stand on her own, and ultimately needed a feeding tube.

In December 2016, Mila was diagnosed with Batten's disease, a rapidly progressing neurological disorder. However, Mila's case was unusual, according to doctors. Batten's disease is recessive, which means it occurs when a patient inherits two mutated versions of the MFSD8 gene—but Mila has only one mutated gene. The other was apparently normal, which should have left her unaffected.

Timothy Yu and colleagues at Boston Children's Hospital examined Mila's intact MFSD8 gene, and in March 2017, they found it contained a DNA error that interfered with the production of a key protein.

The good news was that Yu thought he could make a custom piece of RNA to fix the problem. But such a step would be extraordinarily expensive. To support the necessary research, Mila's mother established Mila's Miracle Foundation, and she managed to raise $3 million.

Yu's team was able to develop a new drug, which they called "milasen," after Mila. They tested it in rodents and consulted FDA, which in January 2018 permitted doctors to give the drug to Mila.

Doctors administered the drug via spinal tap so it could go directly into Mila's brain. Within a month, Mila started improving, according to her mother, Julia Vitarello. Mila started having fewer and shorter seizures and now rarely needs her feeding tube. Instead, she's able to eat pureed foods. Mila still can't stand by herself, but when she's held, her neck and back stay straight.

According to the New York Times, Mila remains very disabled, and she has lost the last few words of her vocabulary. Vitarello acknowledged that milasen won't cure Mila, but added that Mila was seven when she received her fist dose. "What if the next Mila is treated when she is four or five?" Vitarello asked, adding that milasen's development "is opening up an entirely new treatment path."

Experts express concern over personalized medicine

Milasen is believed to be the first drug developed for just one person, but Yu and colleagues acknowledged that they're unsure what may come next.

According to Rachel Sher, VP of regulatory and government affairs at the National Organization for Rare Disorders, there are more than 7,000 rare diseases, more than 90% of which have no treatment approved by FDA. That means there may be thousands of patients in a similar situation as Mila, and there aren't enough researchers to design customize drugs for all of them, the Times reports.

And even if there were enough researchers, cost would be a concern, Steven Joffe, professor of medical ethics and health policy at the University of Pennsylvania, said. The government wouldn't pay for the drugs, nor would drug companies or insurers, Joffe said. "Unfortunately, that leaves it to families. It feels awfully uncomfortable, but that is the reality."

Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, expressed concern about how a custom drug's efficacy might be evaluated. As for cost, Woodcock said, "We have to figure it out, collectively, because these people are suffering—many of them children. If we have the scientific ability to develop treatments for these rare diseases, we should find a way to make the financial side of this work" .


Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. Patient-Customized
Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019 Oct 9.
doi: 10.1056/NEJMoa1813279. [Epub ahead of print]

Abstract
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).


Courtesy of a colleague

A 10-year-old boy with fainting spells and seizure activity


Shatha M. Khatib. A 10-Year-Old Boy With Fainting Spells and Seizure Activity - Medscape - Sep 25, 2019.
https://reference.medscape.com/viewarticle/884107_1

A 10-year-old boy with a history of multiple fainting spells is brought to an outpatient pediatric clinic by his parents. These spells are sometimes complicated by generalized tonic-clonic "seizurelike" activity.

The patient first started experiencing these attacks 8 months ago. His mother has noticed that the fainting most often occurs either in the early morning, after the sounding of an alarm clock, or during some type of sports activity. The child states that the seizures occur without warning, and they are sometimes associated with urinary incontinence or vomiting. According to the patient's family, the child remains unconscious for about 1 minute, after which he awakens abruptly, with no evidence of confusion and full recall of all of the events preceding the attack. 

The patient was born full-term, without any complications. He has no chronic medical conditions and is not on any medications. As a result of experiencing similar symptoms, his father was diagnosed with epilepsy and started on treatment at age 8 years; however, the father has been without treatment and has not had any attacks since age 14 years. The patient's paternal uncle was also diagnosed with epilepsy at age 10 years; he died during a seizure at age 19 years. The patient has an 8-year-old brother who is well, with no history of seizures or fainting spells.

Physical Examination and Workup

Upon physical examination, the patient is a well-appearing and well-developed boy whose weight and height are in the 50th and 60th percentiles, respectively. His oral temperature is 98.6°F (37°C). His pulse is strong at 66 beats/min, with a regular rhythm. His blood pressure is 105/65 mm Hg, and his respiratory rate is 15 breaths/min.

Head and neck examination findings are normal. The lungs are clear to auscultation, and normal respiratory effort is noted. Cardiac auscultation reveals normal S1 and S2 heart sounds, and no audible murmurs, rubs, or gallops are heard. His abdomen is soft, with no tenderness. No organomegaly is detected. The neurologic examination reveals intact cranial nerves and intact speech. Sensory and motor functions are normal in all extremities, without any pronator drift. The deep tendon reflexes are brisk and symmetric throughout. The patient's Romberg sign is negative, and his gait is stable.

The laboratory analysis, including a complete blood cell count and a basic metabolic panel with serum electrolytes (including calcium and magnesium), is normal. Chest radiography and brain CT findings are also normal. An ECG is obtained (Figure).


The patient's ECG showed a prolonged QT interval (Figure) The corrected QT (QTc) was 0.56 second. In addition, a biphasic T wave was seen in the precordial leads. His father's ECG  also showed a prolonged QT interval (QTc, 0.55 second) and a high-amplitude, rounded T wave in leads V2 and V3. On the ECG of the patient's 8-year-old brother, the QTc was 0.52 second, and T/U wave abnormalities in leads V2 and V3 were also detected.

In the context of the patient's history of recurrent fainting and the family history of "seizures" and sudden death, the prolonged QT intervals noted were very suggestive of intermittent ventricular arrhythmias caused by congenital long QT syndrome (LQTS).

LQTS is an electrical disease of the ventricular myocardium that is characterized by prolonged ventricular repolarization, which results in prolongation of the QT interval on the surface ECG and an increased risk for sudden death. It is characteristically associated with the potentially life-threatening cardiac arrhythmia known as torsade de pointes, which is a form of polymorphic ventricular tachycardia.

A prolonged QT interval may be acquired (usually resulting from drugs or electrolyte disturbances) or congenital. The congenital form is caused by mutations in the gene coding for the cardiac potassium, sodium, or calcium ion channels; about 400 mutations in 10 gene loci have been identified.  The distinct genetic types are designated LQT1-LQT10. LQT1, LQT2, and LQT3 account for over 90% of cases of LQTS, with some estimated prevalences of 45%, 45%, and 7%, respectively.  The specific genotype influences the clinical course, the kinds of triggering events that may initiate arrhythmias, the prognosis, and the recommended form of treatment. An underlying genetic predisposition has been identified in some patients with the acquired form of LQTS.

Traditionally, congenital LQTS has been characterized as two clinical entities:

Romano-Ward syndrome, which is inherited in an autosomal dominant fashion and only has cardiac manifestations.

Jervell and Lange-Nielsen syndrome, which is inherited in an autosomal recessive fashion and is associated with sensorineural deafness.

Most of the epidemiologic and clinical data on congenital LQTS come from reports from the International LQTS Registry. The registry, which began in 1979 and is still ongoing, is a major source of data on the incidence, natural history, and prognosis of patients with congenital LQTS.[4]
The incidence of congenital LQTS is difficult to determine, but it is estimated to be 1 case per 2500-10,000 population, with most estimates around 1 case per 5000 population.[5] The range is broad because a large number of cases go undiagnosed; about 20%-50% of affected patients may not demonstrate QT prolongation on resting ECG. Technical difficulties and methodological controversies in accurately measuring the QT interval are in part to blame. It is nonetheless one of the most common causes of autopsy-negative, unexplained sudden death.

Women are more commonly affected than men. Patients with congenital LQTS usually present in childhood, adolescence, or early adulthood, and they usually present with palpitations, syncope or near syncope, seizures, or cardiac arrest. Syncopal episodes associated with secondary seizures may be misdiagnosed as primary seizure disorders. The seizures are probably secondary to hypoperfusion of the brain during arrhythmic events.

Cardiac dysrhythmias can be initiated by an external trigger, such as emotional stress, exercise, or sudden loud noises (ie, an alarm clock or telephone); however, this is not always the case. Ventricular arrhythmias may also occur during sleep, which is commonly seen in patients with the LQT3 genotype. In fact, the kind of triggering event is often linked to the underlying mutation, with certain triggers more commonly associated with certain genotypes.

As many as 10% of patients are only diagnosed with LQTS at the time of sudden death.[6] Mortality can be as high as 70% in patients who remain untreated over a 10-year period.[3] This emphasizes the importance of presymptomatic diagnosis and treatment. Important clues indicating that a patient may have LQTS include abnormal ECG findings, a family history of unexplained death, or hearing loss (which is present in around 4% of patients with LQTS).

In patients with suspected congenital LQTS, the initial evaluation should be directed at calculating the QTc interval on a resting ECG. The QTc interval is the QT interval corrected for heart rate because, under normal physiologic circumstances, the actual measured QT interval adjusts with the heart rate; in other words, it is longer at slower rates and shorter at faster rates. QTc is calculated by dividing the measured QT by the square root of the R-R interval (the Bazett formula), both of which are measured in seconds…

A scoring system for the diagnosis of congenital LQTS was established in 1985 by Schwartz and colleagues  and revised in 1993 but still serves as the best guide for clinicians today. It incorporates the ECG criteria (the measured resting QTc interval, history of torsade de pointes, presence of T-wave alternans or notched T wave on ECG, and low heart rate for age), the clinical criteria (syncope or congenital deafness), and family history (family members with definite LQTS or unexplained sudden death at < 30 years of age). Points ranging from 0.5 to 3 are assigned to each of the above criteria, and the points are added to calculate the LQTS score. Depending on the patient's score, the probability of having LQTS is rated as low (< 1 point), intermediate (2-3 points), or high (≥ 4 points). Additional testing, such as cold-water facial immersion or exercise testing, may be applied in patients in whom the diagnosis is still unclear.

Genetic testing for congenital LQTS is now available in specialized centers; however, the practical application of genetic testing is limited because of the complexity and heterogeneity of congenital LQTS. In addition, as many as 25% of patients have unknown mutations; therefore, a negative test does not exclude the disease. Once an index case with congenital LQTS is identified, evaluation needs to extend to all first-degree relatives, and treatment must be established where indicated.
The guidelines published by the American College of Cardiology, the American Heart Association, and the European Society of Cardiology consider "lifestyle modifications," defined as the contraindication of competitive sports and of all drugs known to prolong the QT interval, as a class I recommendation and an important strategy for the prevention of fatal arrhythmia in patients with congenital LQTS. The mainstay of medical treatment for LQTS is the use of beta-blockers.  Beta-blockers shorten the QT interval, which decreases the risk for torsade de pointes arrhythmia and reduces the incidence of syncope and sudden cardiac death. They are effective in approximately 70% of patients…

Because of the appreciable risk for torsades de pointes arrhythmia and sudden cardiac death without treatment, all symptomatic patients with congenital LQTS should be treated. Treating asymptomatic patients is more controversial; however, because sudden cardiac death can be the first manifestation of LQTS, a safe approach would be to treat even asymptomatic patients with at least medical therapy.

Thursday, October 10, 2019

Subcortical heterotopic gray matter brain malformations


Oegema R, Barkovich AJ, Mancini GMS, Guerrini R, Dobyns WB. Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals. Neurology. 2019 Oct 1;93(14):e1360-e1373.

Abstract

OBJECTIVE:
To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.

METHODS:
SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.

RESULTS:
Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).

CONCLUSION:
This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Lacosamide in pediatric patients with focal seizures


Farkas V, Steinborn B, Flamini JR, Zhang Y, Yuen N, Borghs S, Bozorg A, Daniels T, Martin P, Carney HC, Dimova S, Scheffer IE; SP0969 Study Group. Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures. Neurology. 2019 Sep 17;93(12):e1212-e1226.

Abstract

OBJECTIVE:
To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures.

METHODS:
In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance.

RESULTS:
Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%).

CONCLUSIONS:
Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures.

CLINICALTRIALSGOV IDENTIFIER:
NCT01921205.

CLASSIFICATION OF EVIDENCE:
This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

Monday, October 7, 2019

Posterior reversible encephalopathy syndrome in children


Darwish AH. Posterior Reversible Encephalopathy Syndrome in Children: A Prospective Follow-up Study. J Child Neurol. 2019 Sep 30:883073819876470. doi:10.1177/0883073819876470. [Epub ahead of print]

Abstract

AIM:
To evaluate clinical and radiologic presentation, and neurologic outcome of pediatric posterior reversible encephalopathy syndrome (PRES).

PATIENTS AND METHODS:
The study included 24 children (14 males and 10 females) diagnosed with PRES who were prospectively followed for 2 years. They were evaluated using Wechsler Intelligence Scale, electroencephalograph (EEG), and brain magnetic resonance imaging (MRI).

RESULTS:
The mean age of the studied patients at the time of diagnosis of PRES was 6 years (±2.2). Chemotherapy for cancer represented 66.7% of the causes of PRES in the studied children, followed by renal disorders and immunosuppressive agents for hematopoietic stem cell transplantation. Twenty-seven attacks of PRES were reported as 3 children developed a second attack of PRES. Normal intelligence quotient was found in 95.8% of studied children after PRES. Residual abnormalities in follow-up MRI were demonstrated in 3 children. Epilepsy and residual MRI lesions were reported in 2 of the 3 children with recurrent PRES. Residual lesions in follow-up MRI and epilepsy were more significantly reported after recurrent PRES (P < .05).

CONCLUSIONS:
Neoplastic, renal disorders and hematopoietic stem cell transplantation represent the main disorders associated with PRES in children. Chemotherapeutic drugs, immunosuppressants, and hypertension are the main risk factors for pediatric PRES. The outcome of pediatric PRES is good, but long-term neurologic sequelae can occur, mainly epilepsy and residual MRI abnormalities. Recurrence of PRES is infrequently reported in children receiving chemotherapeutic or immunosuppressive drugs. Recurrent PRES is a risk factor for long-term neurologic sequelae.

Courtesy of:  https://www.mdlinx.com/journal-summaries/pres-chemotherapy-neurologic-sequelae-outcome/2019/10/03/7581028?spec=neurology

Risk factors for perinatal arterial ischaemic stroke


Sorg AL, von Kries R, Klemme M, Gerstl L, Weinberger R, Beyerlein A, Lack N, Felderhoff-Müser U, Dzietko M. Risk factors for perinatal arterial ischaemic stroke: a large case-control study. Dev Med Child Neurol. 2019 Sep 5. doi:10.1111/dmcn.14347. [Epub ahead of print]

Abstract

AIM:
To identify maternal, obstetric, and neonatal risk factors related to perinatal arterial ischaemic stroke (PAIS) diagnosed within 28 days after birth and to understand the underlying pathophysiology.

METHOD:
For case and control ascertainment, we used active surveillance in 345 paediatric hospitals and a population-based perinatal database for quality assurance of hospital care. We analysed complete cases of PAIS using logistic regression. Multivariate analysis was guided by a directed acyclic graph.

RESULTS:
After exclusion of records with missing data, we analysed 134 individuals with PAIS and 576 comparison individuals. In univariate analysis, male sex, preterm birth (<37wk gestational age), small for gestational age (SGA), low umbilical artery pH (<7.1), low 5-minute-Apgar score (<7), multiple pregnancies, hypoxia, intubation/mask ventilation, nulliparity, Caesarean section, vaginal-operative delivery, chorioamnionitis, and oligohydramnios were associated with an increased risk. Mutual adjustment yielded male sex (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.20-2.73), multiple birth (OR 3.22; 95% CI 1.21-8.58), chorioamnionitis (OR 9.89; 95% CI 2.88-33.94), preterm birth (OR 1.86; 95% CI 1.01-3.43), and SGA (OR 3.05; 95% CI 1.76-5.28) as independent risk factors.

INTERPRETATION:
We confirmed the increased risk in males and the role of chorioamnionitis and SGA for PAIS, pointing to the importance of inflammatory processes and fetal-placental insufficiency. Multiple birth and preterm birth were additional risk factors.

WHAT THIS PAPER ADDS:
Chorioamnionitis and small for gestational age (SGA) precede perinatal arterial ischaemic stroke (PAIS). Chorioamnionitis and SGA are independent risk factors for PAIS. Inflammatory processes and fetal-placental insufficiency are the likely underlying mechanisms. Multiple birth and preterm birth are additional risk factors.

Courtesy of:  https://www.mdlinx.com/journal-summaries/perinatal-arterial-ischaemic-stroke-pathophysiology-hypoxia/2019/09/12/7578095?spec=neurology

Brain tumor presenting as focal epilepsy

https://www.youtube.com/watch?v=GV_oZcQzPQ8

Sunday, October 6, 2019

Childhood stroke


When single mom Hayley Clark found her 10-year-old daughter collapsed on the bathroom floor, she never suspected that a stroke was the cause of her “healthy” daughter’s medical scare.

Gracie Whittick, 10, suffered a stroke on Sept. 26 as she was getting ready for school, her mom told South West News Service (SWNS), a British news agency.

"It was all completely out of the blue. There were no warning signs at all, she was fine before. She was getting ready for school and the next second she was on the floor,” she recalled.

"It happened in seconds. I thought she had fainted on the floor and I had to get her to come around. The right side of her face was drooping. She couldn’t lift her arms, move her arms or legs,” she continued, noting she immediately called an ambulance.

Doctors at Queen Elizabeth Hospital King’s Lynn in Norfolk, England, later told confirmed a blood clot on the left side of Gracie’s brain had caused the stroke. The young girl underwent a three-hour surgery to remove 96 percent of the clot. It’s unclear at this time what caused the clot.

"The whole thing is really surreal. Doctors still don't know why it happened; she had a heart scan and that has come back as normal,” she said.

The stroke impacted the right side of her body. The 10-year-old, who is right-handed, now has trouble using her right arm. She’s also struggling with memory issues. She began walking again recently, but tires quickly and will sometimes resort to a wheelchair, her mother said.

"She keeps getting really confused and she is getting frustrated with it all,” she said.

“The whole thing is really surreal. To me, a stroke is an old people thing. It isn’t something that happens to a healthy 10-year-old girl,” Clark added, noting Gracie enjoys dancing and gymnastics.

Though relatively uncommon, pediatric strokes can and do occur. According to the Children’s Hospital of Philadelphia, pediatric stroke affects an estimated 12 in 100,000 children under the age of 18.  However, there may be more cases of pediatric stroke as it is “thought to be frequently undiagnosed or misdiagnosed,” says a 2011 medical review on pediatric stroke.

Children most at risk are those with sickle cell anemia or congenital heart defects and other conditions.

“Previously healthy children who are found to have hidden disorders such as narrow blood vessels or a tendency to form blood clots easily,” are also at risk, according to the hospital.

Gracie is expected to recover but will likely remain in the hospital for another six weeks, SWNS reported.

“She doesn't remember anything, I don't think she understands what happened. She is only 10,” Clark said. "It has been a shock to all of us. It has just been a hideous time. But she has been so lucky with this, it all could've been a lot worse."

https://www.foxnews.com/health/girl-suffers-stroke-recovering

Saturday, October 5, 2019

CDKL5 genetic disorder


Approximately one in 42,000 children are born with a disease called CDKL5 Deficiency Disorder, according to a new medical report recently published in the journal Brain and presented last month at the 13th European Paediatric Neurology Society Congress in Athens, Greece. This means that each year there are over 100 new children born with the disease in the EU alone, and over 3,000 in the world.

The disease leads to frequent seizures shortly after birth and severe impairment in neurological development, with most affected people being unable to walk, talk or care for themselves. "When our daughter was diagnosed in 2009 they told us there were approximately 200 cases in the world," says Carol-Anne Partridge, chair of CDKL5 UK and the International CDKL5 Alliance, which represents patient organizations from 18 countries. "Today we know that these children were simply not being diagnosed correctly," she adds.

The study, by a medical team from the Royal Hospital for Children in Glasgow, kept track of all births in Scotland during three years and applied genetic testing to all children under 3 years of age who developed epilepsy. "We found that as many as 1 in 4 children with epilepsy have a genetic syndrome", explains Professor Sameer Zuberi, corresponding author for the study, "and a small group of genes explains most of the cases."

Among these genes is CDKL5, which encodes a protein necessary for proper brain functioning. Mutations in the CDKL5 gene produce CDKL5 Deficiency Disorder, with one of the first symptoms being early-onset epilepsy. There is no therapy approved for treating the disease now known to affect thousands of people.

But therapies are being developed and the disease has recently attracted much interest from the pharmaceutical industry. There are four clinical trials currently ongoing, and additional companies have announced efforts towards the development of enzyme replacement and gene therapies.

The new disease incidence study highlights the need to increase disease awareness around these genetic disorders previously thought to be much more rare. "Our data suggest that genetic testing should be a primary investigation for epilepsies presenting in early childhood," explains Professor Sameer Zuberi.

Most of these cases are due to de novo (spontaneous) mutations, so they can occur in any family. But genetic testing is not offered to many patients with early childhood epilepsy and neurodevelopmental disabilities. Because of that, only about 10% of all people living with CDKL5 Deficiency Disorder might have a correct diagnosis.

"These new incidence findings demonstrate that there is still much work to do to diagnose CDKL5 Deficiency Disorder correctly," explains Daniel Lavery PhD, Chief Scientific Officer of the Loulou Foundation. "As we partner with pharmaceutical companies to develop new therapies and cures for the disorder, we also need to find the thousands of people that are living with this condition so that they can access these new therapies," he adds.

https://www.mdlinx.com/pediatrics/top-medical-news/article/2019/10/02/7580923

Genetic results. No case had more than one diagnostic result. Shaded bars represent genes for which there is evidence for precision therapy.


Symonds JD, Zuberi SM, Stewart K, McLellan A, O'Regan M, MacLeod S, Jollands A, Joss S, Kirkpatrick M, Brunklaus A, Pilz DT, Shetty J, Dorris L, Abu-Arafeh I, Andrew J, Brink P, Callaghan M, Cruden J, Diver LA, Findlay C, Gardiner S, Grattan R, Lang B, MacDonnell J, McKnight J, Morrison CA, Nairn L, Slean MM, Stephen E, Webb A, Vincent A, Wilson M. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national
cohort. Brain. 2019 Aug 1;142(8):2303-2318.

Abstract
Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

See: https://childnervoussystem.blogspot.com/2016/08/cdkl5-mutations.html
https://childnervoussystem.blogspot.com/2015/09/genetic-causes-of-early-onset-epileptic.html 

Epilepsy genetics


I think my daughter Esmé is extraordinarily unique—from her tiny pudgy feet that she likes to stuff in her mouth to her beautifully lashed blue eyes and outrageously untamed hair. It’s a mom thing. I guess it is a symptom of loving another person more than life itself.

But my daughter is also unusual in a more scientific way: in her genes.

The testing conundrum

In November 2011, when Esmé was around 10 months old, we were considering stopping genetic testing. Esmé’s microarray had come back showing nothing by way of genetic changes. We understood that Esmé probably still had a genetic disorder: She was unable to roll over or sit up. She was almost silent, tube-fed and having seizures.

I still had some deep dark hope that she would grow out of all of these challenges—a hope that was threatened by my need to understand Esmé’s health, to find genetic answers. A hope that was complicated by the limits of what genetics might be able to tell us.

A year later, Esmé was in the midst of seizures that were spiraling out of control, not responding well to any of the medications we tried. We found ourselves again wanting to know more. We hoped that any insight into her condition would help us better treat her.

I had no idea how far the following three and a half years would bring me in search of answers. I traveled to Europe and the west coast of the U.S. to meet with researchers from as far away as Australia—geneticists who spend their time at the cutting edge, just beyond what is accepted about genetics.

And we had no idea how many more questions the testing would wind up raising.

A mutation…or two?

In the fall of 2012, Esmé’s doctors ordered a newly available Infantile Epilepsy testing panel from the company GeneDx. This panel uses next-generation sequencing to look for changes in the known genes associated with infantile epilepsy, finding even very small genetic changes very quickly. (At the time, the test took approximately 12 weeks and tested for approximately 36 genes; in its current form, the test takes four weeks and tests for 53 genes.)

Esmé at Boston Children’s Hospital when the Infantile Epilepsy Panel was ordered.

In December, we received a call explaining that the test had found a single small mutation in a gene associated with infantile epilepsy and developmental delay almost exclusively in girls. Heather Olson, MD, our neurologist at Boston Children’s Hospital, explained that the gene was called PCDH19 and that Esmé’s specific mutation had never been reported, so it was unknown whether it was expected to be disease-causing. The Epilepsy Genetics group felt it was, more likely than not, at least a partial explanation. So, we took our place somewhere around the 100th documented case of PCDH19 epilepsy.

From what little information I was able to find, there were aspects of this disorder that seemed much like my daughter’s symptoms—drug resistant, cyclical clustering seizures with cyanosis (turning blue) and behavioral differences. However, essentially all the girls I learned about over the coming months lacked the medical fragility, multi-system involvement, extremely low tone and severe developmental delays we saw in Esmé—who, at 2 years old, was still not sitting up, babbling or eating by mouth.

However, this was the only lead we had to explain Esmé—so I took it and ran with it. I became increasingly involved in the PCDH19 community, starting the Cute Syndrome Foundation. During its first 18 months, we funded about $120,000 worth of PCDH19 research and awareness projects, including a project at Boston Children’s modeling PCDH19 mutations in zebrafish.

But as more and more cases of PCDH19 were diagnosed, the gap between Esmé’s symptoms and the others’ became increasingly evident.

So about two years after our infantile epilepsy panel, we dug deeper into Esmé’s genes—this time with whole-exome sequencing—to see if we could come up with more answers… and perhaps find something else we could do to help Esmé. We assumed that she likely had PCDH19 epilepsy and a second disorder that affected her muscles, movement and some of her internal organs.

We didn’t expect to find a second mutation in a gene associated with infantile epilepsy—but that is what we found.

The second mutation

The exome showed that Esmé had a second “mutation of unknown significance” in SCN8A—a recently discovered gene associated with intractable epilepsy, movement disorders and severe developmental delay. The test results also stated that Esmé’s PCDH19 mutation had been reclassified as “unlikely to be pathogenic.”

Fortunately, through the Cute Syndrome Foundation I had the chance to form relationships with a number of clinicians and researchers who work with rare genetic epilepsies. Interestingly, as I started to get in touch with some of these researchers, there seemed to be disagreement about whether one or the other or both mutations were significant in Esmé’s case. There was also a lot of suspicion about what else might be causing her symptoms.

My daughter’s genes are truly putting scientific knowledge to the test. The Cute Syndrome Foundation now also supports SCN8A research and will be co-funding a $20,000 SCN8A grant with two other SCN8A family organizations to improve the pace of research. (Read more on family-driven SCN8A research.)

An answer…or not?

Understanding whether a mutation is disease-causing is a complicated process. It involves theory about what parts of the gene are very similar across different species, what amino acids are interchanged in the mutation and how the mutation might alter the protein produced by the gene. It can also involve functional tests in the laboratory and animal models to measure the effect of the mutation.

Increasingly, it also requires scientists to think bigger than the individual gene—to see how different genes might interact. It also means looking in new places in human DNA for answers that may have been previously overlooked.

So, for now, we will wait while science continues to expand its understanding of the human genome and begin to answer some of the questions we have about Esmé’s life, health and future.

And just as before…only time will tell.

But for now, I suppose, I am content to understand the most important thing of all: Esmé is certainly one of a kind. As we all are.

In that way, I find myself back where I started…beyond wanting to know.


Courtesy of a colleague

Thursday, October 3, 2019

New biomarker blood test might flag TBI not evident on CT scans


A simple blood test could potentially help triage and evaluate patients in the emergency department with suspected traumatic brain injury (TBI) and normal CT findings, according to an August 23 report in The Lancet Neurology.

The blood test, which is under development, measures the concentration of glial fibrillary acidic protein (GFAP), a protein considered to be a specific biomarker of astrocyte injury, which tends to be elevated with TBI.

Some patients with suspected TBI with normal CT findings show pathology on MRI, the authors of the study noted. So they wanted to assess whether the GFAP test could have the “discriminative ability to identify MRI abnormalities in patients with normal CT findings.”

The multi-center study included 450 suspected TBI patients who had normal CT scans and underwent testing with GFAP and MRI. MRI detected numerous head injuries missed by CT, and the analysis found that patients with the highest concentrations of GFAP were far more likely to have an MRI that indicated TBI.

“This study builds upon a lot of prior work and excitement about the promise of biomarkers in the treatment of traumatic brain injury,” said lead author Geoffrey Manley, MD, PhD, professor and vice chair of neurosurgery at University of California, San Francisco.

In the case of GFAP, “the biomarker appears to be more sensitive than a head CT for diagnosing traumatic brain injury,” he said.

The biomarker test, under development by Abbott and still in clinical testing, is conducted using a hand-held blood analyzer that delivers results in about 15 minutes, Dr. Manley said.

Another biomarker test for mild TBI (concussion) was given the go-ahead by the US Food and Drug Administration (FDA) last year, but it is more of a traditional lab test with results taking several hours. That test, marketed by Banyan Biomarkers, measures two biomarkers, GFAP and UCH-L1 and is intended for use in patients being considered for initial CT scanning.

Patients with a suspected head injury are typically given a CT scan to rule out brain swelling and bleeding. If the scan appears abnormal, further evaluation with MRI may be done. Dr. Manley said it is not unusual for patients to be sent home from the emergency department thinking they have nothing to worry about when they in fact have mild TBI.



Plasma GFAP concentration using a point-of-care platform (A) shows fair discrimination (AUC 0.777) between patients with MRI-positive findings and patients with MRI-negative findings in patients with CT-negative traumatic brain injury. GFAP at 9-16 hours post injury (B) shows improved discrimination to good—area under the curve (AUC) 0.852—suggesting temporal effects of GFAP release or accumulation in the systemic circulation after traumatic brain injury and time for optimal or repeat measurement.

Dr. Manley said that he does not believe that GFAP or any other biomarker will be the singular tool for diagnosing TBI. He expects that like with heart attack, where troponin testing is one component of evaluation, TBI biomarkers will be among several diagnostic tools used to arrive at a firm diagnosis.

“I see this as being a triage tool,” he said, but cautioned that the study included only adult patients who got to the emergency room because of a car accident or a fall. He said more research is needed before he could say whether the test “is ready for use in kids with concussions.”

A Subset Analysis

The latest report on the GFAP biomarker test stems from a study known as TRACK-TBI (Transforming Research and Clinical Knowledge in Traumatic Brain Injury), a large prospective study being conducted at 18 Level 1 trauma centers in the US. A sub-analysis was done of 450 of the participants, most of whom were classified as having mild TBI due to a traffic accident or fall. They all had normal findings on CT scan (and a Glasgow Coma Scale score 13-15) and consented to the blood test within 24 hours of their injury and an MRI scan seven to 18 days post-injury. The study also included orthopedic trauma patients and healthy controls for comparison.

Of the 450 suspected TBI patients with normal CT scans, 120 (27 percent) had MRIs indicative of TBI. When the researchers compared MRI findings to GFAP levels, they found that GFAP concentrations were higher in patients with positive MRI scans (median plasma GFAP concentration of 414.4 pg/mL) compared with those with negative MRI scans (median plasma GFAP concentration of 74.0 pg/mL).

Of the 90 patients with GFAP concentrations in the lowest quintile, only seven (8 percent) had abnormal MRI findings, while 58 (64 percent) of those with GFAP concentrations in the highest quartile had abnormal MRI findings, the study said. GFAP levels also correlated with MRI lesion types, the researchers said.


“These results indicate that the diagnostic utility of GFAP might extend beyond CT-visible pathology and might help to identify patients with more subtle injury,” the researchers said....

Dr. Lecky said the findings that GFAP concentration at nine to 16 hours post-injury discriminated well between patients with MRI-positive findings and MRI-negative findings were positive.

“These results are promising,” she wrote, “but, as the investigators acknowledge, are some distance from suggesting that GFAP assays should become part of current emergency department management of patients with TBI and negative CT scans. The clinical significance of the positive MRI findings is unknown; data on patient symptom severity at 2 weeks or later follow-up were not reported in the study. If the frequencies of disabling concussion symptoms do not differ in the MRI-positive and MRI-negative cohorts during follow-up, it is hard to argue that either GFAP or the MRI scans are providing key information to guide further management.”

She noted that nearly half of the study participants with “negative CT scans did not have MRI as part of their follow-up, and because their characteristics are not reported, it is difficult to assess the potential for selection bias.”

In addition, she said it would be time consuming and expensive to do an MRI on every suspected TBI patient who had a normal CT.

Dr. Lecky said a biomarker test could be useful for sorting out which suspected TBI patients need head imaging and/or medical follow up, but she cautioned that t he biomarker test needs to be further investigated before it is ready for clinical use.

https://journals.lww.com/neurotodayonline/Fulltext/2019/10030/New_Biomarker_Blood_Test_Might_Flag_TBI_Not.4.aspx?

Yue JK, Yuh EL, Korley FK, et al; for the TRACK-TBI Investigators. Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: A prospective multicentre study https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30282-0/fulltext. Lancet Neurol 2019; Epub 2019 Aug 23.


Summary

Background
After traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on CT scan. Some patients with suspected TBI with normal CT findings show pathology on MRI. We assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings.

Methods
TRACK-TBI is a prospective cohort study that enrolled patients with TBI who had a clinically indicated head CT scan within 24 h of injury at 18 level 1 trauma centres in the USA. For this analysis, we included patients with normal CT findings (Glasgow Coma Scale score 13–15) who consented to venepuncture within 24 h post injury and who had an MRI scan 7–18 days post injury. We compared MRI findings in these patients with those of orthopaedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform. We used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 h (time between injury and venepuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings within 24 h of injury. The Dunn Kruskal–Wallis test was used to compare GFAP concentrations between MRI lesion types with Benjamini–Hochberg correction for multiple comparisons. This study is registered with ClinicalTrials.gov, number NCT02119182.

Findings
Between Feb 26, 2014, and June 15, 2018, we recruited 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopaedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 (95% CI 0·726–0·829) over 24 h. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414·4 pg/mL, 25–75th percentile 139·3–813·4), followed by patients with CT-negative and MRI-negative findings (74·0 pg/mL, 17·5–214·4), orthopaedic trauma controls (13·1 pg/mL, 6·9–20·0), and healthy controls (8·0 pg/mL, 3·0–14·0; all comparisons between patients with CT-negative MRI-positive findings and other groups p<0·0001).

Interpretation

Medical mayhem 12


A Virginia doctor was sentenced to 40 years in prison on Wednesday for prescribing a half-million doses of opioids to patients over two years, prosecutors said.

Dr. Joel Smithers, 36, was sentenced in U.S. District Court in Abingdon. He was found guilty in May of more than 800 counts of illegally prescribing opioids, including oxycodone and oxymorphone that killed a West Virginia woman.

Smithers prescribed more than 500,000 doses of opioids to patients from Virginia, Kentucky, West Virginia, Ohio and Tennessee while based in Martinsville, Va., from 2015 to 2017, authorities said.
This physician perpetuated, on a massive scale, the vicious cycle of addiction and despair.

U.S. Attorney Thomas Cullen said Smithers’ sentence, while severe, “serves as just punishment” for his actions. “This physician perpetuated, on a massive scale, the vicious cycle of addiction and despair,” Cullen said in a statement.

Smithers, a married father of five from Greensboro, N.C., testified that he was a caring doctor who was deceived by some of his patients.

Some patients remained fiercely loyal to him, testifying that they needed the powerful opioids he prescribed to cope with chronic pain.

Judge James Jones recommended that Smithers serve his sentence in a prison close to his family, and that he receive mental health treatment, WSET-TV reported.

Smithers was also ordered to pay an $86,000 fine and serve three years of supervised release after his prison term, according to court documents.

Smithers wrote in a court filing that he plans an appeal. His attorney did not immediately respond to an email seeking comment on the sentence.

https://www.foxnews.com/us/virginia-doctor-40-years-prescribing-opioid-pills

Work related injury


A construction worker who allegedly fell 15 feet onto a steel bar that impaled him through his nostril before exiting through his skull miraculously survived the horrific injury and remained conscious throughout the ordeal.

After the accident, which occurred on Saturday in China, Li Xuedong, 45, was allegedly driven two hours away to General Hospital of Shenyang Military Region while his family members held the steel bar in place, AsiaWire reported.

Xeudong arrived at the hospital with six inches of the bar sticking out through the top of his head, but doctors didn’t know what the extent of the damage was inside of his skull. According to AsiaWire, brain scans showed “there was minimal bleeding, which was very positive.”


The hospital then allegedly called in a fire service who shortened the steel bar before he was whisked into surgery to have the remaining pieces removed.  He is said to be in stable condition.

“The patient is conscious and lucid,” a hospital spokesperson told AsiaWire.

https://www.foxnews.com/health/man-impaled-nostril-skull

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.

Abstract
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

Triggers

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.