Sunday, July 31, 2016

A teachable moment

How often do we do the same?

Niess MA, Prochazka A. Preoperative chest x-rays: a teachable moment. JAMA
Intern Med. 2014 Jan;174(1):12.

Mr X, a man in his mid 50s with a history of mild intermittent asthma and an increasingly painful umbilical hernia, presented to a general surgery clinic for a preoperative evaluation. Basic laboratory test results and cardiopulmonary examination findings were normal, and a reducible hernia was noted. A chest radiograph (CXR) was obtained for the indication of preoperative evaluation in a patient with asthma older than 55 years. The CXR revealed a 7-mm left perihilar lung nodule, with a radiologist recommending further evaluation of the lung with computed tomography (CT). As a result, hernia surgery was delayed and CT scan of the chest was undertaken.

Four weeks later, Mr X followed up to review the results of his CT scan, which revealed no pulmonary nodule but revealed a right adrenal nodule. The radiologist recommended that dedicated adrenal CT imaging be ordered by the medical team, further delaying surgery. Adrenal CT revealed findings consistent with a benign adenoma. Hernia repair was finally completed more than 6 months after his preoperative evaluation. Throughout this time, Mr X noted persistent pain from his hernia and anxiety over the positive test results.

The value of preoperative CXR has never been established. The Royal College of Radiology examined the utility of preoperative CXR in 8 hospitals and 10 619 patients in 1979. It concluded, “In view of the absence of clinical usefulness of routine [preoperative CXR] in… nonemergency operations,” there was widespread overuse, and “the policy of abandoning routine [preoperative CXR]… should be discussed.” Since that time, little evidence has surfaced to support preoperative CXR, but the practice continues. Recently, the Choosing Wisely campaign identified preoperative CXR as a priority area to raise awareness of its overuse.

Assessing the utility of this screening method requires estimating what fraction of CXRs have unexpected findings that prove useful in management. Most studies define a CXR-related change in management as delay or cancellation of surgery or a change in anesthesia protocol, neither of which have been shown to lead to better patient outcomes.

Existing studies on changes in anesthesia management do not include randomized controlled trials; they are predominantly retrospective trials. Reviews of the topic consistently cite the same nonblinded and nonrandomized studies. Silvestri et al conducted the largest multicenter study to date (6111 patients). Patients undergoing elective surgery who had submitted to a preoperative CXR at the surgeon’s discretion were enrolled. Anesthesiologists were interviewed after the surgical procedure and asked whether preoperative CXR changed management. Results showed that preoperative CXR resulted in a revision of anesthesia management from 0% to 13.5% of the time depending on the anesthesiologist questioned. Given the nonblinded, retrospective format of the survey, these results are prone to bias; the variability in responses is more consistent with the variability of anesthesiology preference than useful predictors of the utility of preoperative CXR.

In the absence of better evidence, the American Society of Anesthesiologists (ASA) stated in 2001, “[the ASA] does not believe that extremes of age, smoking, stable COPD [chronic obstructive pulmonary disease], stable cardiac disease, or resolved recent upper respiratory infection should be considered unequivocal indications for chest radiography.”

In 2005, Joo et al published a systematic review of 14 articles evaluating the practice of preoperative CXR. Although this review considered the same nonrandomized, nonblinded, largely retrospective trials referenced earlier in this article, the authors took into account the quality of the evidence and concluded that routine preoperative CXR should not be performed in asymptomatic patients. By their assessment, most abnormalities are chronic, are expected, or do not affect management or postoperative outcome.

Despite the evidence that preoperative CXR is unlikely to be beneficial, it continues to be used in daily practice. Exposing a patient to multiple additional studies prolongs surgical delay, increases exposure to radiation, prolongs and exacerbates underlying anxiety, and increases the likelihood of additional incidentalomas. The existing studies would likely label Mr X’s case a success; preoperative CXR had identified an unexpected abnormality that changed management by delaying surgery. However, a closer look at an individual case such as Mr X’s may actually illustrate a less rosy view of the consequences of preoperative CXR. He had more than 100 times the radiation of a single CXR, anxiety due to multiple incidental findings, and one objective patient-oriented outcome—delay in the management of his painful hernia.

Metachromatic leukodystrophy effect on caregivers

Eichler FS, Cox TM, Crombez E, Dali CÍ, Kohlschütter A. Metachromatic
Leukodystrophy: An Assessment of Disease Burden. J Child Neurol. 2016 Jul 7. pii:
0883073816656401. [Epub ahead of print]


Metachromatic leukodystrophy is accompanied by severe motor and cognitive dysfunction. This is the first survey of metachromatic leukodystrophy caregiver perspectives to identify relevant clinical/quality-of-life outcomes for patients/caregivers. Interviews and 1 focus group were conducted with 30 caregivers representing 23 patients. Caregivers were asked about their experiences, including diagnostic process, signs/symptoms, symptoms affecting caregivers' and patients' lives, and treatment priorities. Caregivers reported loss of physical autonomy, weight loss, limited social relationships, frequent crying, and challenging sibling relationships. Most troublesome symptoms were immobility (9/30) and respiratory difficulties (6/30). Health care visits were frequent: 8/22 patients had experienced ≥11 hospitalizations since diagnosis, and 14/22 caregivers reported that these lasted ≥4 days. Caregivers also experienced work problems, feelings of fear/sadness, and loss of social relationships. Caregivers/physicians consider a therapy that could improve decline in mobility, pain, cognitive ability, communication, or food intake as conferring the greatest benefit. In conclusion, a so-far-unreported physical/economic burden in these families is presented.

Courtesy of:

Juvenile metachromatic dystrophy and bone marrow transplantation

Groeschel S, Kühl JS, Bley AE, Kehrer C, Weschke B, Döring M, Böhringer J,
Schrum J, Santer R, Kohlschütter A, Krägeloh-Mann I, Müller I. Long-term Outcome
of Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Juvenile
Metachromatic Leukodystrophy Compared With Nontransplanted Control Patients. JAMA
Neurol. 2016 Jul 11. doi: 10.1001/jamaneurol.2016.2067. [Epub ahead of print]

Allogeneic hematopoietic stem cell transplantation (HSCT) has been the only treatment option clinically available during the last 20 years for juvenile metachromatic leukodystrophy (MLD), reported with variable outcome and without comparison with the natural course of the disease.
To compare the long-term outcome of patients who underwent allogeneic HSCT with control patients who did not among a cohort with juvenile MLD.
Patients with juvenile MLD born between 1975 and 2009 and who received HSCT at a median age of 7 years (age range, 1.5-18.2 years) and nontransplanted patients with juvenile MLD born between 1967 and 2007 were included in this case-control study. The median follow-up after HSCT was 7.5 years (range, 3.0-19.7 years). Patients underwent HSCT at 3 German centers between 1991 and 2012. The analysis was done between July 2014 and August 2015.
Survival and transplantation-related mortality, loss of gross motor function (Gross Motor Function Classification in MLD), loss of any language function, and magnetic resonance imaging (MRI) severity score for cerebral changes. To explore prognostic factors at baseline, patients who underwent HSCT (hereafter, transplanted patients) were a priori divided into stable vs progressive disease, according to gross motor and cognitive function.
Participants were 24 transplanted patients (11 boys, 13 girls) and 41 control patients (22 boys, 19 girls) who did not receive transplantation (hereafter, nontransplanted patients) with juvenile MLD. Among the transplanted patients, 4 children died of transplantation-related mortality, and 2 additional children died of rapid MLD progression 1.5 and 8.6 years after HSCT, resulting in a 5-year survival of 79% (19 of 24). Among the nontransplanted patients, 5-year survival after disease onset was 100% (41 of 41). However, 11 died of MLD progression, resulting in similar overall survival within the observation period. Nine of the long-term survivors after HSCT had disease progression, while 11 showed stable disease. Compared with the nontransplanted patients, the transplanted patients were less likely to lose their gross motor or language function and demonstrated significantly lower MRI severity scores at the latest examination. Patients after HSCT were more likely to have a stable disease course when undergoing HSCT at an early stage with no or only mild gross motor deficits (Gross Motor Function Classification in MLD level 0 or 1) and an IQ of at least 85, when age at disease onset was older than 4 years, or when MRI severity scores were low (preferably ≤17).
Among patients with juvenile MLD, patients who underwent HSCT had a better gross motor and language outcome and lower MRI severity scores compared with nontransplanted patients. Transplantation at a presymptomatic or early symptomatic stage of juvenile MLD is associated with a reasonable chance for disease stabilization.

Chen X, Gill D, Shaw P, Ouvrier R, Troedson C. Outcome of Early Juvenile Onset
Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case
Series and Review of the Literature. J Child Neurol. 2016 Mar;31(3):338-44.

The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed. All three transplanted patients remain well, and the parameters evaluated remain stable. Of the treated patients, the two sisters had ongoing evidence of demyelinating sensorimotor neuropathy on nerve conduction tests, and with a early sensorimotor neuropathy in the older sister , and the other patient has mild intellectual impairment. One of the two un-transplanted controls, 15 years after MLD diagnosis, has relentlessly progressed to full dependency with epilepsy, severe mental retardation, dystonic movements, dysphagia and recurrent respiratory problems. Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. Our data show that, in comparison with their untreated siblings, UCBT significantly slowed the progression of the disease in the treated patients. We conclude that UCBT benefits children with pre-symptomatic early juvenile onset MLD by favourably altering the natural history of the disease.

Friday, July 29, 2016

Medical child abuse revisited 3

When the Department of Children and Families sought emergency custody last year of a 7-year-old girl whom doctors suspected had been poisoned by her parents, it didn't have to start a new file on the couple.

The department had been aware of Christopher and Julie Conley for at least six years, going back to 2009, when the girl was a toddler suffering from what a prosecutor has called unexplained medical issues.

The department's counsel was able to convince a juvenile court judge at that time that there was reasonable proof that the Conleys had harmed their daughter through medical child abuse, also known as Munchausen by proxy.

The child was removed from their care and according to court filings by Assistant Northwestern District Attorney Linda Pisano, "every single medical condition went away" during that time.

Still, the child was returned to her parents in 2011. Pisano said her medical issues came back sometime later, after DCF ceased to monitor the girl and closed the case.

The indictments grand juries returned against the parents charge them with abusing the girl going back to July 27, 2013.

On April 15, 2015, according to prosecutors, either one or both of her parents poured a caustic substance into her cecostomy tube, a medical tube used to flush her intestines. She became critically ill and lost two-thirds of her bowel and part of her bladder. Christopher Conley confessed to the crime but later recanted.

So why was the girl returned to her parents after DCF had determined she was more likely than not medically abused?

The decision was made by a juvenile court judge who heard arguments from both sides, including from DCF officials who opposed letting the girl go home…

An expert in Munchausen by proxy said that a judge's decision to return a child to their parents who medically abused them flies in the face of what research shows: people who medically abuse their children once will do it again.

"The risk of reabuse in confirmed Munchausen by proxy cases is very high," said Marc Feldman, a clinical professor of psychiatry at the University of Alabama who has studied Munchausen by proxy cases for 25 years…

The girl, now 8, has been living with a foster family since being discharged from the hospital.

In the case of Christopher and Julie Conley of Northampton, there is a fairly strong piece of evidence of medical abuse by at least one of the parents in that their daughter was seriously injured with a caustic substance April 15, 2015. 

But her parents for years before that maintained that she has mitochondrial disease, the same disease with which Pelletier was diagnosed. Court records have not clarified whether the Conley's daughter was officially diagnosed with it.

Like Pelletier's case, doctors at Boston Children's Hospital first raised the question of medical abuse, but court documents do not indicate that they filed a report with DCF. The Conleys moved their daughter to Tufts Medical Center, where doctors suspected abuse and filed a report.

Christopher Conley confessed to pouring Liquid-Plumr into his daughter's intestinal tube, although he later recanted. His wife has maintained her innocence, but she was also charged with similar crimes more than five months later.

A Department of Children and Families official said in court that Christopher Conley's time sheets at work have made investigators wonder if he could have been home when he was alleged to have poisoned his daughter, which points to his wife.

But another thing mentioned in court documents about Julie Conley's role in the suspected medical abuse is her level of involvement in her daughter's medical care. She was described as the primary care giver for her daughter, very knowledgeable and interested in her daughter's care, present at all her appointments and the one who makes medical decisions for the child.

The prosecutor in the case said medical staff indicated that both parents "either did not mention previous medical treatment and/or testing done and misrepresented, minimized or exaggerated medical testing or results."

But Feldman said that he was "wary of condemning the mother" based on behavior in a hospital.

Sometimes mothers accused of Munchausen by proxy are pushy or argumentative, Feldman said, which can strain doctors' relationships with them. He said that while a person who disagrees with doctors and insists the child has a different or undiagnosed condition may be more likely to be medically abusing the child, "it's not proof."

And while doctors have said a caustic substance is the only explanation of the Conley girl's injuries last year, there is at least some possibility that the girl had medical problems she was born with. Christopher Conley told police he was attempting to kill his daughter because she was suffering — it's still criminal, but it's not an intention typically seen in Munchausen by proxy cases.

In court Allen has said that the girl's parents believe she has mitochondrial disease, severe hypoglycemia, seizures, and other issues.

A charitable foundation that provides free family photos for children with serious illnesses posted an online album of photos of the Conleys Sept. 25, 2014. It named mitochondrial disease and other illnesses and also said that the girl was born with a duplication of her 22nd chromosome.

Sudden unexpected infant death and safe sleeping environment

The AAP expanded its recommendations for preventing sleep-related deaths in 2011.The new recommendations include supine sleeping, room sharing without bed sharing, using a firm sleep surface, avoiding soft bedding, reducing exposure to tobacco smoke, and breast feeding.  In 2014, there was not a single sleep-related death in Minnesota in which the infant was found in a safe sleeping environment as defined by the AAP. More specifically, every case involved either soft bedding or a shared sleep surface…

Physicians and other health care providers who come in contact with parents of infants and expectant parents have an opportunity to discuss safe sleep practices and the reasons for them. Our review of medical records from SUID cases suggests that parents often receive a clear message about placing infants to sleep on their backs but less clear messages about the dangers of bed sharing and soft bedding. Several parents mentioned that they knew a bed was not safe for infants, so they placed pillows around the infant to prevent them from falling off. Parents of one infant who died suddenly and unexpectedly after being placed on his stomach told death scene investigators that they thought they were following their provider’s recommendation for “tummy time.”

In addition to increasing and targeting education about safe sleeping practices, policy changes could help prevent SUIDs. The large disparities in SUID rates by race is a notable finding. The number of American Indians and Asians in our study was small. However, the magnitude of the disparities between the rates of SUID for these groups and others are consistent with what we have measured in the past. A limitation of this study is that data were only available for the mother’s race. Including the father’s race may have affected the SUID rates by race. The Advancing Health Equity in Minnesota Report to the Legislature identifies health disparities, such as those that affect infants of color, and recommends changes that address institutional discrimination and social determinants of health. Smoking during pregnancy has been consistently identified as a risk factor for sudden infant death, and policies that support preventing tobacco use and smoking cessation are important to preventing SUIDs.


 All infant deaths are tragic, especially those that could have been prevented. Many factors affect a baby’s risk of SUID including social determinants of health, a caregiver’s understanding of safe sleep practices and ability to consistently provide a safe sleep environment, and exposure to tobacco. Public health, law enforcement, health care practitioners and other community members all have roles to play in addressing these issues and helping parents make Minnesota a safer place for babies. 

Thursday, July 28, 2016

CHD2 mutations

Inspired by a patient.

Trivisano M, Striano P, Sartorelli J, Giordano L, Traverso M, Accorsi P,
Cappelletti S, Claps DJ, Vigevano F, Zara F, Specchio N. CHD2 mutations are a
rare cause of generalized epilepsy with myoclonic-atonic seizures. Epilepsy
Behav. 2015 Oct;51:53-6.

Chromodomain helicase DNA-binding protein 2 (CHD2) gene mutations have been reported in patients with myoclonic-atonic epilepsy (MAE), as well as in patients with Lennox-Gastaut, Dravet, and Jeavons syndromes and other epileptic encephalopathies featuring generalized epilepsy and intellectual disability. The aim of this study was to assess the impact of CHD2 mutations in a series of patients with MAE. Twenty patients affected by MAE were included in the study. We analyzed antecedents, age at onset, seizure semiology and frequency, EEG, treatment, and neuropsychological outcome. We sequenced the CHD2 gene with Sanger technology. We identified a CHD2 frameshift mutation in one patient (c.4256del19). He was a 17-year-old boy with no familial history for epilepsy and normal development before epilepsy onset. Epilepsy onset was at 3years and 5months: he presented with myoclonic-atonic seizures, head drops, myoclonic jerks, and absences. Interictal EEGs revealed slow background activity associated with generalized epileptiform abnormalities and photoparoxysmal response. His seizures were highly responsive to valproic acid, and an attempt to withdraw it led to seizure recurrence. Neuropsychological evaluation revealed moderate intellectual disability. Chromodomain-helicase-DNA-binding protein 2 is not the major gene associated with MAE. Conversely, CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity, which might overlap with MAE, Lennox-Gastaut, Dravet, and Jeavons syndromes.

Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, Ogilvie
CM, Lionel AC, Marshall CR, Vaags AK, Hashemi B, Boisvert K, Mathonnet G, Tihy F,
So J, Scherer SW, Lemyre E, Stavropoulos DJ. CHD2 haploinsufficiency is
associated with developmental delay, intellectual disability, epilepsy and
neurobehavioural problems. J Neurodev Disord. 2014;6(1):9.

The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.
We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.
Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.
The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.

Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A,
Djémié T, Afrikanova T, Gormley P, von Spiczak S, Kluger G, Iliescu CM, Talvik T,
Talvik I, Meral C, Caglayan HS, Giraldez BG, Serratosa J, Lemke JR,
Hoffman-Zacharska D, Szczepanik E, Barisic N, Komarek V, Hjalgrim H, Møller RS,
Linnankivi T, Dimova P, Striano P, Zara F, Marini C, Guerrini R, Depienne C,
Baulac S, Kuhlenbäumer G, Crawford AD, Lehesjoki AE, de Witte PA, Palotie A,
Lerche H, Esguerra CV, De Jonghe P, Helbig I; EuroEPINOMICS RES Consortium. De
novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic
epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet.
2013 Nov 7;93(5):967-75.


Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.

Elicited intrusive thoughts

Irina Popa, Cristian Donos, Andrei Barborica, Ioan Opris, Mihai Dragoş Mălîia, Mirela Ene, Jean Ciurea ,Ioana Mîndruţă.  Intrusive thoughts elicited by direct electrical stimulation during stereo-electroencephalography.  Front. Neurol., 18 July 2016

Cortical direct electrical stimulation (DES) is a method of brain mapping used during invasive presurgical evaluation of patients with intractable epilepsy. Intellectual auras like intrusive thoughts, also known as forced thinking (FT), have been reported during frontal seizures. However, there are few reports on FT obtained during DES in frontal cortex. We report three cases in which we obtained intrusive thoughts while stimulating the dorsolateral prefrontal cortex and the white matter in the prefrontal region. In order to highlight the effective connectivity that might explain this clinical response, we have analyzed cortico-cortical potentials evoked by single pulse electrical stimulation….

Intrusive thoughts are a psychological phenomenon present in different neurological and psychiatric disorders. Understanding the structure and physiology of the brain networks eliciting this response will create new diagnostic and therapeutic opportunities for disorders such as schizophrenia, obsessive–compulsive disorder, or post-traumatic stress disorder.

The term forced thinking (FT) was first used by Penfield and Jasper, and it describes a rare ictal manifestation of frontal seizures. Since then, we found only a few reports where the authors have elicited “a little familiar thought” probably similar to a déjà vu state while stimulating the temporo-polar cortex . Given the scarcity of literature data on FT during direct electrical stimulation (DES), the network involved is still a matter of research…

Patient reported that “the stimulation induces the disappearance of the word in my mind and replaces it with something else.” She was not able to remember what that thought was. The effect lasted for 5 s, as long as the electrical stimulation was applied. Moreover, at an intensity of 3 mA, while performing a mental task (word generation in a semantic field), the patients stopped performing the task and reported again that “the stimulation induces the disappearance of the word in my mind and replaces it with the idea of leaving.” No afterdischarges were recorded, and the patient could restart the activity after the stimulation. This time, she also presented right head and eye version…

The patient reported that he had “a though that seems to come from nowhere.” In other trials of stimulation (Y′03-04, 3 mA), the patient reported a thought that he could not remember, but “could be something embarrassing if said out loud.”…

Patient reported: “I feel like someone erases all my thoughts and replaces them with something else that is capturing all my attention.” These intrusive thoughts impair the stream of thinking; therefore, the patient ceases the word generation task…

Consistent with the current knowledge, during frontal lobe stimulation, we were able to elicit intrusive thoughts invading patients’ mind and pushing away their own thoughts, with no emotional involvement. The responses were clearly different from auditory hallucinations or the inner speech phenomena described as verbal thinking. The stimulation was performed in DLPFC in P1 and in the white matter underlying the PFC mantle in P2 and P3…

Our results demonstrate that FT can be initiated by stimulating very well-defined regions of the PFC. A larger network, as evidenced by the connectivity analysis using cortico-cortical evoked potentials, may be involved in these behavioral and psychological manifestations.

Courtesy of:

Can ultrasound diagnose autism?

Bradstreet JJ, Pacini S, Ruggiero M. A New Methodology of Viewing Extra-Axial
Fluid and Cortical Abnormalities in Children with Autism via Transcranial
Ultrasonography. Front Hum Neurosci. 2014 Jan 15;7:934.

Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF).
TUS was accomplished using a linear probe (10-5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2(®)) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe).
Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05-0.07 cm, (3) 0.08-0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects' mean score was 2.79 ± 0.93.
TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.

Siniscalco D. The searching for autism biomarkers: a commentary on: a new
methodology of viewing extra-axial fluid and cortical abnormalities in children
with autism via transcranial ultrasonography. Front Hum Neurosci. 2014 May

It’s worth taking a moment to appreciate how remarkable these results are. Using ultrasound, Bradstreet et al. are claiming to have found markers which are pretty much 100% predictive of the presence of autism. Compare this to the situation with structural MRI scanning: Haar et al. found that the very best methods achieved no more than 60% accuracy at predicting ASD (where 50% is chance performance) based on brain structure. So either ultrasound is much better than MRI for detecting ASD, or something’s gone wrong here.

What might have gone wrong? In Bradstreet et al.’s study, the abnormalities were rated manually by someone who reviewed the ultrasound images. It is not stated that this person was blind to the group (autism or control) of the subjects in question. If the rater wasn’t blinded, the ratings might have been influenced (consciously or subconsciously) by the rater’s expectation of finding abnormalities in the autism group.

A related concern is that no data is provided about the reliability of the EAF and cortical dysplasia ratings. Reliability means the extent to which two raters (or the same rater at two different times) assigns the same rating to the same subject. Establishing the reliability of a novel measure is considered crucial before it can be deployed to examine group differences. Neither the blinding nor the reliability issue are addressed anywhere in the paper. I’m surprised that this paper passed peer review.

Finally, it may be relevant that the authors of this paper have ‘interesting’ track records. Marco Ruggiero has published papers arguing that HIV does not cause AIDS. Stefania Pacini, along with Ruggiero, has promoted the controversial cancer therapy GcMAF and Jeff Bradstreet had (before his death last year) a long history of ‘treating’ autism with a variety of unconventional therapies, including GcMAF.

Courtesy of Doximity

PAF antagonism to prevent epileptogenesis

Musto AE, Rosencrans RF, Walker CP, Bhattacharjee S, Raulji CM, Belayev L,
Fang Z, Gordon WC, Bazan NG. Dysfunctional epileptic neuronal circuits and
dysmorphic dendritic spines are mitigated by platelet-activating factor receptor
antagonism. Sci Rep. 2016 Jul 22;6:30298.

Temporal lobe epilepsy or limbic epilepsy lacks effective therapies due to a void in understanding the cellular and molecular mechanisms that set in motion aberrant neuronal network formations during the course of limbic epileptogenesis (LE). Here we show in in vivo rodent models of LE that the phospholipid mediator platelet-activating factor (PAF) increases in LE and that PAF receptor (PAF-r) ablation mitigates its progression. Synthetic PAF-r antagonists, when administered intraperitoneally in LE, re-establish hippocampal dendritic spine density and prevent formation of dysmorphic dendritic spines. Concomitantly, hippocampal interictal spikes, aberrant oscillations, and neuronal hyper-excitability, evaluated 15-16 weeks after LE using multi-array silicon probe electrodes implanted in the dorsal hippocampus, are reduced in PAF-r antagonist-treated mice. We suggest that over-activation of PAF-r signaling induces aberrant neuronal plasticity in LE and leads to chronic dysfunctional neuronal circuitry that mediates epilepsy.

From the article:

We conclude that an increase in PAF activates PAF-r in the hippocampus during epileptogenesis, thus mediating neuronal network hyper-excitability and seizure susceptibility. By blocking PAF-r and using the PAF-r antagonist during epileptogenesis, aberrant connectivity in the hippocampus was limited and, as a consequence, onset of epilepsy was reduced. We speculate that PAF-r activity could mediate aberrant connectivity in epileptogenesis.

Taken together, our observations suggest that the neuronal circuitry in the epileptic brain is enhanced by PAF-r over-activity during epileptogenesis. More experimental studies need to be conducted to elucidate the molecular and neurotransmission-related mechanisms involved in this process. Furthermore, understanding PAF antagonism and the potential therapeutic usefulness of PAF receptor antagonists is relevant to developing disease-modifying therapeutic interventions for patients at risk for epilepsy.

Courtesy of LinkedIn

Exoskeleton for spinal muscular atrophy

Researchers have introduced the world's first infant exoskeleton which is designed to help children with spinal muscular atrophy, a degenerative illness. Weighing 12 kilos, the apparatus is made of aluminium and titanium, and is designed to help patients walk- in some cases for the first time.

Furthermore, it will also be used in physiotherapy in hospitals to prevent the secondary effects associated with the loss of mobility in this illness. The technology, which has been patented and licensed jointly by CSIC (the Spanish National Research Council) and its technology-based business unit, Marsi Bionics, is currently in the preclinical phase.

The brace consists of long support rods, or orthoses, which are adjusted to fit around the child's legs and torso. In the joints, a series of motors mimic human muscles and give the child the necessary strength to stand upright and walk. Finally, a series of sensors, a movement controller, and a battery with 5 hours of life complete the system.

"The number one drawback in developing this type of paediatric exoskeleton is that the symptoms of neuromuscular illnesses- such as spinal muscular atrophy- change over time, as much in the articulations as in the body.That's why it's fundamental to have an exoskeleton capable of independently adapting to these changes. Our model includes intelligent joints which alter the brace's rigidity automatically and adapt to the symptoms of each individual child at whenever required," explains Elena Garcia, from the Automatics and Robotics Centre, a CSIC/Politechnic Univerity of Madrid.

The exoskeleton is aimed at children between the ages of 3 and 14. With five motors in each leg (each requiring its own space to function), the minimum possible length of each leg is restricted. Furthermore, the unpredictability of the involuntary body movements of under-3s have forced researchers to set a lower age limit for the device. In other pathologies, which don't restrict any joint movement and so require fewer motors, it would be possible to build a smaller frame," adds García…
By using the device, Elena García and her team hope to help patients walk and in so doing prevent the setting in of scoliosis, as well as the chain of resulting conditions caused by the inability to stand upright and walk.

With finance coming from the Spanish Ministry of the Economy and Competition, and through the EU's Echord ++ programme, the project is being carried out with the help of medical specialists at the Sant Joan de Déu Children's Hospital in Barcelona and the Ramón & Cajal University Hospital in Madrid.

Wednesday, July 27, 2016

Questcor please note

Massey AT, Lerner DK, Holmes GL, Scott RC, Hernan AE. ACTH Prevents Deficits
in Fear Extinction Associated with Early Life Seizures. Front Neurol. 2016 May

Early life seizures (ELS) are often associated with cognitive and psychiatric comorbidities that are detrimental to quality of life. In a rat model of ELS, we explored long-term cognitive outcomes in adult rats. Using ACTH, an endogeneous HPA-axis hormone given to children with severe epilepsy, we sought to prevent cognitive deficits. Through comparisons with dexamethasone, we sought to dissociate the corticosteroid effects of ACTH from other potential mechanisms of action.
Although rats with a history of ELS were able to acquire a conditioned fear learning paradigm and controls, these rats had significant deficits in their ability to extinguish fearful memories. ACTH treatment did not alter any seizure parameters but nevertheless was able to significantly improve this fear extinction, while dexamethasone treatment during the same period did not. This ACTH effect was specific for fear extinction deficits and not for spatial learning deficits in a water maze. Additionally, ACTH did not alter seizure latency or duration suggesting that cognitive and seizure outcomes may be dissociable. Expression levels of melanocortin receptors, which bind ACTH, were found to be significantly lower in animals that had experienced ELS than in control animals, potentially implicating central melanocortin receptor dysregulation in the effects of ELS, and suggesting a mechanism of action for ACTH.

Taken together, these data suggest that early treatment with ACTH can have significant long-term consequences for cognition in animals with a history of ELS independently of seizure cessation and may act in part through a CNS melanocortin receptor pathway.

TBCK mutation

Guerreiro RJ, Brown R, Dian D, de Goede C, Bras J, Mole SE. Mutation of TBCK
causes a rare recessive developmental disorder. Neurol Genet. 2016 May

To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.
Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.
All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).
This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.

From the article:

Because both parents are healthy and 3 of 4 children, of both sexes, were affected, we assumed a recessive mode of inheritance. Whole-genome genotyping identified a single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553–108,609,628) that was shared by both affected siblings but was absent from the unaffected (tables e-1 and e-2, figure e-1 at Inspection of the whole-exome data for genetic variability within this region led to the identification of a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del). Sanger sequencing confirmed segregation of the mutation with disease.  The only tissue available was a lymphocyte cell line from II-3. However, quantitative PCR analysis revealed no significant differences in transcript levels.

A splicing mutation in TBCK, discovered during a large-scale WES project in consanguineous families, has been recently reported. The clinical symptoms in the patient described previously and the patients described here are remarkably similar and include global developmental delay, epilepsy, dysmorphism, and hypotonia. However, the first patient also displayed ventricular septal defects and did not have precocious puberty. The family described here is not known to be consanguineous…

TBCK is a poorly characterized protein and currently has no assigned function, although it is reported to be a putative Rab GTPase activating protein. Recent work has suggested that TBCK may have a role in epidermal growth factor signaling, endocytosis, and cell migration. Others have shown that TBCK knockdown suppresses mechanistic target of rapamycin (mTOR) signaling and inhibits cell proliferation. Conversely, others have reported that TBCK activity inhibits cell proliferation.8 The paucity of articles directly investigating TBCK function, and the conflicting evidence put forward by those that have, reveals the need for further work to define the function of TBCK in the context of specific cell types, and the potentially different roles for alternative isoforms. The deletion mutation reported here falls within exon 11 and creates a premature stop codon. Clearly, more extensive functional assays are needed to understand the role of TBCK and the downstream effects of the mutations so far identified.

The data presented herein and previously3 strongly argue for the role of TBCK in this novel syndrome.

Monday, July 25, 2016

Fighting FIRES with fire

Mirás Veiga A, Moreno DC, Menéndez AI, Siscart IM, Fernández MD, Sánchez EG,
González MG, Sáez FG. Effectiveness of Electroconvulsive Therapy for Refractory
Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome.
Neuropediatrics. 2016 Jul 19. [Epub ahead of print]


Febrile infection-related epilepsy syndrome (FIRES) is a rare condition which evolves into refractory status epilepticus (SE), with poor outcome in most cases. Conventional antiepileptic drugs fail to control SE in FIRES patients. We report the case of a previously healthy 4-year-old boy who was diagnosed with FIRES. One week after pharyngitis and high fever he started seizures, followed by refractory SE. Benzodiazepines, phenytoin, high-dose barbiturates that induce burst suppression, high doses of corticosteroids, plasmapheresis, immunoglobulins, propofol, lidocaine, ketamine, inhaled desflurane, ketogenic diet, lacosamide, and therapeutic hypothermia were tried at different times in a period of 8 weeks, but all of them were ineffective. Electroconvulsive therapy (ECT) has been used in refractory SE in children. We report a case in which ECT was successfully used for treatment of refractory SE in a pediatric patient with FIRES syndrome.

Niemann-Pick type C therapeutic investigations

Alam MS, Getz M, Haldar K. Chronic administration of an HDAC inhibitor treats
both neurological and systemic Niemann-Pick type C disease in a mouse model. Sci
Transl Med. 2016 Feb 17;8(326):326ra23.

Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.

Pipalia NH, Cosner CC, Huang A, Chatterjee A, Bourbon P, Farley N, Helquist P,
Wiest O, Maxfield FR. Histone deacetylase inhibitor treatment dramatically
reduces cholesterol accumulation in Niemann-Pick type C1 mutant human
fibroblasts. Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5620-5.


Niemann-Pick type C (NPC) disease is predominantly caused by mutations in the NPC1 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles. We report the use of a series of small molecule histone deacetylase (HDAC) inhibitors in tissue culture models of NPC human fibroblasts. Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the NPC1(I1061T) mutation, and for several of the inhibitors, correction is associated with increased expression of NPC1 protein. Increased NPC1(I1061T) protein levels may partially account for the correction of the phenotype, because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes. The HDAC inhibitor treatment is ineffective in an NPC2 mutant human fibroblast line. Analysis of the isoform selectivity of the compounds used implicates HDAC1 and/or HDAC2 as likely targets for the observed correction, although other HDACs may also play a role. LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the blood-brain barrier and is currently in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM. The findings that HDAC inhibitors can correct cholesterol storage defects in human NPC1 mutant cells provide the potential basis for treatment options for NPC disease.


High frequency of reduced penetrance Huntington alleles

Kay C, Collins JA, Miedzybrodzka Z, Madore SJ, Gordon ES, Gerry N, Davidson M,
Slama RA, Hayden MR. Huntington disease reduced penetrance alleles occur at high
frequency in the general population. Neurology. 2016 Jul 19;87(3):282-8.

To directly estimate the frequency and penetrance of CAG repeat alleles associated with Huntington disease (HD) in the general population.
CAG repeat length was evaluated in 7,315 individuals from 3 population-based cohorts from British Columbia, the United States, and Scotland. The frequency of ≥36 CAG alleles was assessed out of a total of 14,630 alleles. The general population frequency of reduced penetrance alleles (36-39 CAG) was compared to the prevalence of patients with HD with genetically confirmed 36-39 CAG from a multisource clinical ascertainment in British Columbia, Canada. The penetrance of 36-38 CAG repeat alleles for HD was estimated for individuals ≥65 years of age and compared against previously reported clinical penetrance estimates.
A total of 18 of 7,315 individuals had ≥36 CAG, revealing that approximately 1 in 400 individuals from the general population have an expanded CAG repeat associated with HD (0.246%). Individuals with CAG 36-37 genotypes are the most common (36, 0.096%; 37, 0.082%; 38, 0.027%; 39, 0.000%; ≥40, 0.041%). General population CAG 36-38 penetrance rates are lower than penetrance rates extrapolated from clinical cohorts.

HD alleles with a CAG repeat length of 36-38 occur at high frequency in the general population. The infrequent diagnosis of HD at this CAG length is likely due to low penetrance. Another important contributing factor may be reduced ascertainment of HD in those of older age.


CRISPR -- clustered regularly interspaced short palindromic repeats -- is a potent genetic-editing tool. It's called this because each CRISPR unit is made of repeated DNA base-pair sequences that can be read the same way forward or in reverse and are separated by "spacer" pairs. Think of it like an organic Morse code palindrome.

With CRISPR we can now edit any genetic code -- including our own. In the three years since its advent, researchers have used CRISPR to investigate everything from sickle-cell anemia and muscular dystrophy to cystic fibrosis and cataracts. One group has even used it to snip off the cellular receptors that HIV exploits in order to infect the human immune system. If the disease is caused by your genetics -- doesn't matter if it's due to a single malformed gene, as is the case with Huntington's or sickle cell, or if it's the byproduct of hundreds mutations like diabetes and Alzheimer's -- CRISPR can conceivably fix it…

These CRISPR units can easily slice through DNA and replace nucleotide bases with others, but they aren't accurate enough to consistently aim at specific locations. For that, each CRISPR needs an RNA-based "guide," called a Cas (CRISPR associated) gene. These guides search for a specific set of nucleotides, usually a 20-pair sequence, and bind to the site once they locate it. That's a pretty impressive feat, given that the human genome contains around 20,000 genes. Working in unison, a CRISPR/Cas system can target and silence the expression of single genes anywhere along a given strand of DNA about as easily as you can edit a Word document. It's basically "find-and-replace" for genetics…

The biological mechanism behind CRISPR is actually quite ancient. See, scientists used to think that bacteria were equipped only with innate immunity -- the lowest, most budget form of biological defense around. Since a microbe's restriction enzymes will blindly attack and destroy any unprotected DNA they come in contact with, scientists figured that it was just automatic, a simple reflex. Multicellular organisms, conversely, enjoy acquired immunity, which enables them to mount specific counters to different threats. It wasn't until they discovered CRISPR that researchers figured out bacteria and archaea have been leaning on acquired immunity for eons. They'd been using it as a rudimentary adaptive immune system against viruses…

"I would bet that within 20 years, somebody is going to make a unicorn," Hank Greely, director of Stanford University's Center for Law and the Biosciences, told me during a recent phone call. "Some Silicon Valley billionaire with a 12-year-old daughter will get her a unicorn for her birthday. It will involve taking genes that grow horns and moving them into a horse."…

In 2014, a team of geneticists in China managed to give wheat full immunity against powdery mildew -- one of the most common and widespread plant pathogens on the planet -- by cutting just three genes out of its DNA. Similarly, researchers at the King Abdullah University of Science and Technology's Center for Desert Agriculture have used CRISPR technology to "immunize" tomatoes against the yellow leaf curl virus while a team from the National Institute for Biotechnology and Genetic Engineering (NIBGE) in Pakistan has done the same for cotton leaf curl. And just last year a Japanese team drastically increased the shelf life of tomatoes by editing the gene that controls the rate of their ripening…

What you will see is an explosion of novel uses for the technology. Gene editing is quickly moving from the realm of pure academia and into the hands of the general public and private enterprise. This transition resembles that of another transformative technology: personal computers. Computers went from being, essentially, toys for adults to a keystone of the modern era. CRISPR has the potential to do the same but for biology.

Take Ethan Perlstein for example. "I initially wanted to be a professor," he explains. "Like a lot of people who get trained in graduate school, especially in biomedical sciences, are thinking we're going to be professors ... that's how you can be a scientist professionally." However, the nation's glut of postgraduates has long outpaced the supply of available professorships. "My goal was academia; reality suggested that I take another path. And actually through my explorations on Twitter, I learned about rare diseases." His subsequent interactions with the social media communities that spring up around these rare diseases led him to found Perlstein Lab.

This San Francisco-based biotech startup is using CRISPR technology to drastically accelerate research into some of humanity's least-studied diseases. "There are about 4,000 inherited diseases that are caused by a single broken gene," Perlstein said, with roughly 5 percent of those manifesting during childhood and nearly all of which have no known pharmaceutical treatment. Specifically, Perlstein's team is working on drugs that can treat Niemann-Pick Type C, a lysosomal storage disorder that causes a buildup of toxic material within cells; and N-glycanase 1 Deficiency, a congenital glycosylation disorder that causes a whole host of issues, from cognitive impairment to joint deformities. Both of these devastating illnesses are caused by a single recessive gene, potentially by just one incorrect base pairing.

"These rare diseases, especially the ones that are caused by a single broken gene, tend to involve pathways and networks within the cell that are very ancient," Perlstein explained. What's more, those primal genes are disproportionately more likely to "break" than, say, the relatively new genes that control your autoimmune system. Their ancient nature enables the lab to effectively model them in simple animals -- specifically, fruit flies, zebrafish and yeasts.

"In the past, there have been technologies available with which to make disease models but that would essentially require taking a sledgehammer to the genome," Perlstein said. "CRISPR changes the situation as it allows for very elegant and precise changes to happen -- down to a single letter change." So once researchers identify the genetic source of the disease, they're able to "program" that same fault into their animal models and measure the effect of the disease in them.

By using CRISPR to break a test animal's genes in the exact same place and the exact same way as in the patient, Perlstein's researchers are able to create a perfectly customized model. Plus they can do so far more quickly than traditional methods would allow. "Depending on the kind of mutation you're trying to create [using CRISPR], it can be quite fast," Perlstein said. "You're only really limited by the breeding time of the animal."

Since the diseases that Perlstein's team research are recessive, the lab can't introduce these gene breaks directly into the models and then immediately study them. Instead, the team introduces these breaks into an organism and then breeds a second generation. Those organisms are then screened those that possess both copies of the recessive gene. Once a sufficient population of models that carry the gene defect has been bred, the lab leverages an automated system to expose them to thousands of chemicals and compounds to see if they have any positive effect -- reversing, or at least reducing the disease's symptoms.


Saturday, July 23, 2016

Sarah Wisely

Sarah Wisely is nothing short of an inspiration. Powered by an innate desire to teach, share and empower, she emailed our home office team in hopes of sharing her life story with our community. It is a story that moved us all so deeply that we were immediately obligated to host a visit and subsequent photo shoot in the Navy Yard here in Philadelphia. Sarah embodies the very essence of who we are at Free People, and we’re very proud to call her our friend.

Last spring I was septic for the 22nd time in three years, with multiple infections causing my lungs to rapidly shut down. Sepsis is an infection that permeates the blood and spreads to your organs,  causing them to shut down and basically fail. The infections that spread throughout my entire body also made their way to my heart, placing me in a state of severe congestive heart failure. Having stared death in the face numerous times, this only motivated — and continues to push — me to fight even harder and live the best life I possibly can, and more.

I always revisit the time when one of my favorite doctors walked into the room, sat by my bed, and suggested that I consider hospice. Hospice is essentially a place where doctors make you comfortable in preparation to pass on. She knew I’d been fighting for a long time and was curious if I was sick of fighting, if I wanted to give up and let my infections take over my body so I could finally be at peace. She also explained that she wasn’t sure if I’d recover, and that I’d be battling the result of being severely septic life long. I looked her in the eyes while she was holding my hand and said “I’m not done here yet, let me fight, I will win.” I fought the 22nd toughest battle of my life and fought hard every day to overcome what has been thrown at me.

Long story short, this illness, along with the many surgeries I’ve had to knock it down, has left permanent scars all over my body. But I know that doesn’t make me any less beautiful. I know I can use everything I’ve been through as fuel to help myself and all women alike be the best they can be and embrace who they are. What’s the point of going through struggles if you don’t turn them around into something good, something positive?

Sarah Elizabbeth Wisely was born on July 26, she was born sick they didn't find out what she had until she was 9 years old. That means that she has to eat out of a feeding tube but she can eat apples and peaches. She is a very smiley person even though she is sick almost all the time. She loves making people laugh and laughing herself. She is outgoing, lovable, stronge, friendly, nice, and a fighter. She is sick all the time but thats not stopping her. Life with EE, HES, && Crones gets hard and is overwelming but hey it makes her stronger person and she is proud of that. All she wants to do is raise awareness so kids that suffer with EE, HES && Crones can live a normal life. And they can feel good about it and she is determind to make a difference.  Even though she is sick day and night she continous to fight for it and enjoys life because she is a stronge girl who has family and friends that loves and supports her. Here is what she goes through everyday: 

Around 3 a.m. my day begins by waking with diarrhea and vomiting. After a couple of hours rushing to the bathroom sweaty and nauseated, it is time to get ready for school. I suffer multiple symptoms including difficulty swallowing, nausea and vomiting, abdominal and chest pain and many more. Eosinophilic Disease is not curable, at least not yet, and I can only manage the symptoms by getting an amino acid formula through a feeding tube that was surgically placed into my stomach.

I often dream about being able to do the things that normal kids my age do. But the thing I want most of all is to have the opportunity to go through the day not feeling sick. I really do not know what it is like to get a good night's sleep, wake up without feeling nauseous, and get through a day without throwing up and having diarrhea.

Most people don’t understand the struggles of living with an Eosinophilic Disease because the disease is not known by many people. This gala, honoring two special people that have educated themselves about the disease and dedicated themselves to spreading awareness will help all of those who live with an Eosinophilic Disease. Awareness will lead to advances in treating Eosinophilic Disease and maybe, one day my dream will become a reality.

I ask Sarah how is it having EGID and going to school and this is what she say:

I actually hate going to school and being sick. I don't get support from the kids at school at all so it makes it a lot harder. A lot of kids also say i am not sick when they have no clue. But all the teachers are awesome about it.

Mysterious Zika transmission

Health officials said Monday that they are investigating the case of a man in Utah who has contracted Zika virus locally through unknown means, one of the more mysterious cases of transmission yet involving the virus.

The individual, who has not been identified, recently helped care for his father, who had contracted Zika and died earlier this month. The second case had not recently traveled outside the country.

That shifts the focus of the investigation to mosquitoes and the possibility that the new case became infected while caring for his dying father. The older man had a serious illness when he contracted Zika while traveling outside the US.

Though most commonly transmitted through the bite of an infected mosquito, Zika virus can be spread through contact with body fluids from an infected person including semen and blood. The virus is also found in urine and saliva…

The man who died had exceptionally high levels of the Zika virus in his system at the end of his life. Health officials acknowledged the younger man was related to the man who died earlier this month but declined to provide further details; they were father and son, according to a person who was familiar with the case but who was not authorized to speak for attribution.

A statement from the CDC said the older man’s blood contained 100,000 times more virus than is normally seen in Zika infection.

It’s too soon to say whether that fact allowed for a type of transmission that hasn’t yet been seen, said Dr. Michael Bell, deputy director of the CDC’s division of health-care quality promotion.

“Currently there’s nothing specific we can say other than recognizing that a high viral load could be a different situation than we would ordinarily see,” said Bell.

“From the infection control perspective, I think it’s early to make a clear statement about what we think could have happened.”

 State officials are working with the CDC to try to interview and test other people who came in contact with the man who died — additional relatives, health-care workers — to see if there were other, undetected secondary cases.

With Zika infection, as many as four out of five cases develop no symptoms; most would go undetected…

“There is a lot of uncertainty around this investigation and we’re currently exploring all avenues for possible transmission,” Dr. Angela Dunn, deputy state epidemiologist, told STAT.

“We’re exploring contact with the deceased patient [as a transmission route] as well as our mosquito trapping and testing for Aedes, the species of mosquito that is known to carry the mosquito virus as well as testing other mosquito species for the Zika virus.”

Dunn said Aedes mosquitoes are not thought to be established in Utah. Trapping efforts are underway around the residences of the man who died and his relative to try to see what types of the insect are present and whether any of them are infected with Zika.

Courtesy of Doximity

Friday, July 22, 2016


McGinnis E, Kessler SK. Lacosamide use in children with epilepsy: Retention
rate and effect of concomitant sodium channel blockers in a large cohort.
Epilepsia. 2016 Jul 19. doi: 10.1111/epi.13466. [Epub ahead of print]

To evaluate the effectiveness of lacosamide (LCM) in pediatric patients, using time to treatment failure as the outcome measure, and to assess the impact of concomitant sodium channel blocker (SCB) use on LCM retention.
This is a retrospective cohort study of patients <21 years old receiving LCM from 2010 to 2015. Kaplan-Meier survival curves were generated for time to LCM failure, defined as discontinuation of LCM or addition of another antiepileptic therapy. The impact of concomitant use of traditional SCB agents (phenytoin, carbamazepine, oxcarbazepine, and/or lamotrigine) and other factors including age, seizure types, fast drug titration, and prior antiepileptic drug history were evaluated using Cox regression.
The analysis cohort included 223 patients, of whom 116 were taking one or more SCBs, with median follow-up of 7.4 months (1-53 months). For all patients, the probability of remaining on LCM without addition of another therapy was 44.7% at 12 months and 25.6% at 24 months. Concomitant SCB use was an independent predictor of time to LCM failure (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.38-2.65, p < 0.001).Although treatment emergent adverse effects were reported more often in patients taking SCB (65% vs. 39%, p < 0.001), intolerability was rarely the sole reason cited for LCM discontinuation, and SCB use was strongly associated with LCM failure, even when controlling for presence of treatment emergent adverse effects (adjusted HR 1.99, 95% CI 1.36-2.90, p < 0.001).
This study provides observational evidence for treatment persistence of LCM in children, in a large cohort with long-term follow-up, using time to treatment failure as the outcome measure. Concomitant SCB use was a key factor increasing risk of LCM failure, but not due to treatment-emergent adverse effects alone.

Courtesy of:

Thursday, July 21, 2016

Prior authorization

A few weeks ago my nurse recorded me making a prior-authorization (PA) phone call for a CT scan I ordered for a patient with a suspicious atraumatic skull mass. I thought, perhaps, the video would show my Facebook followers one of the many hassles of operating within our health care system.

The phone call was fairly typical of interactions with insurance companies -- boring, laborious and nonconclusive. It lasted about 21 minutes. I tried to watch the video right after filming, but I quit after five minutes because I couldn't suffer through the monotonous trauma again so soon. 

A few days later, I braved watching it. I made a few edits, including adding a few snarky subtitles, before sharing it. I posted the video to my practice's Facebook page in the evening. Within a few hours, the post had several dozen likes and shares. Within a week, the video had been shared 299 times and viewed by nearly 20,000 people. A few other physicians with large social media followings also posted my video. The upshot: This video, mostly of me waiting on hold, has now been viewed nearly 100,000 times on Facebook!

I have a decent social media following for a solo family physician, but this mundane video quickly surpassed the reach of anything else I had ever shared. Although this may not be "cat riding on a Roomba" viral, I was blown away at how many people were interested in the video. I have received dozens of messages from doctors and clinic staff thanking me for shining a light on this growing problem.

Why? PA phone calls rank high among physicians' top most burdensome issues, with one study estimating that physicians spend more than 868 million hours each year in PA-related activities. Researchers have actually quantified the absurd amount of time practices spend on administrative tasks.

But most outsiders are unlikely to understand the scope of this daily administrative burden. An AAFP survey found that the average family physician spends two hours each week on prior authorizations -- and that doesn't include staff time spent on the issue…

Although I understand and appreciate this effort, our convoluted payment schemes are sure to make progress on this issue, if possible, extremely slow. Time matters because this red tape is threatening the viability of small, independent primary care practices in the short term…

Given all of the entrenched parties in health care today, I can't offer any easy solutions to this problem. Third-party payers will, understandably, require some form of "determination of need." But clearly, this process could be made more efficient, especially given our amazing computing technologies and automation. I will leave that technological fix up to people who are smarter than me.

On a deeper level, I question the notion that a third party's determination of need leads to better and more economical health care decisions. An alternative solution would be to reduce the prevalence of third-party involvement in transactions altogether. This would require returning some portion of monies to the patient and family to manage themselves, paying simply and directly to physicians and facilities. In consultation with a trusted primary care physician, I believe wise and prudent decisions would be made most of the time.

After all, could patients and their primary care physicians actually be any worse or more inefficient stewards of our health care dollars than third parties have already demonstrated themselves to be?

And these inefficiencies aren't just a hassle or expense for physicians or our clinic staffs. Ultimately, they distract us from patient care. Every minute we spend waiting on hold is a minute that could've been spent educating a patient about his or her diabetes. From my experience, family physicians are generally strong patient advocates, but these hoops can strain our relationships with patients who don't all that happens behind the scenes.


Congenital myotonic dystrophy

Johnson NE, Butterfield R, Berggren K, Hung M, Chen W, DiBella D, Dixon M,
Hayes H, Pucillo E, Bounsanga J, Heatwole C, Campbell C. Disease burden and
functional outcomes in congenital myotonic dystrophy: A cross-sectional study.
Neurology. 2016 Jul 12;87(2):160-7.

Herein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood.
Children with CDM and age-matched controls aged 0 to 13 years were enrolled. Participants were divided into cohorts based on the following age groups: 0-2, 3-6, and 7-13 years. Each cohort received age-appropriate evaluations including functional testing, oral facial strength testing, neuropsychological testing, quality-of-life measurements, and ECG. Independent-samples t test or Wilcoxon 2-sample test was used to compare the differences between children with CDM and controls. Probability values less than 0.05 are reported as significant.
Forty-one participants with CDM and 29 healthy controls were enrolled. The 6-minute walk was significantly different between CDM (258.3 m [SD 176.0]) and control participants (568.2 m [SD 73.2]). The mean lip force strength was significantly different in CDM (2.1 N [SD 2.8)] compared to control participants (17.8 N [SD 7.6]). In participants with CDM, the mean IQ (65.8; SD 18.4) was 3 SDs below the mean compared to standardized norms. Measurements of grip strength, sleep quality, and quality of life were also significantly different. Strength measures (oral facial strength, grip strength, and 6-minute walk) correlated with each other but not with participant IQ.
This work identifies important phenotypes associated with CDM during childhood. Several measures of strength and function were significantly different between participants with CDM and controls and may be useful during future therapeutic trials.

Johnson NE, Ekstrom AB, Campbell C, Hung M, Adams HR, Chen W, Luebbe E,
Hilbert J, Moxley RT 3rd, Heatwole CR. Parent-reported multi-national study of
the impact of congenital and childhood onset myotonic dystrophy. Dev Med Child
Neurol. 2016 Jul;58(7):698-705.

The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1).
We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests.
One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens' lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia.

A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under-recognized.

The scarlet E

In the 21st Century epilepsy remains a stigma & burden

Epilepsy is the most common serious neurological condition, which affects between 5 and 10 per thousand persons in the community. It is estimated that over 50 million people worldwide suffer from epilepsy and that 5 million of them live in India. Thanks to the many developments in medical science, epilepsy is today, eminently treatable. A number of anti-epileptic drugs are available, which have the ability to suppress and control seizures. Certain forms of epilepsy respond well to brain and nerve stimulation procedures and to surgery. When access to the best treatments is available, about two thirds of people with epilepsy either stop having seizures, or have a considerable reduction in their seizures. However, the vast majority of people with epilepsy, experience in countries like India, barriers to healthcare, failing the “Five A Healthcare Test" of availability, accessibility, affordability, acceptability and accountability. It has thus been estimated that over 90% of people with epilepsy in developing nations like India experience a “treatment gap”!

 Epilepsy is also a distressing and stigmatized disorder. In a critical assessment of how epilepsy (The Scarlet E) is presented in the language media, published in the scientific journal Neurology (2000), Krauss and colleagues showed that of 210 media stories published between 1991 and 1996, nearly one-third contained inaccuracies. These included wrong information about epilepsy (14%), unrealistic expectations about new treatments (9%), and exaggeration of the risks associated with seizures (5%). It has been pointed out that this may only be the tip of the "iceberg of ignorance" and that it draws attention also, to the emerging role of the internet, in spreading misinformation about epilepsy. With such a widespread background of stigma, ignorance and social disadvantage, it is hardly surprising that many people with epilepsy are rendered disabled; this is despite the eminently treatable nature of this disorder. 

The tendency to have recurrent seizures that often strike without warning in the most inopportune moments; in school or in the workplace, while attending a social function, a job interview, crossing the road, boarding a train and so on, does understandably impose many restrictions on the person thus affected. A range of associated circumstances that disadvantage people with epilepsy include problems with obtaining and retaining work opportunities and social relationships because of their health condition; secondary psychological factors like depression that follow its persistent adversity; and, perhaps most important, the tendency in society to stigmatize the person with epilepsy, withholding from the affected person opportunities they would normally have enjoyed. The emphasis in epilepsy care, has therefore, in line with the World Health Organization's (WHO) bio-psycho-social model of health, moved to include role functioning across several life domains; going far beyond the seizure episode and medical condition; incorporating educational, occupational, psychological, family and marital functioning, and health related quality of life.

There are a number of aspects to epilepsy that render it disabling; interestingly, many of these are not paid attention to in the conventional clinical management process. First, the fear of seizures results in a restriction (often family or self-imposed) in physical and social activity right through the lifespan, resulting in the denial of a range of opportunity. Second, embarrassment and perceived stigma due to seizures, result in restriction of social, occupational and vocational functioning (often family or self imposed) as appropriate for age and social station. Third, these and other factors result in poor educational and occupational attainment across the lifespan and thus significantly diminished achievement for the person with disability. Here, educational institutions may contribute to the limitation, the fear of epilepsy preventing their engagement with young epilepsy sufferers. Children and adolescents with epilepsy often are asked to leave school due to their recurrent seizures, an act that does not have any justification. Fourth, diminished social achievement and limited peer group interactions often lower potential for marriage, and impact on normal family life and relationships. Both young people with epilepsy and their families go through many anxious moments, in their search for "a suitable spouse". Last, but not least, the considerable financial burden of epilepsy casts its shadow on the person and the family. Anti-epileptic drugs are expensive, especially the newer ones, and in combination can cost about Rs. 100 per day. Other treatments for epilepsy like brain stimulation and surgery are often beyond the reach of the common man. These factors make epilepsy an invisible disability; a condition in which an apparently normal person is rendered disabled, not only by unpredictable recurrent seizures, but also their stigma and psychosocial impact.

Epilepsy exemplifies the challenge of living with chronic disease. On the one hand people in India are profoundly concerned about illness in a member of their community and very conscious of their need for care and support. On the other hand, this high level of concern combined with very closely knit communities, does lead to a lack of privacy about personal medical information and can contribute to the stigma of conditions like epilepsy. To add to this, there is rampant misinformation about epilepsy and other such disorders that remain closely linked in social consciousness with the gods, demons and spirits; to which the popular media contributes, in no small measure. While stigma about illness is almost as old as humankind and is likely to remain, it can as the epilepsy story shows, become a barrier, not only to appropriate medical management, but also to personal and social achievement across the lifespan. In reality, apart from driving a motorized vehicle and taking part in some risky forms of adventure sport, there are very few activities that a person with epilepsy cannot do; they can engage in most forms of education and trade; get married, beget children and have normal family lives, like everyone else. Yet, stigma and misinformation result in most people with epilepsy, underachieving, often the barriers to achievement being within their own family, or indeed themselves.

Epilepsy should remind us about the need for greater focus as a society on the psychosocial impact of all chronic disease. Casting our nets wider, we do find that the burden of stigma and psychosocial disability extends far beyond epilepsy; to diabetes, depression and other psychiatric disorders, cancer, renal failure, indeed the gamut of chronic diseases that afflict humankind. Perhaps its time both the medical profession and our policy makers paid attention to "the scarlet letters" of the 21st Century.

Ennapadam S. Krishnamoorthy
Neuropsychiatrist & Entrepreneur