Monday, October 26, 2020

Levetiracetam for convulsive status epilepticus in childhood

Abdelgadir I, Hamud A, Kadri A, Akram S, Pullattayi A, Akobeng AK, Powell C. Levetiracetam for convulsive status epilepticus in childhood: systematic review and meta-analysis. Arch Dis Child. 2020 Oct 15:archdischild-2020-319573. doi: 10.1136/archdischild-2020-319573. Epub ahead of print. PMID: 33060105. 


Importance: Prolonged seizures are life-threatening emergencies associated with significant morbidity. 

Objective: To determine the efficacy and safety of levetiracetam in treating convulsive status epilepticus (CSE) in childhood. 

Data sources and study selections: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature were searched from inception up to April 2020. Only randomised controlled trials (RCTs) that included children aged 1 month-18 years were assessed. Two reviewers performed data assessment and extraction. 

Data extraction and synthesis: Ten studies out of the 20 637 citations identified were included. 

Main outcomes: Cessation of seizure activities, time to cessation of seizure activities, need for rapid sequence intubation (RSI), intensive care unit (ICU) admission, recurrence of seizures at 24 hours, adverse events and all-cause mortality. 

Results: We included 10 RCTs (n=1907). There was no significant difference in cessation of seizure activities when levetiracetam was compared with phenytoin (risk ratio (RR)=1.03, 95% CI 0.98 to 1.09), levetiracetam to fosphenytoin (RR=1.16, 95% CI 1.00 to 1.35) or levetiracetam to valproate (RR=1.10, 95% CI 0.94 to 1.27). No differences were found in relation to the timing of cessation of seizures for levetiracetam versus phenytoin (mean difference (MD)=-0.45, 95% CI -1.83 to 0.93), or levetiracetam versus fosphenytoin (MD=-0.70, 95% CI -4.26 to 2.86). There were no significant differences with regard to ICU admissions, adverse events, recurrence of seizure at 24 hours, RSI and all-cause mortality. 

Conclusion: Levetiracetam is comparable to phenytoin, fosphenytoin and valproate as a second line treatment of paediatric CSE. 

Courtesy of: 

Thursday, October 22, 2020

Early intervention. The 30,000,000 word gap.

Children’s vocabulary skills are linked to their economic backgrounds. By 3 years of age, there is a 30 million word gap between children from the wealthiest and poorest families. A recent study shows that the vocabulary gap is evident in toddlers. By 18 months, children in different socio-economic groups display dramatic differences in their vocabularies. By 2 years, the disparity in vocabulary development has grown significantly. 

The study, conducted by researchers at Stanford University, tested the language processing of 18- and 24-month-old toddlers using pictures, instructions, and eye response. Each toddler sat in her caregiver’s lap as images of two familiar objects were shown on a screen. (The caregiver wore sunglasses so the child could not be influenced by the caregiver’s responses to the questions or images.) A recorded voice identified one of the objects by name and used it in a sentence (Look at the doggy). The researchers filmed the child’s eye movements, tracking which picture the child looked at (vocabulary) and how long this took in milliseconds (processing time). (Watch a two-minute video of the study at 

Children from higher economic backgrounds looked at the identified object faster and spent more time looking at the correct image. At 24 months, children from the lower economic group were performing at the same level as the 18-month-olds from the high economic group in both speed and accuracy. The study also focused on the way children process new vocabulary. Here, too, young children from homes with low incomes lag behind children of the same age who are growing up in more affluent circumstances.

This new information connects to what researchers discovered earlier. The landmark Hart and Risley study in 1995 identified “remarkable differences” in the early vocabulary experiences of young children. Researcher and author Betty Hart described the results of their observations: “Simply in words heard, the average child on welfare was having half as much experience per hour (616 words per hour) as the average working-class child (1,251 words per hour) and less than one-third that of the average child in a professional family (2,153 words per hour). This is important because vocabulary development during the preschool years is related to later reading skills and school success in general.


At the University of Kansas in the mid-1990s, child psychologists Betty Hart and Todd Risley discovered that the amount of language a child heard spoken in the home was tightly correlated with socioeconomic status. Tina Rosenberg summarized some of their seminal findings in a New York Times’ “Fixes” column earlier this year: 

The disparity was staggering. Children whose families were on welfare heard about 600 words per hour. Working-class children heard 1,200 words per hour, and children from professional families heard 2,100 words. By age 3, a poor child would have heard 30 million fewer words in his home environment than a child from a professional family. And the disparity mattered: the greater the number of words children heard from their parents or caregivers before they were 3, the higher their IQ and the better they did in school. TV talk not only didn’t help, it was detrimental.

And as the Stanford study suggests, language disparities are taking root well before the age of 3. Left unaddressed, those gaps could have life-changing consequences. Citing earlier research on the early childhood language gaps, Fernald and her co-authors write: “Such a large disparity cannot simply be dismissed as a transitory delay, given that differences among children in trajectories of language growth established by 3 years of age tend to persist and are predictive of later school success or failure.”

Wednesday, October 21, 2020

Personalized medicine in genetic epilepsies

Helbig I, Ellis CA. Personalized medicine in genetic epilepsies - possibilities, challenges, and new frontiers. Neuropharmacology. 2020 Aug 1;172:107970. doi: 10.1016/j.neuropharm.2020.107970. Epub 2020 Jan 20. PMID: 32413583.


Identifying the optimal treatment based on specific characteristics of each patient is the main promise of precision medicine. In the field of epilepsy, the identification of more than 100 causative genes provides the enticing possibility of treatments targeted to specific disease etiologies. These conditions include classical examples, such as the use of vitamin B6 in antiquitin deficiency or the ketogenic diet in GLUT1 deficiency, where the disease mechanism can be directly addressed by the selection of a specific therapeutic compound. For epilepsies caused by channelopathies there have been advances in understanding how the selection of existing medications can be targeted to the functional consequences of genetic alterations. We discuss the examples of the use of sodium channel blockers such as phenytoin and oxcarbazepine in the sodium channelopathies, quinidine in KCNT1-related epilepsies, and strategies in GRIN-related epilepsies as examples of epilepsy precision medicine. Assessing the clinical response to targeted treatments of these conditions has been complicated by genetic and phenotypic heterogeneity, as well as by various neurological and non-neurological comorbidities. Moving forward, the development of standardized outcome measures will be critical to successful precision medicine trials in complex and heterogeneous disorders like the epilepsies. Finally, we address new frontiers in epilepsy precision medicine, including the need to match the growing volume of genetic data with high-throughput functional assays to assess the functional consequences of genetic variants and the ability to extract clinical data at large scale from electronic medical records and apply quantitative methods based on standardized phenotyping language.

Tuesday, October 20, 2020

Non-steroid non-vigabatrin therapies of infantile spasms. A Hussain potpourri.

Hussain SA, Navarro M, Heesch J, Ji M, Asilnejad B, Peters H, Rajaraman RR, Sankar R. Limited efficacy of zonisamide in the treatment of refractory infantile spasms. Epilepsia Open. 2020 Jan 24;5(1):121-126. doi: 10.1002/epi4.12381. PMID: 32140650; PMCID: PMC7049796.


A series of relatively small studies collectively suggest that zonisamide may be effective in the treatment of infantile spasms. Using a large single-center cohort of children with infantile spasms, we set out to evaluate the efficacy and safety of zonisamide. We retrospectively identified all patients with infantile spasms who were treated with zonisamide at our center. For each patient, we recorded dates of birth, infantile spasms onset, response (if any), and most recent follow-up. To quantify zonisamide exposure, we recorded daily dosage and patient weight at each sequential encounter so as to allow calculation of peak and weighted-average weight-based dosage. We identified 87 children who were treated with zonisamide, of whom 78 had previously been treated with hormonal therapy or vigabatrin. Peak and weighted-average zonisamide dosage were 7.1 (interquartile range 3.6, 10.2) and 5.4 (interquartile range 3.0, 8.9) mg/kg/day, respectively. Whereas five (6%) patients exhibited resolution of epileptic spasms, only two (2%) patients exhibited video-EEG confirmed resolution of both epileptic spasms and hypsarrhythmia (electroclinical response). Importantly, both electroclinical responders had not previously been treated with hormonal therapy or vigabatrin; in contrast, none of the 78 children with prior failure of hormonal therapy or vigabatrin subsequently responded to zonisamide. Zonisamide was well tolerated, and there were no deaths. This study suggests that zonisamide exhibits favorable tolerability but very limited efficacy among patients who do not respond to first-line therapy. 

Hussain SA, Asilnejad B, Heesch J, Navarro M, Ji M, Shrey DW, Rajaraman RR, Sankar R. Felbamate in the treatment of refractory epileptic spasms. Epilepsy Res. 2020 Mar;161:106284. doi: 10.1016/j.eplepsyres.2020.106284. Epub 2020 Feb 3. PMID: 32058261.


Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weighted-average weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted.

Hussain SA, Dlugos DJ, Cilio MR, Parikh N, Oh A, Sankar R. Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study. Epilepsy Behav. 2020 Jan;102:106826. doi: 10.1016/j.yebeh.2019.106826. Epub 2019 Dec 6. PMID: 31816477.


Purpose: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. 

Methods: Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. 

Results: Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. 

Conclusions: The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

The economic burden of caregiving in epilepsy

Hussain SA, Ortendahl JD, Bentley TGK, Harmon AL, Gupta S, Begley CE, Khilfeh I, Knoth RL. The economic burden of caregiving in epilepsy: An estimate based on a survey of US caregivers. Epilepsia. 2020 Feb;61(2):319-329. doi: 10.1111/epi.16429. Epub 2020 Jan 17. PMID: 31953846.


Objective: The burden of caregiving for persons with epilepsy (PWEs) has not been examined previously i the United States. We assessed the clinical impact and direct and indirect economic costs for caregivers of PWEs.

Methods: An internet survey of 500 caregivers of PWEs was conducted from May to July 2015 using a combination of validated instruments and questions designed specifically for this survey. Caregivers were stratified by PWE age (adult/child) and disease severity (low: 0 vs high: 1 + seizures in the prior month). Annual self-reported direct and indirect costs were reported per caregiver and extrapolated to all US caregivers. The economic burden of caregiving for PWEs was defined as the difference between costs for caregivers and the general population. 

Results: Caregivers reported that PWEs averaged 11.4 seizures in the prior month. Eighty percent of respondents were female and the average age was 44.3. Since becoming a caregiver, many reported anxiety (52.8%), depression (41.0%), and insomnia (30.8%). Annual mean direct medical costs for caregivers of children with low vs high seizure frequency were $4344 and $10 162, respectively. Costs for caregivers of adult PWEs were $4936 and $8518. Mean indirect costs associated with caregiving for a child with low vs high seizure frequency were $20 529 and $40 137; those for caregivers of an adult were $13 981 and $28 410. The cost estimates are higher vs the general US population; annual per-person healthcare utilization costs were $2740 and productivity loss costs were $5015. When extrapolating to the US population of PWE caregivers, annual costs exceeded $62 billion vs $14 billion for the general population, resulting in a caregiver burden of nearly $48 billion. 

Significance: The clinical and economic burden of caregivers for PWE were substantial, and greatest for those caring for children with frequent seizures. The impact on caregivers should be considered when estimating the value of interventions that control epilepsy.

Prednisolone/prednisone as adrenocorticotropic hormone alternative for infantile spasms

 Li S, Zhong X, Hong S, Li T, Jiang L. Prednisolone/prednisone as adrenocorticotropic hormone alternative for infantile spasms: a meta-analysis of randomized controlled trials. Dev Med Child Neurol. 2020 May;62(5):575-580. doi: 10.1111/dmcn.14452. Epub 2020 Jan 5. PMID: 31903560.


Aim: To compare the efficacy and safety of prednisolone/prednisone and adrenocorticotropic hormone (ACTH) in the treatment of infantile spasms using a meta-analysis of randomized controlled trials (RCTs). 

Method: In a systematic literature search of electronic databases (MEDLINE, Embase, the Cochrane Library), we identified RCTs that assessed prednisolone/prednisone compared with ACTH/tetracosactide in patients with infantile spasms. The electroclinical response and adverse events were evaluated. 

Results: Six RCTs (616 participants) were included in the meta-analysis. Compared with prednisolone/prednisone, ACTH/tetracosactide was not superior in terms of cessation of spasms at day 14 (relative risk 1.19, 95% confidence interval [CI] 0.74-1.92), day 42 (relative risk 1.02, 95% CI 0.63-1.65), and resolution of hypsarrhythmia on electroencephalogram (relative risk 1.14, 95% CI 0.71-1.81); the incidences of common adverse reactions caused by ACTH/tetracosactide were not lower than that of prednisolone/prednisone for irritability (relative risk 0.79, 95% CI 0.57-1.10), increased appetite (relative risk 0.78, 95% CI 0.57-1.08), weight gain (relative risk 0.86, 95% CI 0.56-1.32), and gastrointestinal upset (relative risk 0.60, 95% CI 0.35-1.02), though it seemed less frequent. 

Interpretation: Prednisolone/prednisone elicits a similar electroclinical response as ACTH for infantile spasms, which indicates that it can be an alternative to ACTH for treating infantile spasms. What this paper adds Prednisolone/prednisone is as effective as adrenocorticotropic hormone (ACTH) in electroclinical response of infantile spasms. Prednisolone/prednisone and ACTH cause similar and tolerable adverse effects, whose incidences are comparable. High-dose prednisone/prednisolone might be preferable to low dose for achieving freedom from spasms.

Kelley SA. Corticosteroids and ACTH for infantile spasms: are we closer to equipoise? Dev Med Child Neurol. 2020 May;62(5):540-541. doi: 10.1111/dmcn.14483. Epub 2020 Feb 12. PMID: 32052417.

Monday, October 12, 2020

CUX2 mutation

Inspired by a patient

Barington M, Risom L, Ek J, Uldall P, Ostergaard E. A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder. Eur J Hum Genet. 2018 Sep;26(9):1388-1391. doi: 10.1038/s41431-018-0184-5. Epub 2018 May 24. PMID: 29795476; PMCID: PMC6117349.


In most patients with intellectual disability (ID), the etiology is unknown, but lately several de novo variants have been associated with ID. One of the involved genes, CUX2, has twice been reported to be affected by a de novo variant c.1768G>A; p.(Glu590Lys) in patients with ID or epileptic encephalopathy. CUX2 is expressed primarily in nervous tissues where it may act as a transcription factor involved in neural specification. Here we describe a third case who was diagnosed with epilepsy including general and myoclonic seizures, moderate to severe cognitive disability, and infantile autism. The patient was heterozygous for the c.1768G>A; p.(Glu590Lys) variant in CUX2 identified by whole exome sequencing. These findings strongly suggest a causal impact of this variant and add to our understanding of a subset of patients with ID, seizures, and autism spectrum disorder as well as suggest an important role for the CUX2 gene in human brain function.

Chatron N, Møller RS, Champaigne NL, Schneider AL, Kuechler A, Labalme A, Simonet T, Baggett L, Bardel C, Kamsteeg EJ, Pfundt R, Romano C, Aronsson J, Alberti A, Vinci M, Miranda MJ, Lacroix A, Marjanovic D, des Portes V, Edery P, Wieczorek D, Gardella E, Scheffer IE, Mefford H, Sanlaville D, Carvill GL, Lesca G. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. Ann Neurol. 2018 May;83(5):926-934. doi: 10.1002/ana.25222. Epub 2018 Apr 30. PMID: 29630738; PMCID: PMC6021218.


Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). 

Methods: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. 

Results: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. 

Interpretation: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum.

Pfisterer U, Petukhov V, Demharter S, Meichsner J, Thompson JJ, Batiuk MY, Martinez AA, Vasistha NA, Thakur A, Mikkelsen J, Adorjan I, Pinborg LH, Pers TH, von Engelhardt J, Kharchenko PV, Khodosevich K. Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis. Nat Commun. 2020 Oct 7;11(1):5038. doi: 10.1038/s41467-020-18752-7. PMID: 33028830.


Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.

Tuesday, October 6, 2020

Clinical therapeutic management of human mitochondrial disorders

Josef Finsterer.  Clinical therapeutic management of human mitochondrial disorders.  Pediatric Neurology.  Article in press’


Despite recent advances in the elucidation of etiology and pathogenesis of mitochondrial disorders (MIDs), their therapeutic management remains challenging. This review focuses on currently available therapeutic options for human MIDs.

Current treatment of MIDs relies on symptomatic, multidisciplinary therapies of various manifestations in organs such as the brain, muscle, nerves, eyes, ears, endocrine organs, heart, intestines, kidneys, lungs, bones, bone-marrow, cartilage, immune-system, and skin. If respiratory-chain functions are primarily or secondarily impaired, antioxidants or cofactors should be additionally given one-by-one. To all MID patients an individually-tailored diet and physical training-program should be offered. Irrespective of the pathogenesis, all MID patients should avoid exposure to mitochondrion-toxic agents and environments. Specific treatment can be offered for stroke-like episodes, mitochondrial epilepsy, mitochondrial neuro-gastro-intestinal encephalopathy (MNGIE), Leber’s hereditary optic neuropathy (LHON), thiamine-responsive Leigh syndrome, primary coenzyme-Q-deficiency, primary carnitine-deficiency, Friedreich ataxia, ethylmalonic encephalopathy, acyl-CoA-dehydrogenase-deficiency, pyruvate-dehydrogenase deficiency, and hereditary vitamin-E-deficiency. Preventing the transmission of mtDNA-related MIDs can be achieved by mitochondrion-replacement therapy (spindle transfer, pronuclear transfer). 

In conclusion, specific and non-specific therapies for human MIDs are available and beneficial effects have been anecdotally reported. However, double-blind, placebo-controlled studies to confirm effectivity are lacking for the majority of the measures applied to MIDs. Transmission of certain MIDs can be prevented by mitochondrion-replacement therapy. A multidisciplinary approach is required to meet the therapeutic challenges of MID patients.


Prenatal predictors of motor function in children with open spina bifida

Corroenne R, Yepez M, Pyarali M, Johnson RM, Whitehead WE, Castillo HA, Castillo J, Mehollin-Ray AR, Espinoza J, Shamshirsaz AA, Nassr AA, Belfort MA, Sanz Cortes M. Prenatal predictors of motor function in children with open spina bifida: a retrospective cohort study. BJOG. 2020 Sep 25. doi: 10.1111/1471-0528.16538. Epub ahead of print. PMID: 32975898.


Objectives: To identify predictors for intact motor function (MF) at birth and at 12 months of life in babies with prenatally versus postnatally repaired open spina bifida (OSB). 

Design: Retrospective cohort study SETTING: Texas Children's Hospital, 2011 to 2018 POPULATION: Patients who underwent either prenatal or postnatal OSB repair METHODS: Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of diagnosis (US1), 6 weeks postoperatively (or 6 weeks after initial evaluation in postnatally repaired cases) (US2), and at the last US before delivery (US3). At birth and 12 months, MF was assessed clinically. Intact MF (S1) was defined as the observation of plantar flexion of the ankle. Results from logistic regression analysis are expressed as Odds-ratio[95% confidence interval, p-value]. 

Results: 127 patients were included [93 prenatal repair (51 fetoscopic, 42 open-hysterotomy repair); 34 postnatal repair]. In the prenatal repair group, predictors for intact MF at birth and 12 months included: absence of clubfeet (11.3[3.2-39.1], p<0.01 and 10.8[2.4-47.6], p<0.01), intact MF at US1 (19.7[5-76.9], p<0.01 and 8.7[2-38.7], p<0.01), at US2 (22[6.5-74.2], p<0.01 and 13.5[3-61.4], p<0.01) and at US3 (13.7[3.4-55.9], p<0.01 and 12.6[2.5-64.3], p<0.01) and having a flat lesion (11.2[2.4-51.1], p<0.01 and 4.1[1.1-16.5], p=0.04). In the postnatal repair group, the only predictor of intact MF at 12 months was having intact MF at birth (15.2[2-113.3], p=0.03). 

Conclusion: Detection of intact MF in-utero from mid-gestation to delivery predicts intact MF at birth and at 12 months in babies who undergo prenatal OSB repair. 

Courtesy of:

Sunday, October 4, 2020

A doctor gave me an inept diagnosis for a neurological problem. I should know: I’m a neurologist.

 I love riding bicycles — I’ve been doing it for almost all of my 78 years. So, while visiting my daughter in California in April 2018, I couldn’t refuse a friend’s suggestion of a 15-mile bike ride through fields of flowers and cherry blossoms (a far cry from the barren spring of my home state of Maine). He cheated a bit, riding an e-bike, but I kept up on a borrowed pedal bike with handlebars two inches lower than my own. This required continued neck extension during the ride. 

I felt fine afterward, but within hours I developed neck pain with numbness and tingling radiating down my arms. I went to the emergency department (ED) of an elite medical center two days later, telling the staff that I was a neurologist with suspected cervical (neck) spine disease and possible spinal cord and root compression, a condition in my own specialty. I asked to have a cervical MRI scan performed, plus blood studies to detect a possible spine infection, as I’ve had one before. 

The spinal consultant tested my reflexes with the side of his hand. When I asked about his reflex hammer he replied that he didn’t have one or need one — even though this is tantamount to evaluating the heart or lungs without a stethoscope. 

He initially neglected to examine for the Babinski sign, a classic clinical test, which, if positive, would have strongly suggested spinal cord compression. When I remarked on this failure, he performed the procedure incorrectly. He checked my sensation with his index finger and did not examine other sensations, gait, coordination or hand dexterity. 

The MRI showed clear-cut spinal cord compression due to arthritis, and a neck mass behind the spinal canal. It was an abscess — a pus collection — but the hospital’s radiologist read it as a blood clot. The blood studies revealed active infection: marked elevations in inflammatory markers, plus increased white blood cells of the “should be concerned” variety. These obvious and dangerous abnormalities were not pursued and I was not informed of them. I spent six hours in the ED, then was discharged and told to follow up with a spine surgeon within two weeks. 

Two days later, I traveled home to Maine and reviewed my medical records online. I recognized the severity and complexity of my problem and went to my hospital, was admitted and underwent urgent spine surgery and long-term intravenous antibiotics. Left untreated, these abnormalities might well have caused a catastrophe: I could have become quadriplegic, unable to move my arms and legs or even breathe on my own. My response to the ED visit cannot be expected of the average patient, who would have been in deep trouble.

While recovering, I sent multiple letters detailing the specifics of my deficient care to the hospital’s chief executive. The hospital’s representatives responded, refusing to admit culpability or apologize for these failures. The spine service supervisor even excused the consultant, stating he “conducted the examination to the best of his ability.” 

The lack of recognition of the serious infection went unmentioned in the representatives’ letters. 

In view of the multiple serious medical errors committed during my ED visit, I offered to present and discuss my case to emergency and spine service staff. As a career academic neurologist, I thought a physician analyzing his own medical condition in his own specialty, intending to educate, would be an illuminating and teachable moment for medical staff and students and a healing opportunity for me.

My offer was ignored. 

In 1999, the Institute of Medicine issued its landmark report, “To Err is Human: Building a Safer Health System,” which estimated that as many as 98,000 hospital deaths a year were caused by medical errors. The report made national headlines and generated much subsequent discussion on the causes and effects of medical errors, and the ethics of transparency and disclosure. In response, many hospitals changed their practices and procedures, but two decades later, as my experience suggests, even the best hospitals and doctors remain resistant to admitting error, in large part because they fear malpractice lawsuits. 

Recent research bolsters this view. Several years ago, researchers posed two hypothetical scenarios involving medical error — a delayed breast cancer diagnosis, and a delayed response to a patient’s symptoms because of uncoordinated care — to 300 primary care physicians. More than 70 percent of the doctors surveyed said they would provide “only a limited or no apology, limited or no explanation, and limited or no information about the cause.” Further, when hospital representatives, rather than physicians, respond to medical errors by denying, minimizing or covering them up, physicians often conclude that their hospitals have no interest in confronting these errors head-on. Sure sounds like my situation.

My experience also exemplifies the phenomenon known as “the normalization of deviance” discussed by Diane Vaughan in her 1996 book on the space shuttle Challenger disaster. Vaughan concludes that multiple problems preceding the shuttle launch were recognized, but then rationalized, and “normalized” when they didn’t cause a disaster — until they ultimately did. 

Since the spine consultant did not own a reflex hammer, nor think he needed this basic tool, nor know how to do a proper neurological examination, and he and the ED staff did not recognize that the elevated inflammatory markers were indisputable evidence of serious infection, I could not have been the first patient so poorly evaluated — and, without doubt, not the last. Further, the consultant’s supervisor excused his mistakes, thereby deeming his deviances acceptable. 

The responses to my letters came from hospital patient service representatives, thus this denial and normalization was institutional, in support of Vaughan’s premise “that individual behavior cannot be understood without taking into account the organizational and environmental context of that behavior.” Vaughan mentions that sometimes the normalization of deviance only becomes evident after whistleblower revelation.

I am that whistleblower, “the canary in the coal mine.” 

The hospital’s administrator tasked with patient communication and resolution, and a widely known advocate for these subjects, was unaware of my complaints until I found her by happenstance 18 months later (listening to the TED Radio Hour while in my car) and contacted her. She was initially supportive of my request to present my own case for discussion and analysis, but now, more than 10 months later, she has yet to follow through. 

She wrote to me: “Hospitals don’t seem to know what to do with the opportunity you present. I don’t think the challenge is unique to [this institution]. A forum for these kinds of discussions — constructive, insightful patient feedback does not exist.” 

Initially, she told me that since my SOL is up I might have a better chance of making my presentation. I asked: “What is a SOL?” She said: “statute of limitations.” I said: “I don’t want to sue, I want to teach.”  

Of course, if I had been quadriplegic on a respirator I would have sued. But since I saved my own skin, that was not necessary. The aphorism, “A physician who treats himself has a fool for a patient,” only applies if competent care is available. 

For me, four years of medical school and five years of postgraduate training had a uniquely personal advantage. I’m just sorry that a teachable moment for the benefit of future patients, and a healing activity for me, was missed. 

Steven Horowitz is a retired academic neurologist who continues to teach medical students as an adjunct clinical professor of neurology at the Tufts University School of Medicine. He is also on the teaching faculty of the Maine Medical Center.