Friday, March 31, 2017

Primary carnitine deficiency identified by whole exome sequencing

Interesting, but it seems like obtaining carnitine levels initially would have led to the diagnosis faster. In this setting primary carnitine deficiency would seem to be high on the differential.(Stanley CA, DeLeeuw S, Coates PM, Vianey-Liaud C, Divry P, Bonnefont JP, Saudubray JM, Haymond M, Trefz FK, Breningstall GN, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol. 1991 Nov;30(5):709-16.)

Lahrouchi N, Lodder EM, Mansouri M, Tadros R, Zniber L, Adadi N, Clur SB, van Spaendonck-Zwarts KY, Postma AV, Sefiani A, Ratbi I, Bezzina CR. Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death. Eur J Hum Genet. 2017 Mar 15. doi: 10.1038/ejhg.2017.22. [Epub ahead of print]

Pediatric cardiomyopathy is a rare but severe disease with high morbidity and mortality. The causes are poorly understood and can only be established in one-third of cases. Recent advances in genetic technologies, specifically next-generation sequencing, now allow for the detection of genetic causes of cardiomyopathy in a systematic and unbiased manner. This is particularly important given the large clinical variability among pediatric cardiomyopathy patients and the large number of genes (>100) implicated in the disorder. We report on the performance of whole-exome sequencing in members of a consanguineous family with a history of pediatric hypertrophic cardiomyopathy and sudden cardiac death, which led to the identification of a homozygous stop variant in the SLC22A5 gene, implicated in primary carnitine deficiency, as the likely genetic cause. Targeted carnitine tandem mass spectrometry analysis in the patient revealed complete absence of plasma-free carnitine and only trace levels of total carnitine, further supporting the causality of the SLC22A5 variant. l-carnitine supplementation in the proband led to a rapid and marked clinical improvement. This case illustrates the use of exome sequencing as a systematic and unbiased diagnostic tool in pediatric cardiomyopathy, providing an efficient route to the identification of the underlying cause, which lead to appropriate treatment and prevention of premature death. 

From the article

The proband was a 3-year-old girl of Moroccan descent who was born to a 25-year-old female at 39 weeks of gestation via caesarian section. She had normal development until the age of 2 years. In the months prior to admission, the parents noted progressive fatigue, shortness of breath and pallor. The patient had no learning difficulties or mental retardation. She was referred to a pediatric cardiologist and at the time of presentation was in a good overall condition. During physical examination, pallor of skin and conjunctivae were observed. No audible heart murmur was noted and the peripheral pulse was normal. She had normal neurological examination and no dysmorphic features were identified. Her electrocardiogram (ECG) revealed high voltage R and deep S waves in V5 and V2, respectively, suggesting left ventricular hypertrophy, tall peaked T-waves and a short QTc interval, (318 ms; Figure 1a). Trans-thoracic echocardiography revealed situs solitus levocardia with atrioventricular and ventricular arterial concordance. There was good systolic function with a shortening fraction of 36%. Severe concentric hypertrophy was observed without outflow or intra-cavity obstruction (Figure 1c). The left ventricular posterior wall and the interventricular septum were measured 8.3 mm (normal range (NR), 3.2–6.1; z-score,11 3.26; height, 102 cm; weight, 14 kg) and 10.5 mm, respectively (NR, 3.5–7.1; z-score, 3.45; Table 1). There was no mitral regurgitation and the rest of the heart was normal. Her creatine kinase level was 110 U/l (NR, 30–200) and hemoglobin level measured 7 g/dl (NR, 11–13). The patient lived in an isolated area of the south of Morocco with limited access to specialized clinical infrastructure and unfortunately biochemical testing for known treatable causes of pediatric cardiomyopathy was not performed at this stage. In addition, there is, at present, no nationwide newborn screening program in Morocco...

Because of a remarkable family history of two siblings dying suddenly at young age, she was referred for further investigation to the department of medical genetics in Rabat (Morocco). The pedigree of the family is shown in Figure 2. The proband (II-5) is the offspring of consanguineous parents. Her oldest brother (II-1) died suddenly at 6 months of age. Her sister (II-2) had a very similar clinical course as the proband with progressive fatigue and shortness of breath. She was seen by a pediatric cardiologist and diagnosed with severe hypertrophic cardiomyopathy at the age of 3 years. Unfortunately, she died suddenly shortly after the diagnosis was made. The third sibling (a boy, II-3) died at 20 weeks of gestation. His fetal ultrasound showed severe hypertrophic cardiomyopathy. The patient’s only living sibling (II-4) is 7 years old and is doing well. Considering the significant family history and heterogeneity of genetic causes of pediatric cardiomyopathy,12, 13 we performed WES to detect the potential underlying genetic cause to assist in the making of a definite diagnosis....

To follow-up on our genetic findings, we performed targeted tandem mass spectrometry analysis of plasma carnitine levels in the patient revealing complete absence of free carnitine (0 μmol/l; ref., 30–50 μmol/l) and a trace level of total carnitine (<1 μmol/l; ref., 43–65 μmol/l) further establishing the diagnosis of PCD.

Courtesy of ResearchGate

Anoxic-epileptic seizures

In appreciation of my friendship and collaboration with Dr. J.B.P. Stephenson

Stephenson J, Breningstall G, Steer C, Kirkpatrick M, Horrocks I, Nechay A,
Zuberi S. Anoxic-epileptic seizures: home video recordings of epileptic seizures
induced by syncopes. Epileptic Disord. 2004 Mar;6(1):15-9.

Occasionally, but more often than has been reported, true epileptic seizures are triggered by non-epileptic syncopes. This combination of syncope and epileptic seizure has been called an anoxic-epileptic seizure. A few examples of such anoxic-epileptic seizures, including the induction of status epilepticus, have been reported in books and medical journals, but no video-recordings have been published. We show here home video recordings of the first three known examples of the transition from the triggering syncope and anoxic seizure, to the subsequent epileptic seizure. In the first two children, a neurally-mediated syncope, probably mediated by prolonged expiratory apnoea (so-called breath-holding spells), induces a long, clonic epileptic seizure with some features of myoclonic absence. In the third example, a compulsive Valsalva in an older autistic child provokes a vibratory tonic epileptic seizure. In addition, we show two further video clips of the most usual type of epileptic seizure induced by syncopes in very young children. In one, the video recording begins after the end of the triggering syncope and shows a rhythmic clonic seizure that includes repetitive vocalizations. The final recoding is of a spontaneous epileptic seizure with features of myoclonic absence: this child had both epilepsy and identical episodes induced by syncopes, that is, anoxic- epileptic seizures. Not only paediatricians and paediatric neurologists, but also adult neurologists and epileptologists in general, should be aware of the important clinical scenario of true epileptic seizures induced by syncopes. This phenomenon is not considered in any international classification. (Published with videosequences)

(You need to be patient with the download on these videos.  For a while it seems like nothing is happening)

Thursday, March 30, 2017

Post-ictal generalized EEG suppression as a marker of SUDEP risk

Joon Y. Kang, Amin H. Rabiei, Leslie Myint, Maromi Nei.  Equivocal significance of post-ictal generalized EEG suppression as a marker of SUDEP risk. Seizure.  In press.

•PGES is a frequent but inconsistent finding in patients after generalized convulsive seizure.
•PGES is shorter in patients who die from definite or probable SUDEP compared to living controls.
•Earlier nursing intervention correlates with shorter seizure duration after GCS.

Our objective was to determine the significance of PGES as a possible EEG marker of increased risk for SUDEP and explore factors that influence PGES.

We identified 17 patients who died due to definite or probable SUDEP and 52 living control patients with drug resistant focal epilepsy who underwent EEG monitoring and least one seizure recorded on EEG. We reviewed 305 seizures on EEG and when available, on video, for presence or absence of PGES, the duration of PGES immediately after seizure end, seizure type, state seizure occurred (sleep vs. wake), tonic duration and time from seizure onset to initial nursing intervention. We noted that majority (93% in SUDEP group and 83% living controls) with PGES had additional brief bursts of suppression. We measured the time from the end of seizure to end of last brief suppression to determine the time to final PGES.

SUDEP patients had statistically significant shorter PGES duration compared to living controls (unadjusted:-32.8s, 95%CI[−54.5, −11.2], adjusted:-39.5 s, 95% CI[−59.4, −19.6]). SUDEP status was associated with longer time to final PGES compare to living controls, but this was not statistically significant. Earlier nursing intervention was associated with shorter seizure duration. PGES occurred only after GCS. Time to nursing intervention, tonic duration or state did not have a statistically significant effect on PGES.

PGES is an equivocal marker of increased SUDEP risk. Earlier nursing intervention is associated with shorter seizure duration and may play a role in reducing risk of SUDEP.

Courtesy of:


Tuesday, March 28, 2017


In December, 2015, the Migration Board rejected their final appeal, and, in a letter, told the family, “You must leave Sweden.” Their deportation to Russia was scheduled for April. Soslan said that to his children Russia “might as well be the moon.” Georgi read the letter silently, dropped it on the floor, went upstairs to his room, and lay down on the bed. He said that his body began to feel as if it were entirely liquid. His limbs felt soft and porous. All he wanted to do was close his eyes. Even swallowing required an effort that he didn’t feel he could muster. He felt a deep pressure in his brain and in his ears. He turned toward the wall and pounded his fist against it. In the morning, he refused to get out of bed or to eat. Savl poured Coca-Cola into a teaspoon and fed Georgi small sips. The soda dribbled down his chin.

At the recommendation of neighbors, Georgi’s parents called Elisabeth Hultcrantz, an ear-nose-and-throat doctor who volunteers for the charity Doctors of the World. Three days after Georgi took to his bed, Hultcrantz drove to his home, a red wooden cottage with white trim in the farmlands of Garpenberg, a hundred and twenty miles northwest of Stockholm. Georgi was wearing boxers and short athletic socks. He appeared to be asleep. A tulip-patterned blanket had been pulled up to his chin. When Hultcrantz touched him, his eyelids trembled, but he didn’t move. Using a pillow, she propped up his head, but it flopped to the side. “He provides no contact whatsoever,” she wrote.

After a week, Georgi had lost thirteen pounds. Hultcrantz, a professor emeritus at Linköping University, urged the family to take him to the emergency room in Falun, a city forty miles away. He hadn’t eaten for four days and had not spoken a full sentence in a week.

A doctor at the hospital wrote that Georgi “lies completely still on the examination table.” His reflexes were intact and his pulse and blood pressure were normal. The doctor lifted Georgi’s wrists a few inches above his forehead and then dropped them. “They fall down on his face,” she wrote. A nurse noted that he showed “no reaction to caregiving.”

The next day, a doctor inserted a feeding tube through Georgi’s nostril. “He showed no resistance,” Soslan said. “Nothing.” Georgi was given a diagnosis of uppgivenhetssyndrom, or resignation syndrome, an illness that is said to exist only in Sweden, and only among refugees. The patients have no underlying physical or neurological disease, but they seem to have lost the will to live. The Swedish refer to them as de apatiska, the apathetic. “I think it is a form of protection, this coma they are in,” Hultcrantz said. “They are like Snow White. They just fall away from the world.”

The apathetic children began showing up in Swedish emergency rooms in the early two-thousands. Their parents were convinced that they were dying. Of what, they didn’t know; they worried about cholera or some unknown plague. Soon patients with the condition filled all the beds in Stockholm’s only psychiatric inpatient unit for children, at Karolinska University Hospital. Göran Bodegård, the director of the unit, told me that he felt claustrophobic when he entered the rooms. “An atmosphere of Michelangelo’s ‘Pietà’ lingered around the child,” he said. The blinds were drawn, and the lights were off. The mothers whispered, rarely spoke to their sick children, and stared into the darkness.

By 2005, more than four hundred children, most between the ages of eight and fifteen, had fallen into the condition. In the medical journal Acta Pædiatrica, Bodegård described the typical patient as “totally passive, immobile, lacks tonus, withdrawn, mute, unable to eat and drink, incontinent and not reacting to physical stimuli or pain.” Nearly all the children had emigrated from former Soviet and Yugoslav states, and a disproportionate number were Roma or Uyghur. Sweden has been a haven for refugees since the seventies, accepting more asylum seekers per capita than any other European nation, but the country’s definition of political refugees had recently narrowed. Families fleeing countries that were not at war were often denied asylum…

In a hundred-and-thirty-page report on the condition, commissioned by the government and published in 2006, a team of psychologists, political scientists, and sociologists hypothesized that it was a culture-bound syndrome, a psychological illness endemic to a specific society. Every culture possesses what Edward Shorter, a medical historian at the University of Toronto, calls a “ ‘symptom repertoire’—a range of physical symptoms available to the unconscious mind for the physical expression of psychological conflict.”…

Georgi spent three nights at the hospital in Falun before being sent home with a special supportive mattress. His friends called and texted him repeatedly, but they received no response. Georgi’s teachers called his family to find out why he had been absent for a week. Floridan, the headmaster, said that Georgi’s classmates were in tears when he explained what had happened. He told them, “Georgi has waited such a long time to get an answer about whether he can stay here in Sweden, and he has more or less given up. He finds no meaning in school or to even exist.”

A physiotherapist at the hospital advised Georgi’s parents to turn on the lights in his bedroom every morning, and to immerse him in the daily routine of the household. Georgi was rolled to the dinner table in a wheelchair; a cushioned headrest propped up his head, though his eyes remained closed. He was fed four hundred and fifty millilitres of nutrients five times a day, through a tube…

In a seventy-six-page guide for treating uppgivenhetssyndrom, published in 2013, the Swedish Board of Health and Welfare advises that a patient will not recover until his family has permission to live in Sweden. “A permanent residency permit is considered by far the most effective ‘treatment,’ ” the manual says. “The turning point will usually be a few months to half a year after the family receives permanent residence.”…

A chipper, gray-haired grandmother, Hultcrantz seems unaware of her power. She sometimes encourages families to “get their tubing”—the feeding tube—as quickly as possible, in order to emphasize their suffering to the Migration Board. Her iPhone is full of photographs that she has taken of refugee children lying in bed. Their eyes are closed, their faces are pale, and they have an expression of dull tranquillity…

In April, four months after Georgi became ill, the family’s deportation was postponed, because his dependence on the feeding tube made flying hazardous. He seemed to be sinking deeper into the condition. Hultcrantz observed that he had begun to drool. At Falun Hospital, a doctor noted that Georgi had “no muscle tone in either the arms or legs,” and that his arm reflexes were “difficult to trigger.” The doctor wrote, “The boy is alive but barely.”…

No apathetic patients are known to have died, but a few have been bedridden for as long as four years…

In late May, 2016, Georgi’s family received another letter from the Migration Board. Their neighbor Ellina Zapolskaia translated it. “The Migration Board finds no reason to question what is stated about Georgi’s health,” she read out loud. “He is therefore considered to be in need of a safe and stable environment and living conditions in order to recuperate.” The family was granted permanent residence in Sweden.

Georgi’s parents immediately went upstairs to his bedroom to tell him. He showed no reaction. “He doesn’t listen,” Zapolskaia said. “He’s not there—not anywhere.” For two weeks, Georgi’s brother, parents, and friends tried to get him to absorb the good news. His family took him in his wheelchair to an ice-skating rink, where his classmates were playing hockey, but the fresh air had little noticeable effect. “You have got the positive!” one of his friends kept shouting. Zapolskaia said, “We tried to show him that our mood had changed.”…

On June 6th, two weeks after the family learned that they could stay in Sweden, Georgi opened his eyes. “It was just a little—a little,” Zapolskaia said. He quickly shut them. “The light was too painful,” Georgi said later. “But I remember that I saw my family.” His body throbbed, as if he had just exercised far beyond his natural capacity…

Like most apathetic children, Georgi regained physical abilities in the reverse order in which he had lost them. He opened his eyes; made eye contact with his family; began to feed himself; started to walk, shakily at first and then more steadily; and finally began to talk in full sentences…

 “All my will—I didn’t have it anymore,” he said. “It felt like I was deep under water.” He struggled to find language that could adequately capture the experience. “I was just very tired,” he said at one point. “It was not like now—I want to go and run.” At another point, he compared it to eating too much: “You don’t have any appetite.” He didn’t seem satisfied with either description and tried again: “My whole body was like water.”

Courtesy of a colleague

Vein of Galen malformation

The pregnancy with this female neonate was complicated by a diagnosis of a large intracranial arteriovenous malformation in the fetus, as well as fetal heart failure with a dilated right atrium and right ventricle and cardiomegaly on fetal echocardiogram. There was also mildly decreased cardiac contractility, and a dilated superior vena cava. Fetal ultrasound examinations did not show evidence of hydrops, and demonstrated normal growth.

A planned cesarean section delivery was performed due to the intracranial arteriovenous malformation. The membranes were ruptured at delivery. The amniotic fluid was normal in quantity and was clear. The neonate was in vertex presentation. She was then intubated for a preplanned angiogram. Her  birth weight was 2060 grams.

There was mild dilatation of both lateral and 3rd ventricles. The 4th ventricle was normal in size. Findings consistent with a large (slightly greater than 2 cm) vein of Galen aneurysm were noted.
MR angiography as well as routine sequences demonstrated that there were both anterior and posterior circulation feeding arteries. There are abnormally enlarged basilar and vertebral arteries as well as the posterior cerebral arteries and branches. Both posterior communicating arteries are markedly enlarged as are the anterior communicating arteries and anterior cerebral arteries and their branches. Middle cerebral arteries appear normal in caliber. The abnormally enlarged vein of Galen drains through an enlarged straight sinus and torcula into bilateral large transverse sinuses and sigmoid sinuses. Jugular veins are also seen to be abnormally enlarged.

The posterior fossa had a normal appearance. The supratentorial brain, however, appeared markedly atrophic with prominent extra-axial fluid spaces in a symmetric pattern. There was a diminished quantity of white matter. Brain parenchyma had an  abnormally heterogeneous signal intensity.

A postnasal echocardiogram obtained on the neonate demonstrated a widely patent aortic arch with significant diastolic reversal. There was a stretched foramen ovale with right-to-left shunting. There was aneurysmal right-to-left bowing of the atrial septum. The right ventricle was markedly enlarged with reduced systolic function. There was mild right ventricular hypertrophy. There was mild-to-moderate tricuspid valve insufficiency. There was prominent flow in the right superior vena cava and innominate vein.

She was transitioned from amplitude integrated EEG, which showed intermittent seizures, to conventional EEG and ongoing frequent focal electrographic seizures were noted. These were much more frequent from the left hemisphere than the right hemisphere.  These were typically brief, and lasted less than 1 minute.  Some of the longer ones lasted up to 2 minutes before resolving spontaneously.  Again, the patient probably had 2 to 3 (sometimes more) electrographic seizures per hour during this recording.  With some electrographic seizures, she would desaturate, but not with everyone.  Otherwise, there was no clinical correlate.  Age-anticipated markers of state modulation and sleep architecture were not appreciated.  This was a diffusely suppressed record (voltages of 10 microvolts or less), consistent with diffuse cerebral dysfunction.

The seizures were refractory to treatment with phenobarbital, fosphenytoin and levetiracetam.  Ultimately, the parents decided to pursue palliative care and limitation of support.  Shortly thereafter, the patient passed away.

Monday, March 27, 2017

16p13.11 microdeletions


Inspired by a patient

Many babies with a 16p13.11 microdeletion are born completely healthy. Others have a birth defect which can be quite minor or more serious. Most of the birth defects reported among babies with 16p13.11 microdeletion have only occurred in just a few babies, so they may be a coincidence, and it is still not clear if all of the birth defects reported here are actually caused by the 16p13.11 microdeletion. 

However, one common finding is that on investigation, 17 people with the microdeletion 8 have some anomaly of the brain structure that shows on magnetic resonance imaging (MRI). Various anomalies have been detected and there appears to be no consistent feature. 

Children and adults with the microdeletion may have hands that are not perfectly formed. One child has fingers which are fused (syndactyly). Two children have fingers which do not fully straighten. These features do not usually cause medical problems but in some cases do have an impact on functionality. 

The feet of children with 16p13.11 microdeletions may also not be perfectly formed. One child had rocker bottom feet. He had serial casting on his feet for 6 weeks from birth which brought his feet into the correct position. He then wore special boots for 23 hours a day for 4 months to maintain the correct position. He will continue to wear his boots at night until he is 4 years old (he is now 3½). Another has feet that pronate (roll inwards) and wears ankle foot orthotics (AFOs) on both feet to correct her foot position and help her to bear weight. 

In five babies the heart was affected: three babies had small holes in the heart which all resolved spontaneously and needed no treatment. Another baby had cardiomegaly (an enlarged heart) at birth but on follow-up at 3 months the heart was normal. Another baby had hypertrophic cardiomyopathy (the muscle of the heart is thickened) which needed no intervention. Two baby boys were born with undescended testes and one had a very small penis (micropenis). One baby boy was born with hypospadias, where the opening usually at the end of the penis is on the underside, generally corrected with surgery. 

Two babies had brachycephaly (a flat head) which necessitated wearing a cranial helmet (Unique). 

One baby was born with a cleft palate (an opening in the roof of the mouth, usually closed surgically). 

In one baby the kidneys and drainage system for urine were affected. One baby was born with a hollow chest (pectus excavatum). 

One girl had a urethral caruncle for a short period which resolved itself. A urethral caruncle is a soft, fleshy protrusion of the urethral lining from the urethral opening. The urethra is the tube that drains urine from the bladder. One baby had a twisted neck (torticollis)…

In general children with a 16p13.11 microdeletion are happy, kind, affectionate and social. However, they are as vulnerable to frustration as other children with a communication difficulty and a small minority succumb to temper tantrums and aggression. One adult described in the medical literature was very talkative with intermittent verbal aggression and self-mutilation. 

Autistic traits or autistic spectrum disorder (ASD) have also been reported in several people with a 16p13.11 microdeletion. A diagnosis of autism can be extremely helpful in accessing services and tailoring the educational and behavioural therapy to meet the specific needs of a child with autism. Two children find socialising difficult, one of whom has been diagnosed with an anxiety disorder. Four children have obsessive compulsive disorder (OCD), an anxiety-related condition in which people experience frequent intrusive and unwelcome obsessional thoughts, often followed by repetitive compulsions, impulses or urges. Sensory issues have also been reported to affect four children. One person has Tourette syndrome (a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalisations called tics). 

One person in the medical literature is described as having psychotic depression (depression accompanied by hallucinations and delusions) which developed after the onset of epilepsy and another has psychosis (a condition that affects a person’s mind and causes changes to the way that they think, feel and behave and can result in an inability to distinguish between reality and imagination) which is controlled with medication…

A 16p13.11 microdeletion is tiny, so it can only be found using molecular techniques such as MLPA or microarrays (array-CGH) or targeted cytogenetic testing using FISH. These techniques show whether particular genes are present or not. The features of a 16p13.11 microdeletion are likely to be a result of the loss of a number of different genes found in this region. The typical 16p13.11 microdeletion is 1.65Mb and encompasses around 15 genes. Some people have a slightly larger deletion, however, it seems that these people have the same features as those with the smaller, typical microdeletion. NDE1 which is expressed in the brain has been postulated to be responsible for the microcephaly that is often seen in those with a 16p13.11 microdeletion. 

Mutations in NDE1 in humans have been shown to cause microcephaly. Mice missing this gene have a small brain. 

NTAN1 is a candidate for some of the features of a 16p13.11 microdeletion. Mice missing this gene have altered social behaviour and memory. 

It is important to remember that while identifying the gene(s) responsible for certain features of a 16p13.11 microdeletion is valuable and may help guide future studies, it does not lead directly to immediate improved treatment. Additionally, even if the supposedly responsible gene is missing it does not always mean that the associated feature(s) will be present. Other genetic and environmental factors often have a role in determining the presence or absence of a particular feature. 

Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

Aran A, Segel R, Kaneshige K, Gulsuner S, Renbaum P, Oliphant S, Meirson T, Weinberg-Shukron A, Hershkovitz Y, Zeligson S, Lee MK, Samson AO, Parsons SM, King MC, Levy-Lahad E, Walsh T. Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome. Neurology. 2017 Mar 14;88(11):1021-1028.

To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.
Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12A123.7 cells.
Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis. The older brother died of respiratory failure at 5 days of age. The proband, now 4.5 years old, has been mechanically ventilated since birth with virtually no milestones achievement. Whole exome sequencing revealed homozygosity of SLC18A3 c.1078G>C, p.Gly360Arg in the affected brothers but not in other family members. SLC18A3 p.Gly360Arg is not reported in world populations but is present at a carrier frequency of 1:30 in healthy Yemeni Jews. SLC18A3 encodes the vesicular acetylcholine transporter (VAChT), which loads newly synthesized acetylcholine from the neuronal cytoplasm into synaptic vesicles. Mice that are VAChT-null have been shown to die at birth of respiratory failure. In human VAChT, residue 360 is located in a conserved region and substitution of arginine for glycine is predicted to disrupt proper protein folding and membrane embedding. Stable transfection of wild-type and mutant human VAChT into neuronal-like PC12A123.7 cells revealed similar mRNA levels, but undetectable levels of the mutant protein, suggesting post-translational degradation of mutant VAChT.

Loss of function of VAChT underlies severe arthrogryposis and respiratory failure. While most congenital myasthenic syndromes are caused by defects in postsynaptic proteins, VAChT deficiency is a presynaptic myasthenic syndrome.

Transparency update


CNN deliberately exaggerated the death rate of infants undergoing heart surgery at St. Mary’s Medical Center, purposefully painting a renowned surgeon as an incompetent doctor who butchers babies for profit, the physician’s lawyer told a judge on Friday. 

Dr. Michael Black is suing CNN for libel and defamation for its story on June 1, 2015, about St. Mary’s pediatric cardiac surgery program. The hospital closed the program a few months later and its CEO resigned.

“CNN intentionally manipulated statistical data to support its false narrative that Dr. Black was unfit to perform operations on these very sick children,” said his attorney, Libby Locke, after a hearing on whether to dismiss her client’s lawsuit.

“Through their defamatory articles and videos, CNN has deprived Palm Beach of an incredibly valuable pediatric cardiac surgery program.”

She urged Circuit Judge Richard Oftedal to reject the motion to dismiss and to allow a jury to decide what Black’s reputation is worth. She noted how the news network took a quote from one grieving parent that Black was offering up babies as sacrificial lambs,” and juxtaposed it with a photograph of the doctor.

Black contends in the defamation and libel lawsuit that CNN;’s story unfairly disparaged him and forever damaged his reputation. He still is employed at St. Mary’s, but has not done any surgery since the program was closed in August 2015.

The doctor is also facing several malpractice suits filed by parents of babies who died after heart surgery at St. Mary’s, but Friday’s hearing was about Black’s defamation claims against the cable news giant. CNN is trying to get Oftedal to dismiss the lawsuit.

Locke, his attorney, told the judge CNN went so far as to manipulate the calculations to report St. Mary’s death rate as three times the national average for pediatric heart surgery programs. She said CNN ignored data from the Society of Thoracic Surgeons that found St. Mary’s death rate for infant cardiac surgeries fell within the norm.

Instead, the news network compared raw data of open and closed heart surgeries with just open heart surgeries. It also compared raw death rate figures with those adjusted for the complexity of the surgery and illness of the patient, Locke said.

The Palm Beach Post reported in several articles about troubles with CNN’s data. The network eventually posted on its website a story explaining its methodology. Florida’s Agency for Health Care Administration got into the fray, calling CNN’s reporting sensationalistic.

Friday was the first time the two sides really squared off in front of the judge since Black filed his suit in February as judge entertained argument over CNN’s motion to dismiss Black’s suit.

The cable news network told Oftedal that CNN’s reporting is protected because Black as a prominent surgeon of a major pediatric heart surgery program was a public figure.

Sunday, March 26, 2017

Motor plasticity in the adult nervous system

Aguilar MJ. Recovery of motor function after unilateral infarction of the basis pontis. Report of a case. Am J Phys Med. 1969 Dec;48(6):279-88.

The purpose of this paper is to report a case of nearly complete recovery of motor function in a 72-year-old man within 4 years of a “stroke” which manifested itself clinically by a right hemiplegia. At autopsy, 6 years later, the lesion was seen to have destroyed the major portion of the left rostra1 basis pontis. The distal corticospinal tract in the left lower pons and medullary pyramid and its crossed and uncrossed continuations in the spinal cord exhibited marked atrophy, demyelination and gliosis. Examination under high magnification, however, revealed the presence of partially spared longitudinally oriented fiber bundles in both medialmost and lateralmost portions of the basis pontis and of spared, widely scattered intact myelinated axons in the pyramidal tract distal to the lesion.

After 2 years of intensive physical therapy, the patient recovered all motor function on the right except for slight clumsiness in performing skilled movements with the right hand. The disparity between the severity of the pyramidal tract lesion and the mildness of the motor disability strengthens the case for the existence of motor plasticity in the adult human nervous system.

From the article

In April 1960 the patient was hospitalized for a cerebral thrombosis with resultant right hemiplegia and difficulty with speech. Deep tendon reflexes on the right were hyperactive and there was a Babinslii sign on the right. Following discharge, physical therapy was initiated. Four months later a follow-up examination revealed marked improvement in the patient's speech and muscle power.
There remained a slight right facial weakness, slight weakness of the muscles of the right upper extremity and a more marked weakness of the right iliopsoas, hamstring and peroneal muscles. Deep reflexes in the right upper and lower extremities remained hyperactive; the plantar response on the right was equivocal.

Systematic physical therapy was continued over the following 2 years. At the end of this period the patient had recovered almost completely from the hemiplegia and speech difficulty. In May 1964 (4 years after the cerebrovascular accident) neurological examination revealed no residuals save for slight clumsiness in using the right hand for fine movements, such as when the patient buttoned his shirt or tied his shoelaces. He had no difficulty with writing, and his speech was normal. Muscle power and tone were good, and no reflex changes were present…

In reporting his progress with the development of a vision substitution system, Bach-y-Rita recounts evidence of both sensory and motor plasticity of the brain, with special reference to special retraining and rehabilitative techniques designed to enhance this innate ability of one neural system to assume the functions of another. He cites, among other work, that of Foerster, in which training led to restitution of arm and hand movements in adult humans despite anatomically verified complete pyramidal tract degeneration.


A case demonstrating recovery of motor function within 4 years after infarction of half of the basis pontis is reported, and the neuropathological findings are detailed. The patient had the benefit of prompt and extended physical therapy. Accumulating evidence from anatomical, physiological and clinical studies appears to support the concept of considerable motor plasticity in the adult brain.

Courtesy of The Brain That Changes Itself by Norman Doidge, MD.  Penguin Books, 2007.  Pp 20-23. 
Courtesy of my daughter

Core Jewish values at the end of life

What follows is an attempt to formulate in a simple, non-technical manner four basic Jewish values that should guide our health care decisions. In our complex world, these values are often in tension with one another, and we need to apply much work and thought situationally to resolve the tension by determining which values control the specific case at hand. While there is no simple formula that can plot a clear path forward in all situations, identifying the core values can help us recognize that path.

Value 1: Pursue Life…

In the early 80’s, a fellow student at the Ner Israel Rabbinical College suffered from advanced liver disease. After a waiting period, he travelled to Pittsburgh where he was given a liver transplant, at the time a rare procedure. The surgeon, the pioneering Dr. Thomas Starzl, commented to a friend of the patient that he had once been puzzled by what appeared to be an extremely high number of Orthodox Jewish people with serious liver disease. Eventually he came to realize that the numbers affected by the disease were not exceptional. What was exceptional was the numbers of the Orthodox who came running to Pittsburgh upon hearing through their communal networks that there was a crazy doctor there who offered hope through transplantation.

The pursuit of life is a core Jewish value.

Value 2: Cherish Life of Any Quality or Duration…

The value underlying this mandate was articulated beautifully by one of the fathers of the field of modern Jewish Medical Ethics, the British Chief Rabbi, Lord Immanuel Jakobovits z”l. As he saw it, human life is of infinite value, and elementary mathematics teach us that any fraction of the infinite is equally infinite. We can therefore never turn away from our mandate to pursue and preserve life because we view it as unworthy.

In discussions of quality of life, some suggest that in certain situations it would be appropriate to apply the Biblical phrase, “My death would be better than my continuing to live.” This seems a rather ironic citation. Its source is the prophet Yonah (Chapter 4), who finds himself sitting in the blazing heat outside the city of Nineveh. After the gourd that had shielded him withered and died, Yonah declared his disgust with continued life in such heat. This statement leads to a strong rebuke from God, who places this attitude in the context of Yonah’s apparent general disregard for the value of human life, as expressed in his objection to God’s saving the city of Nineveh. God clearly corrects Yonah and makes him understand that the value of life is so great that it compels us to pursue life even if it offends our sense of justice or our personal comfort. My continuing to live is far better than dying.

The value placed on life of any quality is something to which many of us are very sensitive, as we recall that the same evil Nazi machinery that destroyed millions of Jews as ostensibly inferior beings also set out to destroy hundreds of thousands of the mentally and physically handicapped. Yet in the span of a few decades we have seen a dizzying evolution in society’s attitudes in this area. In the 1990’s Dr. Jack Kevorkian was widely seen as a monster – “Dr. Death” – for facilitating the suicides of the suffering, impaired and terminally ill. Today, physician assisted suicide in many such situations is legal in a number of states and lobbied for in others.

Judaism places infinite value on life of any quality or expected duration.

Value 3: There is a Time to Die

Despite the great value we place on life, we recognize that there may come a time where we suspend the pursuit of life. This recognition was brought out by the author of the 13th Century “Sefer Chasidim” (n. 234), who noted that King Solomon (Koheles 3:2) included death amongst all those matters for which there is an appropriate time: “There is a time to give birth and a time to die.” Yet all the other items listed are activities in which we choose to engage, and regarding which we are taught that there are appropriate times. Death, however, is not typically a choice. As such, what practical guidance is provided by declaring that there is a time to die?

Sefer Chasidim explained that death may indeed be a choice. At times when a person is deathly ill and his soul is clearly ready to leave him, the option exists to engage in loud screaming that may agitate him (the example given by the Sefer Chasidim), or to perform chest compressions, thus keeping him alive for a few more days of suffering. In such situations, King Solomon counsels us to submit and recognize that there is a time to die, and we must step aside and let the patient go.

According to the mainstream consensus amongst widely respected Halachic authorities, this ruling would not justify the withdrawal of life support, nor the withholding of basic elements of human sustenance, including artificial hydration and feeding. It would however discourage extraordinary measures such as resuscitation or intubation of an end stage or very frail patient, in whom such efforts have no hope of accomplishing more than granting a few additional painful days…

The gifted surgeon and author Atul Gawande said it best:

“Death is the enemy. But the enemy has superior forces. Eventually, it wins. And, in a war that you cannot win, you don’t want a general who fights to the point of total annihilation. You don’t want Custer. You want Robert E. Lee, someone who knew how to fight for territory when he could, and how to surrender when he couldn’t, someone who understood that the damage is greatest if you fight to the bitter end.”

As believing Jews, we recognize our human limitations and understand that there is a time to accept our mortality.

Value 4: Practice Kindness and Sensitivity

Ultimately, medicine should be an expression of human compassion, rather than the exercise of a technical skill. As such, medical practitioners must never lose sight of their obligation to bring care and sensitivity to the patient. And while life of any quality is of primary and infinite value, there may be times when fulfilling that value will cast too onerous a burden upon the patient, in the form of continued and irremediable physical or emotional pain.

The Talmud (Ksubos 104a, Bava Metzia 84a, Ran Nedarim 40a) gives examples of situations like these where indeed the pursuit of life seemed to be suspended, as people shifted to pray for the patient’s demise. These sources led the most widely respected Halachic authorities to rule that while life may be worthy of pursuit at all times, we cannot and do not compel the patient to do so if it will lead to real and enduring pain and suffering. This ruling was limited to situations that featured active physical pain or exceptional emotional torment, and did not include cases of diminished activity and function, such as dementia or coma…

When we reach the point where the soul is indeed visibly struggling to leave, or where we recognize that our efforts will at best leave the patient to suffer interminably, we must continue our efforts to care for patients and family, but in a different modality. Instead of focusing on conquering or healing the disease, we must ensure that they are not left alone, that their pain is addressed as best as possible, and that they are given an environment and circumstances where their comfort is an active goal.

The phantom Pokemon

This has happened to me too many times to count.  With certain of the episodes, I would realize what is happening and try to cry out, hoping my wife would awaken me.  Occasionally, this worked.  I am told that my cry was more like a repeated whimper.

In Moscow this past summer, a woman drifted-off to sleep after playing Pokemon Go on her smartphone. Later that night, she was awoken by a crushing pressure. She opened her eyes and reportedly saw that she was being assaulted by a real-life Pokemon character. Not a person in a Pokemon outfit, an actual Pokemon. Panicking, but unable to speak, she struggled with the creature while her boyfriend slumbered ignorantly beside her. Eventually, she was able to rise, and the Pokemon vanished. After a brief search of her home, the woman proceeded to report the assault the police.

News of the woman’s police report was quickly, and somewhat gleefully, picked up by a variety of international tabloids. It rattled about the internet, and eventually surfaced on my Twitter feed. But my first thought, as an experimental psychologist with a particular focus in anomalous perceptual experiences was, “Well, that could have happened to anybody.” Although it’s impossible to definitively explain this woman’s experience, I nevertheless felt quite confident that this late-night Pokemon assault fit neatly into our existing understanding of sleep. Indeed, given what we now know about this mysterious neuropsychological state – and the strange sensations it can bring – one might arguably describe her experience as ‘normal’.

The short, seemingly paradoxical, explanation is that she could have been awake and she could have been dreaming. Setting aside the Pokemon for a moment, let’s first consider her report of waking up, unable to move, with a crushing presence on top of her. The technical term that might apply here is ‘sleep paralysis,’ a subtype of parasomnia, or sleep disturbance. Beyond the inability to move, these periods of wakeful paralysis are often accompanied with vivid multisensory hallucinations. Effectively, imagery from your dreams can actually intrude into your waking reality…

Sleep paralysis researchers Brian Sharpless and Karl Dograhmji have collected 118 different terms from around the world that describe sleep paralysis-like experiences: Germans have terms for hexendrücken – witch pressing – and alpdrücken –  elf pressing. Norwegian folktales include svartalfar – evil elves that shoot people with paralysing arrows before perching on their chests. The Japanese have a term, kanashibari, in reference to being magically bound by invisible metal. In parts of Switzerland people speak of tchutch-muton, an evil nightmare fairy that disguises itself as a black sheep. Kurds refer to mottaka, an evil spirit that suffocates people in the night. The Iranians have a term called bakhtak, which refers to a type of jinn that sits on the sleeper’s chest. Scientists have theorised that sleep paralysis experiences might be result in some modern accounts of alien abductions. So I don’t feel it’s a huge logical leap to include Pokemon assaults…

For comparison’s sake, consider this account by Jon Loudner, who gave ‘evidence’ during the infamous Salem Witch Trials in 1692:

“… I going well to bed, about the dead of the night felt a great weight upon my breast, and awakening, looked, and it being bright moonlight, did clearly see Bridget Bishop, or her likeness, sitting upon my stomach. And putting my arms off of the bed to free myself from that great oppression, she presently laid hold of my throat and almost choked me. And I had no strength or power in my hands to resist or help myself. And in this condition she held me to almost day.”

Like the Muscovite woman in 2016, Jon experienced a vision of a figure on top of him, accompanied by a crushing sensation and paralysis, although in his case, the best explanation he could come up with was an assault by a local witch. You can see the distinct parallels with the Pokemon case that have emerged as hallmarks of sleep paralysis cases. He woke in the night, was unable to move, and had the experience of a figure on top of him, disrupting his breathing…

What is known is that, typically, when we dream, our actions are confined to our imagination. We all have a built-in safety mechanism, which you can think of as something like a circuit breaker; it effectively blocks your brain’s motor planning signals from becoming motor action signals. This mechanism prevents us from physically acting out the actions that we dream of making. Thus, when you’re being chased by a monster in a dream, you don’t actually rise up and charge into the bedroom wall, or evolutionarily-speaking, tumble out of your tree. However, our brains are highly complex systems, and, as such, are prone to the occasional glitch.

One such glitch is fairly well known: sleepwalking occurs when the paralysis eases too early, while you’re still asleep. On the flip side, sometimes the paralysis lingers – even after you’ve awoken. This typically happens just on the threshold of sleep – either just as you’re waking up or just as you’re drifting off. You can be conscious, with your eyes open, but be completely unable to move your body. Again, this is a fairly common occurrence, but the experience can be understandably alarming…

Researchers have shown that sleep paralysis experiences can be induced in laboratory participants when they are repeatedly woken from deep sleep. And outside of laboratories, it’s not particularly unusual for people to experience sleep paralysis in their nightly lives. If you’ve never had an episode yourself, odds are that you know someone who has. Experts estimate that up to 50% of the population will experience sleep paralysis at least once in their lifetime; some people report that their episodes are regular nightly occurrence…

In 2000, a team of scientists led by Robert Stickgold at Harvard Medical School reported that participants who played the video game Tetris would consistently report seeing game-related ‘hypnogogic imagery’- they experienced visions of the iconic falling blocks just before falling asleep. Similar results have been obtained using other types of video games, such as a downhill ski arcade game, a virtual maze, and even Doom. This evidence has been used to support the idea that sleeping might serve to ‘consolidate’ memories from our waking life - consolidation is term that refers to the process of reinforcing and strengthening newly created memories. Various experiments have demonstrated that people who are given memory-based tasks will perform better if they’re given the opportunity to sleep after learning. It seems as though after we’ve been engaged in a learning task, our minds might be using sleep as a sort of rehearsal space to practice problems…

In one experiment, a team at MIT inserted electrodes directly into a part of the rats’ brains known as the hippocampus. In both rats and humans, the hippocampus is the part of the brain, which among other functions, is strongly associated with the way we form memories of physical spaces. The electrodes allowed the researchers to observe the real-time neural activity of specific cells in the hippocampus – with a spike being recorded every time one of the cells was activated. While the rats were wired-up, they learned to navigate a physical maze in exchange for a food reward. Because the hippocampus is involved with spatial learning, the patterns of electrical activity in the hippocampus could be associated with the rat’s location in specific parts of the maze.

But here’s where this method becomes relevant to our Pokemon/Tetris dream discussion: after the rats had learned the maze, the scientists left the electrodes recording as the rats drifted off to sleep. As the rats slept, the cells in the hippocampus would light up with activity. And not just any activity – the patterns of activations that occurred while the rats slept corresponded with the pattern associated with the correct maze runs. Again, we can’t ask the rats what they were actually experiencing, but the results suggest that the rats may have been running the maze in their dreams, effectively practicing the best possible runs that they’d learned before falling asleep.

Courtesy of a colleague.

Saturday, March 25, 2017

Risk of seizure recurrence after a first seizure

Syed Rizvi, Lady Diana Ladino, Lizbeth Hernandez-Ronquillo and José F. Téllez-Zenteno. Epidemiology of early stages of epilepsy: Risk of seizure recurrence after a first seizure .  Seizure.  In press.


• Early antiepileptic drug treatment reduces seizure recurrence risk in the short-term.
• Early antiepileptic drug treatment does not affect the prognosis for the development of epilepsy.
• Focal or nocturnal seizure and prior brain injury increased the risk of seizure recurrence.
• Epileptiform discharges on EEG and neuroimaging abnormalities increased risk of recurrence.
• A Single Seizure Clinic model reduces wait-times and impacts clinical care decisions.


A single unprovoked seizure is a frequent phenomenon in the general population and the rate of seizure recurrence can vary widely. Individual risk prognostication is crucial in predicting patient outcomes and guiding treatment decisions. In this article, we review the most important risk factors associated with an increased likelihood of seizure recurrence after a single unprovoked seizure. In summary, the presence of focal seizure, nocturnal seizure, history of prior brain injury, family history of epilepsy, abnormal neurological exam, epileptiform discharges on electroencephalography and neuroimaging abnormalities, portend increased risk of seizure recurrence. Elucidation of these risk factors in patient assessment will augment clinical decision-making and may help determine the appropriateness of instituting anti-epilepsy treatment. We also discuss the Canadian model of single seizure clinics and the potential use to assess these patients.

From the article:

The overall risk of recurrence after a first generalized tonic–clonic seizure is approximately 30% at 5 years, assuming that subtle prior seizures or known ongoing risk factors are absent .  If the seizure is idiopathic, only 17% had a recurrence at 20 months. If the seizure was idiopathic and the patient had a sibling with seizures, the risk of seizure recurrence increased to 29%, and if the seizure was idiopathic with spike-wave discharges on electroencephalogram (EEG), the risk of seizure recurrence increased to 50%. The recurrence rate is higher in individuals who have a symptomatic etiology compared to those with an idiopathic or cryptogenic etiology. For children with first seizures that are idiopathic/cryptogenic, the recurrence risk is 40% by 2 years, while for symptomatic seizures the estimate of recurrence risk is above 50%.   

Patients with head trauma have a high recurrence risk (46% at 20 months). Overall, a history of a previous neurologic injury is associated with a 2.5-fold increased risk of recurrence. Prolonged seizures, status epilepticus, prior acute symptomatic seizures, and a Todd paralysis also increase the risk of recurrence in patients with remote symptomatic seizures. A population-based study in Italy reported that among ischemic strokes, seizure recurrence risk factors were younger age (p = 0.004) and cortical location of stroke (p = 0.004). Within intracerebral hemorrhages, the only risk factor for seizure recurrence was the presence of a previous early seizure (p = 0.017).

In children, the 5-year recurrence risk after a first seizure hovers around 42%  [41]  . Shinnar et al.  [53]  observed that the risk of seizure recurrence in a child with a first seizure in the presence of epileptiform abnormalities on EEG is comparable to the recurrence risk after a second seizure (>50% likelihood of seizure recurrence). In their quantitative review of 1930 patients, Berg and Shinnar  [1]  determined that an abnormal neurological exam or EEG, and partial epilepsy emerged as the strongest predictors of a second seizure. The lowest seizure recurrence risk was in the idiopathic group with normal EEGs (24%, 95% CI = 19%, 29%) and the highest risk was carried by the group with remote symptomatic seizures and abnormal EEGs (65%, 95% CI = 55%, 76%).

Recently a meta-analysis examining patients who underwent routine EEG after a first unprovoked seizure and were followed for seizure recurrence for at least 12 months, was published. They reported differences between adults and children. An adult with epileptiform discharges on routine EEG after a first unprovoked seizure has a 77% probability of having a second seizure, whilst a child with similar findings has a 66% probability. Another study evaluated the yield of 24-h video-EEG in assessing recurrence risk after a first unprovoked seizure. Chen and colleagues reported a risk of recurrence of 73.2% in the epileptiform discharges abnormality group. Overall, epileptiform abnormalities were associated with an increased risk of seizure recurrence (RR 2.84, 95% CI 1.67–4.82, p < 0.001)  [55]  . Finally there is a study by Dash et al. assessed the yield of portable EEG in adult population. In this study the portable EEG was used in a subgroup of patients with clear single unprovoked seizures. Epileptiform activity was identified in all of them. These patients were started on medication. This study suggests that the identification of epileptiform activity in patients with single unprovoked seizures using prolonged recording could help to avoid seizure recurrence.

A self-propagating mechanism of kindling – seizures promoting the occurrence of more seizures, causing intractable epilepsy – has been cited as a reason to start early AED treatment after a first seizure. However, despite evidence of kindling and secondary epileptogenesis in animal models, there is no firm evidence of this phenomenon occurring in humans. The decision to initiate AED treatment is relatively straightforward in patients who experience two or more unprovoked seizures, and hence have a diagnosis of epilepsy. The decision to treat a patient in the wake of a solitary unprovoked seizure is more complex and requires a thorough consideration of various demographic and personal risk factors such as socioeconomic impact, stigma, sick role, medical comorbidities, patient age, employment, need to drive, insurance concerns, personal preference, and AED side-effect profile and teratogenicity. The adverse effects range from mild symptoms to life threatening reactions and up to 30% of patients discontinue their first prescribed AED due to adverse effects. In the National General Practice Study of Epilepsy, only 15% of patients received AED treatment after a first seizure. AED treatment was justified when there was a high risk of seizure recurrence or potential for serious injury…

Before any treatment decisions are approached, it is critical to determine whether the event is truly a seizure and whether it is in fact the first seizure event. The decision as to whether or not to treat children and adolescents who have experienced a first unprovoked seizure must be based on a risk-benefit assessment that weighs the risk of having another seizure against the risk of chronic therapy. As in adults, early treatment with AED reduces the risk of early seizure recurrence, but does not prevent the development of epilepsy. Additionally, AED therapy in children has potential side effects such as somnolence, headache, anorexia, nausea or abdominal pain, increased irritability, rash, hirsutism, weight gain (7–58%), and significant cognitive, behavioral and psychosocial side effects, particularly affecting brain development during infancy.

Clinicians must involve the patient and caregivers in the shared decision making process. In general, clinicians should advise patients with an unprovoked non-febrile first seizure that the risk of recurrence is highest in the two years following the seizure. Family should also be informed of factors that place a child increase risk, as well as initiation detailed discussion of the side-effect profiles of relevant AED agents. Ultimately, the decision to withhold or initiate AED treatment is based on assessment of individualized risk and benefit as determined by the clinician.

Vagal nerve stimulation with SCN1A gene abnormalities

Fulton SP, Van Poppel K, McGregor AL, Mudigoudar B, Wheless JW. Vagus Nerve Stimulation in Intractable Epilepsy Associated With SCN1A Gene Abnormalities. J Child Neurol. 2017 Apr;32(5):494-498.


Mutations in the SCN1A gene cause a spectrum of epilepsy syndromes. There are 2 syndromes that are on the severe end of this spectrum. The classic severe form, Dravet syndrome, is an epileptic encephalopathy of childhood, causing cognitive decline as well as intractable seizures. Severe Myoclonic Epilepsy of Infancy-Borderline (SMEIB) is a term used to include cases with similar severities as those with Dravet syndrome, but lacking a single feature of classic severe myoclonic epilepsy of infancy. Vagus nerve stimulation is a nonpharmacologic treatment for intractable epilepsy. A retrospective review was conducted of patients with deleterious SCN1A mutations who had vagus nerve stimulation placement for treatment of their intractable epilepsy. These children had onset of their epilepsy between 3 and 29 months of age. Seizure control was assessed 6 months after implantation. Twenty patients are included in the study, with 12 implanted at our institution. Nine of the 12 patients implanted at our institution, who had confirmed pre- and post-implantation seizure assessments, showed improvement in seizure control, which was defined as >50% reduction in generalized tonic-clonic seizures, and 4 of those 12 reported improvement in cognitive or speech development. Seven of the 8 patients not implanted at our institution reported subjective benefit, with 4 relating "marked improvement" or seizure freedom. Vagus nerve stimulation appears to impart a benefit to children with deleterious SCN1A gene abnormalities associated with intractable epilepsy.

Hypothalamic connectivity and abnormal pituitary morphology in children with Prader-Willi syndrome

Lukoshe A, van Dijk SE, van den Bosch GE, van der Lugt A, White T, Hokken-Koelega AC. Altered functional resting-state hypothalamic connectivity and abnormal pituitary morphology in children with Prader-Willi syndrome. J Neurodev Disord. 2017 Feb 21;9:12.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, characterized by endocrine problems and hyperphagia, indicating hypothalamic-pituitary dysfunction. However, few studies have explored the underlying neurobiology of the hypothalamus and its functional connectivity with other brain regions. Thus, the aim of this study was to examine the anatomical differences of the hypothalamus, mammillary bodies, and pituitary gland as well as resting state functional connectivity of the hypothalamus in children with PWS.
Twenty-seven children with PWS (13 DEL, 14 mUPD) and 28 typically developing children were included. Manual segmentations by a blinded investigator were performed to determine the volumes of the hypothalamus, mammillary bodies, and pituitary gland. In addition, brain-wide functional connectivity analysis was performed using the obtained masks of the hypothalamus.
Children with PWS showed altered resting state functional connectivity between hypothalamus and right and left lateral occipital complex, compared to healthy controls. In addition, children with PWS had on average a 50% smaller pituitary volume, an irregular shape of the pituitary, and a longer pituitary stalk. Pituitary volume did not increase in volume during puberty in PWS. No volumetric differences in the hypothalamus and mammillary bodies were found. In all subjects, the posterior pituitary bright spot was observed.
We report altered functional hypothalamic connectivity with lateral occipital complexes in both hemispheres, which are implicated in response to food and reward system, and absence of connectivity might therefore at least partially contribute to the preoccupation with food in PWS.

Courtesy of:

Friday, March 24, 2017

Duplication of the pituitary gland - plus syndrome

Inspired by a patient

Sen D, Arora V. Duplication of the pituitary gland - plus syndrome. Indian J Radiol Imaging. 2016 Jan-Mar;26(1):126-30.

Duplication of the pituitary gland (DPG) is a very rare developmental anomaly that is often associated with other anomalies - the DPG-plus syndrome and occurs due to splitting of the rostral notochord and prechordal plate during blastogenesis. DPG with the constellation of associated anomalies as in our patient has not been reported previously. This article illustrates the importance of imaging the brain in all patients with obvious midline facial anomalies and the complementary role of MRI and CT in such cases.

From the article

Duplications of internal organs are rare. They occur either due to non-union of anlages or division of the primordial organ. Duplication of the pituitary gland (DPG) is a very rare developmental anomaly, with only 40 cases reported till 2012.  With DPG as the common denominator, a large number of associated anomalies have been reported - the DPG-plus syndrome.  In this article, we report a case of pituitary duplication that was associated with duplication of the sella, hypertelorism, cleft palate, a large craniopharyngeal canal and oropharyngeal teratoma, hypoplastic olfactory bulbs and tracts, duplication of the basilar artery, and cervical anterior cleft vertebrae. DPG with this constellation of associated anomalies in the same patient has, to the best of our knowledge, not been reported previously…

DPG is a very rare developmental anomaly with only 40 cases reported till 2012. It has been reported in both the pediatric and adult populations. Most patients are females. DPG is usually detected in unsuspected patients on imaging due to the associated midline craniofacial anomalies.
The rarity of this entity may hence be partially attributable to incidental detection on imaging and early mortality in some patients. While most patients have been diagnosed in the neonatal period, later detection has been due to evaluation for anosmia, delayed onset of puberty and menarche, and precocious puberty.

DPG is frequently associated with multiple other craniofacial defects like broadening or duplication of the sella, broadening of the optic chiasma, duplication of the infundibulum, tubo-mamillary fusion (hypothalamic pseudohamartoma), duplication of the basilar artery, agenesis/hypoplasia of the corpus callosum, hypertelorism, cleft palate, craniopharyngeal canal, oropharyngeal teratomas, and vertebral segmentation anomalies.  Other rare associations that have been reported include duplication of the lips, tongue, mandible; a wide cribriform plate; absent olfactory bulbs and/or tracts; cerebellar hypoplasia; ventricular enlargement; pontine hypoplasia; neuronal migration abnormalities; and supernumerary teeth.  Apart from anomalies of the head and neck region, congenital diaphragmatic hernia has been associated with DPG. The high association of these craniofacial anomalies with DPG is suggestive of a polytopic blastogenesis defect, and hence, Manjila, et al. have proposed the term DPG-plus syndrome…

Thus, these anomalies in our patient as well as the spectrum of other associated anomalies in DPG-plus syndrome can all be explained based on the theory of rostral notochordal splitting during blastogenesis. MRI of the brain is essential in all patients with obvious midline facial anomalies. T1W, T2W and fluid attenuated inversion recovery (FLAIR) axial, and T2W sagittal and coronal images should be acquired in all such patients. The field-of-view (FOV) during acquisition of the sagittal and coronal images should be such as to include the cervical spine. Detection of tubo-mamillary fusion should prompt a dedicated sellar imaging protocol. These sequences may be supplemented by non-contrast and contrast-enhanced fat-suppressed images when a craniopharyngeal mass is detected. Vascular anomalies detected on T2W axial and coronal images may be better delineated by 3D-Time of Flight (3D-TOF) MR angiography (MRA). CT scan has a complementary role as it better delineates osseous craniofacial anomalies and affords 3D reconstructions and surface rendering for pre-surgical planning. Due to the high association of flow-related aneurysms with duplications and fenestrations, periodic surveillance for aneurysms is also warranted.
Notwithstanding the rarity of associated anomalies outside the central nervous system or the spine, a chest radiograph and an abdominal USG should be considered…

DPG is a very rare developmental anomaly that occurs due to splitting of the rostral notochord and prechordal plate during blastogenesis. It is often associated with a large number of associated craniofacial anomalies and, hence, the appellation the DPG-plus syndrome. This case illustrates that it may be worthwhile imaging the brain in all patients with obvious midline facial anomalies and a dedicated sellar protocol in the presence of tubo-mamillary fusion. While MRI is the primary modality of imaging in such patients, the complementary role of CT scan is also highlighted.

Wednesday, March 22, 2017

Acetazolamide for electrical status epilepticus in slow-wave sleep

Fine AL, Wirrell EC, Wong-Kisiel LC, Nickels KC. Acetazolamide for electrical status epilepticus in slow-wave sleep. Epilepsia. 2015 Sep;56(9):e134-8.


Electrical status epilepticus in slow-wave sleep (ESES) is characterized by nearly continuous spike-wave discharges during non-rapid eye movement (REM) sleep. ESES is present in Landau-Kleffner syndrome (LKS) and continuous spike and wave in slow-wave sleep (CSWS). Sulthiame has demonstrated reduction in spike-wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre- and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers.

Moderators and predictors of response to behavior therapy for tics in Tourette syndrome.

Sukhodolsky DG, Woods DW, Piacentini J, Wilhelm S, Peterson AL, Katsovich L, Dziura J, Walkup JT, Scahill L. Moderators and predictors of response to behavior therapy for tics in Tourette syndrome. Neurology. 2017 Mar 14;88(11):1029-1036.

To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders.
Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9-69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression-Improvement score assessed by masked evaluators.
The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction.
Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication.
The child and adult CBIT studies are listed on clinical (NCT00218777 and NCT00231985, respectively).

This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup.

Another approach

At the Rocky Mountain Center for Epilepsy, we use a holistic bio-psycho-social model of care. Through our work together, we will support you in improving your quality of life. We’ll help you:

Learn healthy coping strategies for both real and perceived limitations caused by your seizures
Improve unwanted emotional aspects of your diagnosis, including shame, PTSD, depression, anxiety, and/or anger
Recognize seizure triggers and transform (not avoid) your relationship with them
Learn how to transform feelings of stress and overwhelm
Use nutrition/food to support greater brain health
Gain a deeper understanding of how nervous system activation builds increasingly: including anxiety, depression, symptoms of PTSD, and seizure activity
Learn how to down-regulate nervous system over-activation
Increase mindfulness and self-awareness in regards to smallest emotional, physiological, and physical changes, leading to your ability to “not go into a seizure”
Learn how to regulate your breathing (CO2 levels) to increase oxygen levels available to the brain
Explore questions, insecurities, and hopes around your diagnosis
We use a variety of complementary techniques, depending on each patient’s individual needs. Our work together may include psychotherapy and life coaching, mindfulness training and meditation, stress-reduction techniques, professionally guided support groups, biofeedback, neurofeedback, and aura disruption techniques. Use the following links to learn more about our specialties:

Breathing Biofeedback

Tuesday, March 21, 2017

Sudden unexpected death in epilepsy: Measures to reduce risk

Brendan Mclean; Rohit Shankar; Jane Hanna; Caryn Jory; Craig Newman.   Sudden Unexpected Death in Epilepsy: Measures to Reduce Risk.  Pract Neurol. 2017;17(1):13-20.


This review looks at the strategies that may help to reduce the risk of sudden unexpected death in epilepsy beyond that of trying to achieve seizure cessation, which is not possible for up to 30% of patients with epilepsy. These strategies include seizure safety checklists, mobile phone technology, telehealth and various devices currently available or in development. We highlight interventions where there is evidence of benefit, and draw attention for the need both to involve patients with epilepsy in risk reduction and to improve communication with those at risk…

From the article 

Strategies to reduce the risk of SUDEP must involve not only people with epilepsy but also their general practitioners. General practitioners have the most medical contact with people with epilepsy, not just for their epilepsy but also for other conditions that may also influence risk, such as depression and substance misuse. The UK's National Institute for Health and Care Excellence epilepsy guidelines from 2004 to 2012 clearly state that the risk of death in epilepsy, in particular SUDEP, should be discussed as a priority at the time of diagnosis.  Its equivalent in Scotland, the Scottish Intercollegiate Guidelines Network epilepsy guidelines 2015, suggests discussion about SUDEP at an 'appropriate time'. Despite this risk, there is a tacit avoidance of discussing the risk of death both in primary and secondary care, while the patient organisations and SUDEP Action (formerly Epilepsy Bereaved) vociferously support the patients' view that such should be made transparent. This article sets out strategies that may help clinicians to improve person-centred communication when dealing with epilepsy, to reduce this risk.

Discussing SUDEP has been controversial and some countries still advocate a paternalistic approach on a 'need to know basis'.  A recent court judgement in Scotland supported the view that people with epilepsy and their families were entitled to be provided with such information at an early stage. The timing of such a discussion should be tailored to individual needs. Sometimes an early discussion is not appropriate; for example, if there is active psychiatric comorbidity or epilepsy has occurred in the setting of a malignant cerebral tumour. In patients with intellectual disability, the family and carers usually wish to know as early as possible. In our practice, we have this discussion using a structured approach and aided by the SUDEP and seizure safety checklist at diagnosis in people with intellectual disability, and at the first follow-up in those without…

There are numerous studies looking at the risk factors for SUDEP. An in-depth review of the literature identified 18 risk factors, leading to our development of a safety checklist. Of the 18 factors, 11 were potentially modifiable, particularly non-adherence to antiepileptic medications, substance misuse, mood disorders and sleep disruption (see to register, see training videos and access a copy). There is no absolute risk assigned to each item, nor to the sum of the items, but completing the list allows a discussion around risk modification. Detailed analysis and stratification of the risk factors show that some are more significant than others. Despite initial fears that raising the issues might cause unnecessary alarm, patients tend to receive it positively and using the checklist can modify behaviours…

Device Technology

A recent systemic review into available commercial seizure detection devices showed no suitable robust seizure detection and safety technology though some were clearly promising.[26] Most available devices detect movement and/or physiological changes that occur before or during a seizure such as altered blood oxygen levels, heart rate changes, electrical activity in muscles and changes in galvanic skin resistance. Whether we can call seizure-alert dogs a 'device' is debatable.

Movement Sensors

These comprise a pressure sensor map placed under the mattress or sheets to detect an abnormal movement and absence of movement. While weight and sleep movement adjustments can be made, seizure detection rates are variable, with the most successful devices picking up 89% of tonic–clonic seizures, although one study failed to detect any seizures. Specificity is poor, with frequent false positives, so disrupting sleep of both carers and patients. As with all sensor devices for epilepsy, they also raise issues of individual privacy. Nonetheless, these remain the most popular among parents because of their simplicity.


These detect motion and change in velocity in two or three dimensions. Smartphones are particularly good for this. Sensitivity can be as high as 95%, but again specificity is lower. Speed of detection in one study was a median of 17 s with all detected within 30 s. The use of two accelerometers may improve nocturnal seizure detection.

Physiological Changes

Seizure onset is associated with altered autonomic activity, including decreased skin resistance. When combined with an accelerometer, a galvanic device detected 94% of seizures, but with a significant false positive rate.

Heart rate monitors in one study were 100% sensitive for tonic–clonic convulsions, and almost good for myoclonic seizures, but attempts to refine by adding breathing detectors or electromyographic analysis provided no advantage.

Apnoea devices combined with heart rate monitors are attractive in theory, but studies have not yet shown any benefits.


There are no devices for home use, but when combined with video electroencephalogram (EEG), there was 100% sensitivity within 30 s for tonic–clonic convulsions. Thus, the assessment of a more suitable device is in progress.

Video and Infrared Devices

Video monitoring is feasible, but has not been validated by EEG support. Infrared movement monitors reliably correlate with carer-reported activity, which did not necessarily confirm seizures.[ Using infrared spectroscopy to measure blood oxygen changes failed to detect seizures.

Seizure-alert Dogs

There are numerous anecdotal reports of dogs successfully detecting seizures, but no rigorous studies. Dogs may alert to the seizure itself but not to its onset. Dogs may also react both to non-epileptic seizures and epileptic seizures, and so are not specific. One study reported seizure reduction but our group experienced the tragedy of a patient being killed by her dog that was responding to a seizure.

Antisuffocation Pillows

These are often purchased by families, and are advertised on epilepsy support websites, with one study on carbon dioxide retention properties showing theoretical benefits. There is also the advantage that they are cheap and harmless…

Only long-term studies will determine whether safety checklists, telehealth interventions and mobile technologies have an impact. We have used these approaches for several years, and have seen SUDEP in our region fall in the intellectually disabled community from 4–5/year to nil, and in the non-intellectually disabled community from 6 to 1–2/year. How much of this is from the checklist, and how much from increased awareness among clinicians, the media and people with epilepsy or from improved services in general is difficult to determine. However, these interventions do raise the profile of epilepsy mortality and may contribute to enhanced awareness. Device technology is still in its infancy, and we cannot recommend any single device particularly as none has been shown to prevent SUDEP. The ideal drug—one that suppresses all seizure activity and is free from side effects—may not be developed in our lifetime. Furthermore, clinically based interventions will not capture those individuals at high risk. Self-monitoring by people with epilepsy or carers remains important, although there will still be those whose lifestyles put them at risk. Good communication is essential, but current services are not structured with that in mind. Professionals can only do so much, leaving a service gap between the epilepsy professionals, who see a snapshot of a patient's life, and the day-to-day experiences of people with epilepsy. Empowering people with epilepsy to take responsibility for their condition would do much to bridge that gap.