Craniopagus parasiticus

After her fertility treatments, Egyptian Naglaa Mohamed felt blessed when she found out she was pregnant with twins. However, the pregnancy was difficult, and Naglaa often was left extremely tired and weak. But it wasn't until the delivery the doctors discovered something was terribly wrong. Just minutes after the first baby, Manar, was born, doctors faced serious complications with the remaining twin.

Doctors performed an emergency C-section and quickly learned that the second baby was conjoined…attached at the head!

However, that's not all! The twins had the most unusual birth defect in the world. There are only 10 documented cases in history of craniopagus parasiticus, where one of the conjoined twins fails to fully develop a body. The head of the attached child—later named Islaam—was fully developed with eyes, a nose, mouth and even a brain. It was able to blink and smile but was not able to survive on its own.

"If you look to the babies from the front, you can see quite clearly Manar has her own face, but from the side she's completely attached to her other twin," says Dr. Abla El Alfi, one of the doctors involved in the procedure to detach Islaam from Manar. "Islaam had completely different reactions than Manar. Sometimes Manar was smiling and Islaam was crying. And you can see the different facial reactions of the two babies."

Manar and Islaam had two different brains but shared a common blood vessel that fed off of Manar's vital organs. Because Islaam was so dependent on Manar's body for survival, Manar suffered severe heart failure six times in the first few months of her life. Keeping Manar alive was a daily struggle.

"Islaam didn't have a heart to survive on," Dr. El Alfi explains. "She was surviving on the heart and lungs of Manar. She was getting nutrition from Manar. She was exchanging gases through Manar's lungs. And she was having blood supplied from Manar's heart."

For 10 months, Manar and Islaam remained in the hospital until Manar's condition became so critical doctors feared she wouldn't survive without a miracle.

Because Islaam was literally sucking the life out of Manar, doctors were forced to perform a radical surgery they had never done. In fact, it had only been attempted once in history, and no child had ever survived it! A team of 14 doctors from Benha Children's Hospital outside of Cairo was assembled to perform the highly complicated surgery. The Benha Children's Hospital is a national government referral center that receives critically ill cases from all over Egypt. The team included Dr. Walid Sharshera, neurosurgeon; Prof. Mohamed Farouk, lead anesthesiologist; Dr. Nassif Hefnawi, lead plastic surgeon; Dr. Abla El Alfi, head of the intensive care team; and Prof. Mohamed Lottfy, lead neurosurgeon.

"It was very risky surgery," Dr. El Alfi says. "The mortality rate is 100 percent because nobody had survived it. We had a lot of meetings and we reviewed all the literature of what had happened in cases like this all over the world."  

The only other time this was attempted was in the Dominican Republic, where doctors operated on 8-week-old Rebecca Martinez who was also born with a parasitic head. Sadly, she did not survive.

After months of preparation, the team of surgeons worked seven hours straight to carefully separate Manar from the undeveloped twin. The most critical part of the operation was the actual separation of the two brains, which took another two hours. If not done properly, Manar would die.  

Here's the miracle: Manar survived! She is the first baby in the world to ever survive this surgery.

Prof. Lottfy was the first doctor consulted. "The first time when I saw her, I went there and examined [Manar] and when I looked at the eyes, you can see the individual, she's searching for help," he says. "She's saying, 'Help me.' She's searching all over. Then I became emotionally attached to her. And I decided from the first moment to rescue [her]. Then I talked about my decision with Manar's doctors and went, again, to Cairo. I chose my team. I said to them, 'We have a mission to rescue Manar. If you accept this mission, to be devoted at any time to go to Benha, free of charge, we shall go over and rescue Manar. If you accept this, be with me.'"

How was Manar able to survive this miraculous procedure? "She survived for many reasons…she survived six attacks of heart failure. She was really determined and a fighter," Prof. Lottfy explains.  

Manar is now doing so well she was recently able to leave the hospital for the very first time since she was born. And her first trip is all the way from Egypt to The Oprah Winfrey Show!

https://www.oprah.com/oprahshow/its-a-miracle/all

video   https://www.youtube.com/watch?v=W_kfMhUmQWs

Lotfy M, Sakr SA, Ayoub BM. Successful separation of craniopagus parasiticus. Neurosurgery. 2006 Nov;59(5):E1150; discussion E1150. doi: 10.1227/01.NEU.0000245587.23710.A6. PMID: 17143210.

Abstract

Objective: Craniopagus parasiticus is an extremely rare condition. The first attempt to separate such twins was performed in the Dominican Republic in 2004. The infant died 7 hours after surgery. The aim of this report is to present a case in which surgical separation was successfully performed on February 18, 2005. In February 2006, the child was still alive and in relatively good health. 

Methods: The authors operated on a patient with craniopagus parasiticus at Benha Pediatric Hospital in Egypt, 45 km north of Cairo. The child was 10 months old when the surgery was performed. By minimizing the time of surgery and adequate control of intraoperative bleeding, a successful surgical separation was achieved. Computed tomography, magnetic resonance imaging, magnetic resonance angiography, and computed tomographic angiography provided the information necessary to perform surgery. 

Results: The child underwent operation at the age of 10 months; the duration of surgery was 9 hours. Bleeding was the most serious problem, with the child receiving four liters of blood. The main arterial supply to the parasite was via the middle cerebral artery and was ligated in the Sylvian fissure. Bleeding, however, was mostly venous and was mainly controlled by diathermy and thrombin soaked packs of Surgicel, as well as clipping. After separation of the parasitic head, the dura was repaired using artificial dural grafts. Free bone flaps from the parasite were used to cover the osseous defect in the autosite. Skin flaps from the parasite were also used to cover the cranium. 

Conclusion: This is the second case of craniopagus parasiticus in which separation was attempted. The first patient, operated on in the Dominican Republic, died 7 hours after surgery. In the present case, the child is still alive and without neurological deficit.

 

Network for therapy in rare epilepsies (NETRE): Lessons from the past 15 years

von Stülpnagel C, van Baalen A, Borggraefe I, Eschermann K, Hartlieb T, Kiwull L, Pringsheim M, Wolff M, Kudernatsch M, Wiegand G, Striano P, Kluger G and NETRE Consortium (2021) Network for Therapy in Rare Epilepsies (NETRE): Lessons From the Past 15 Years. Front. Neurol. 11:622510. doi: 10.3389/fneur.2020.622510

Background: In 2005, Network for Therapy in Rare Epilepsies (NETRE)—was initiated in order to share treatment experiences among clinicians in patients with rare epilepsies. Here we describe the structure of the rapidly growing NETRE and summarize some of the findings of the last 15 years. 

Methodology/Structure of NETRE: NETRE is organized in distinct groups (currently >270). Starting point is always a patient with a rare epilepsy/ epileptic disorder. This creates a new group, and next, a medical coordinator is appointed. The exchange of experiences is established using a data entry form, which the coordinator sends to colleagues. The primary aim is to exchange experiences (retrospectively, anonymously, MRI results also non-anonymously) of the epilepsy treatment as well as on clinical presentation and comorbidities NETRE is neither financed nor sponsored. 

Results: Some of the relevant results: (1) first description of FIRES as a new epilepsy syndrome and its further investigation, (2) in SCN2A, the assignment to gain- vs. loss-of-function mutations has a major impact on clinical decisions to use or avoid treatment with sodium channel blockers, (3) the important aspect of avoiding overtreatment in CDKL5 patients, due to loss of effects of anticonvulsants after 12 months, (4) pathognomonic MRI findings in FOXG1 patients, (5) the first description of pathognomonic chewing-induced seizures in SYNGAP1 patients, and the therapeutic effect of statins as anticonvulsant in these patients, (6) the phenomenon of another reflex epilepsy—bathing epilepsy associated with a SYN1 mutation. Of special interest is also a NETRE group following twins with genetic and/or structural epilepsies [including vanishing-twin-syndrome and twin-twin-transfusion syndrome) [= “Early Neuroimpaired Twin Entity” (ENITE)]. 

Discussion and Perspective: NETRE enables clinicians to quickly exchange information on therapeutic experiences in rare diseases with colleagues at an international level. For both parents and clinicians/scientist this international exchange is both reassuring and helpful. In collaboration with other groups, personalized therapeutic approaches are sought, but the present limitations of currently available therapies are also highlighted. Presently, the PATRE Project (PATient based phenotyping and evaluation of therapy for Rare Epilepsies) is commencing, in which information on therapies will be obtained directly from patients and their caregivers.

SLC13A5 deficiency 2

Matricardi S, De Liso P, Freri E, Costa P, Castellotti B, Magri S, Gellera C, Granata T, Musante L, Lesca G, Oertel J, Craiu D, Hammer TB, Møller RS, Barisic N, Abou Jamra R, Polster T, Vigevano F, Marini C. Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene. Epilepsia. 2020 Nov;61(11):2474-2485. doi: 10.1111/epi.16699. Epub 2020 Oct 16. PMID: 33063863.

Abstract

Objective: Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. 

Methods: We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. 

Results: All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. 

Significance: Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.

Yang QZ, Spelbrink EM, Nye KL, Hsu ER, Porter BE. Epilepsy and EEG Phenotype of SLC13A5 Citrate Transporter Disorder. Child Neurol Open. 2020 Jun 8;7:2329048X20931361. doi: 10.1177/2329048X20931361. PMID: 32551328; PMCID: PMC7281881.

Abstract

Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient's seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients' chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study. 

Kopel J, Grooms A, Ganapathy V, Clothier J. Metformin, valproic acid, and starvation induce seizures in a patient with partial SLC13A5 deficiency: a case of pharmaco-synergistic heterozygosity. Psychiatr Genet. 2021 Feb 1;31(1):32-35. doi: 10.1097/YPG.0000000000000269. PMID: 33290383.

Abstract

SLC13A5/NaCT is a sodium-coupled citrate transporter expressed in the plasma membrane of the liver, testis, and brain. In these tissues, SLC13A5 has important functions in the synthesis of fatty acids, cholesterol, and neurotransmitters. In recent years, patients homozygous for recessive mutations in SLC13A5, known as SLC13A5 deficiency [early infantile epileptic encephalopathy-25 (EIEE-25)], exhibit severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting tooth development. Although the pathogenesis of SLC13A5 deficiency remains not clearly understood, cytoplasmic citrate deficits, decreased energy status in neurons, and citrate-zinc chelation are hypothesized to explain the neurological deficits. However, no study has examined the possibility of specific pharmacological drugs and/or lifestyle changes synergizing with heterozygosity of SLC13A5 deficiency to increase the risk of EIEE-25 clinical phenotype. Here, we report on a heterozygous SLC13A5-deficient patient who demonstrated evidence of pharmaco-synergistic heterozygosity upon administration of metformin, valproic acid, and starvation. The report illustrates the importance of careful consideration of the potential adverse effects of specific pharmacological treatments in patients with heterozygosity for disease-causing recessive mutations in SLC13A5.

Arvio M, Lähdetie J. Adult phenotype of the homozygous missense mutation c.655G>A, p.Gly219Arg in SLC13A5: A case report. Am J Med Genet A. 2020 Nov;182(11):2671-2674. doi: 10.1002/ajmg.a.61802. Epub 2020 Aug 17. PMID: 33200910.

Abstract

Homozygous recessive or compound heterozygous mutations in SLC13A5-gene as a cause of Early Infantile Epileptic Encephalopathy subtype 25 (OMIM 615905) were published in 2014. Previous clinical reports describe young patients, aged <34 years. We describe 54- and 56-year-old siblings and show that the disorder linked to SLC13A5 is not just a pediatric problem but may affect the patient for decades resulting in profound intellectual disability, severe motor handicap, and abnormal electroencephalography without active epilepsy. Other diagnostic hints in adults are small size, spasticity and severe abrasion due to amelogenesis imperfecta of the hypoplastic type.

AAV9-based gene treatment candidate currently in development for epilepsy caused by SLC13A5 deficiency

The U.S. Food and Drug Administration (FDA) has granted rare pediatric disease and orphan drug designations for Taysha Gene Therapies’ AAV9-based gene treatment candidate currently in development for epilepsy caused by SLC13A5 deficiency. 

SLC13A5, a rate form of infantile epilepsy caused by SLC13A5 gene mutations, is an autosomal recessive disorder characterized by developmental delay as well as seizures that occur within the first few days of life. 

The gene therapy company’s TSHA-105 candidate is the AAV9-based gene therapy granted these designations and is poised to be the first treatment for SLC13A5-related epilepsy. There are no currently approved treatments for epilepsy caused by SLC13A5, explained Taysha’s President, Founder and CEO, RA Session II, in a statement. “We are encouraged by the early evidence of TSHA-105’s disease-modifying approach and believe these designations will help us potentially accelerate the development of this exciting program,” said Session. “We look forward to working with the FDA to make TSHA-105 available to patients as expeditiously as possible.” 

“We are pleased that the FDA recognizes TSHA-105’s potential as an innovative therapeutic option for SLC13A5 deficiency,” added Rachel Bailey, Ph.D., Assistant Professor in Pediatric Neurology at UT Southwestern. “This disease is a debilitating form of genetic epilepsy in children that significantly impacts movement, motor control, cognition and quality of life, and there remains a need to alter the course of this disease early in life.” 

The FDA granted this rare pediatric disease designation due to the disease’s severity and relatively low prevalence in the population. Only diseases and disorders that affect fewer than 200,000 people in the U.S. receive the rare disease designation. Taysha’s TSHA-105 fell under the agency’s Rare Pediatric Disease Priority Review Voucher Program, which aims to “address the challenges that drug companies face when developing treatments for these unique patient populations,” according to the company’s statement about the designations. 

The program allows companies to become eligible for a priority review voucher after product approval, which is contingent on whether the marketing application “submitted for the product satisfies certain conditions, including approval prior to September 30, 2026 unless changed by legislation.” Sponsors who are issued a priority review voucher for priority review may redeem this voucher for another marketing application for another candidate.

https://www.biospace.com/article/fda-grants-rare-pediatric-disease-orphan-drug-designation-for-taysha-s-rare-epilepsy-candidate/

See:  https://childnervoussystem.blogspot.com/2020/02/slc13a5-deficiency.html

Temporal lobe epilepsy surgery in children and adults

Barba C, Cossu M, Guerrini R, Di Gennaro G, Villani F, De Palma L, Grisotto L, Consales A, Battaglia D, Zamponi N, d'Orio P, Revay M, Rizzi M, Casciato S, Esposito V, Quarato PP, Di Giacomo R, Didato G, Pastori C, Pavia GC, Pellacani S, Matta G, Pacetti M, Tamburrini G, Cesaroni E, Colicchio G, Vatti G, Asioli S, Caulo M; TLE Study Group, Marras CE, Tassi L. Temporal lobe epilepsy surgery in children and adults: A multicenter study. Epilepsia. 2021 Jan;62(1):128-142. doi: 10.1111/epi.16772. Epub 2020 Dec 1. PMID: 33258120.

Abstract

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. 

Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. 

Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. 

Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.

Courtesy of:  https://www.mdlinx.com/journal-summary/temporal-lobe-epilepsy-surgery-in-children-and-adults-a-multicenter-study/5c5rHNWZNtaZTSFGiJPgDm

Extreme prematurity, growth and neurodevelopment at 8 years

Hickey L, Burnett A, Spittle AJ, Roberts G, Anderson P, Lee K, Doyle LW, Cheong JLY; Victorian Infant Collaborative Study Group. Extreme prematurity, growth and neurodevelopment at 8 years: a cohort study. Arch Dis Child. 2021 Feb;106(2):160-166. doi: 10.1136/archdischild-2019-318139. Epub 2020 Aug 3. PMID: 32747376.

Abstract

Objective: Infants born extremely preterm (EP, <28 weeks' gestation) exhibit poorer growth and neurodevelopmental impairment in early childhood compared with their term-born peers. Whether poor growth persists and whether associations of growth with neurodevelopmental functioning have changed in the decades since the introduction of surfactant are not well described. This study aims to (1) compare growth from birth to 2 years then 8 years in children born EP between three different eras, and (2) investigate the associations of growth from birth to 2 years then 8 years with cognitive, academic, executive and motor function at 8 years, and if associations have changed over time. 

Design: Prospective observational cohort studies in the State of Victoria, Australia in three discrete eras: 1991-1992, 1997 and 2005. EP children had weight and head circumference measured at birth, and weight, head circumference and height at 2 and 8 years. Cognitive ability, academic performance, executive function and motor skills were assessed at 8 years, corrected for prematurity. 

Results: 499/546 (91%) of surviving EP children were fully assessed at 8 years. Growth in children born EP did not differ substantially between eras and associations between growth and neurodevelopment did not change over time. Overall, better weight and head growth from birth to 2 years were associated with improved neurodevelopment at 8 years. 

Conclusions: Growth of children born EP has not improved in more recent eras. Better early head and weight growth are associated with improved neurodevelopment in mid-childhood.

Courtesy of:  https://www.mdlinx.com/journal-summary/extreme-prematurity-growth-and-neurodevelopment-at-8-years-a-cohort-study/3dCday88MMe664mtoAM4aQ

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Jin SC, Lewis SA, Bakhtiari S, Zeng X, Sierant MC, Shetty S, Nordlie SM, Elie A, Corbett MA, Norton BY, van Eyk CL, Haider S, Guida BS, Magee H, Liu J, Pastore S, Vincent JB, Brunstrom-Hernandez J, Papavasileiou A, Fahey MC, Berry JG, Harper K, Zhou C, Zhang J, Li B, Zhao H, Heim J, Webber DL, Frank MSB, Xia L, Xu Y, Zhu D, Zhang B, Sheth AH, Knight JR, Castaldi C, Tikhonova IR, López-Giráldez F, Keren B, Whalen S, Buratti J, Doummar D, Cho M, Retterer K, Millan F, Wang Y, Waugh JL, Rodan L, Cohen JS, Fatemi A, Lin AE, Phillips JP, Feyma T, MacLennan SC, Vaughan S, Crompton KE, Reid SM, Reddihough DS, Shang Q, Gao C, Novak I, Badawi N, Wilson YA, McIntyre SJ, Mane SM, Wang X, Amor DJ, Zarnescu DC, Lu Q, Xing Q, Zhu C, Bilguvar K, Padilla-Lopez S, Lifton RP, Gecz J, MacLennan AH, Kruer MC. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nat Genet. 2020 Oct;52(10):1046-1056. doi: 10.1038/s41588-020-0695-1. Epub 2020 Sep 28. Erratum in: Nat Genet. 2021 Jan 11;: PMID: 32989326.

Abstract

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Courtesy of a colleague

CHD2-related CNS pathologies

Wilson, M.-M.; Henshall,D.C.; Byrne, S.M.; Brennan, G.P.CHD2-Related CNS Pathologies.Int.J. Mol. Sci.2021,22,  588.  https://doi.org/10.3390/

Abstract:

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression.  This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins.  In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability.  Our understanding of theme chanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function ofCHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.

Courtesy of Researchgate

 

 

Association of childhood lead exposure with MRI measurements of structural brain integrity in midlife

Reuben A, Elliott ML, Abraham WC, Broadbent J, Houts RM, Ireland D, Knodt AR, Poulton R, Ramrakha S, Hariri AR, Caspi A, Moffitt TE. Association of Childhood Lead Exposure With MRI Measurements of Structural Brain Integrity in Midlife. JAMA. 2020 Nov 17;324(19):1970-1979. doi: 10.1001/jama.2020.19998. PMID: 33201203; PMCID: PMC7672511.  

In this longitudinal prospective cohort study with a median 34-year follow-up, experts explored whether childhood lead exposure is correlated with MRI measurements of lower structural integrity of the brain in midlife. Of 1,037 original candidates, 997 were alive at age 45 years, of whom 564 (57%) received lead testing at age 11 years (302 [54%] male) (median follow-up, 34 [interquartile range, 33.7-34.7] years). At age 11 years, mean blood lead level was 10.99 (SD, 4.63) μg/dL. No statistically significant link was found between childhood blood lead levels and self-reported cognitive problems. Differences in MRI measurements of brain structure that indicated lower structural brain integrity in midlife, including smaller cortical surface area, smaller hippocampal volume, lower global fractional anisotropy, and an older estimated brain age, were correlated with higher childhood blood lead levels. Some results can reflect type I error because of the large number of statistical comparisons. 

Courtesy of:  https://www.mdlinx.com/journal-summary/association-of-childhood-lead-exposure-with-mri-measurements-of-structural-brain-integrity-in/T0iVVhdTjBwN7GrGoydYE 

Sunflower syndrome

Sunflower Syndrome

Sunflower syndrome is a rare epileptic disorder characterized by highly stereotyped seizures.

What Is Sunflower Syndrome?

Sunflower syndrome is a rare, epileptic disorder characterized by highly stereotyped seizures. During these seizures, individuals with Sunflower syndrome turn toward a bright light while simultaneously waving one hand in front of their eyes. This unique behavior is coupled with abrupt lapses in consciousness. 

What causes Sunflower syndrome?

As of today, it is not known what causes Sunflower syndrome. However, the disorder is highly stereotyped and typically begins during the first decade of life. This suggests that there may be a genetic component. Currently, we are conducting research to identify and understand the underlying genetics involved with the disorder. 

What are the symptoms of Sunflower syndrome?

Symptoms of Sunflower syndrome include an initial attraction to bright light, followed by seizure activity that includes episodes of hand waving and disruptions of consciousness. As stated above, these episodes typically start before the age of ten. The attraction to light often precedes the onset of handwaving episodes by days to months. 

Patients with Sunflower syndrome can also experience other types of seizures. These include absence seizures and generalized tonic-clonic seizures. For some, tonic-clonic seizures occur after prolonged exposure to bright light and prolonged hand waving episodes. 

How is Sunflower syndrome diagnosed?

There is currently no clinical or laboratory standard for diagnosing Sunflower syndrome. However, individuals with Sunflower syndrome have abnormal electroencephalograms (EEGs) with features consistent with generalized epilepsy. For this reason, your doctor may obtain an EEG. 

How Is Sunflower Syndrome Treated?

There have not been any clinical trials to investigate the effectiveness of treatments for Sunflower syndrome. For this reason, it is unknown if any anticonvulsant medications or treatments are particularly effective.

Some individuals with Sunflower syndrome and their parents report that providing shade from bright light (via a baseball cap, tinted sunglasses or welder’s glasses) can help reduce the frequency of hand waving episodes. Other individuals report that focusing on specific tasks while in the presence of bright lights can reduce the frequency of hand waving. 

What Other Issues Do Patients Face?

The impacts of Sunflower syndrome have not been fully explored. Because individuals with Sunflower syndrome experience brief disruptions in consciousness, hand waving episodes can impact one’s ability to attend and learn. Furthermore, these disruptions in consciousness may pose a safety risk depending on the child’s activity at the time of the hand waving episode. Children who experience tonic-clonic seizures are at additional risk of injury at the time of those seizures. 

Some patients also report experiencing anxiety, which may in part be caused by the inability to prevent or control hand waving episodes. Children with Sunflower syndrome may also experience added stress from clinicians, family members and friends who believe that the hand waving episodes are self-induced and under conscious control. Children often report that they are told to “just stop” causing themselves to have seizures.

Stigma surrounding Sunflower syndrome

Sunflower syndrome was originally described as a self-induced photosensitive epilepsy. However, the “self-induced” designation may be inaccurate.

It was initially believed that individuals with Sunflower syndrome were consciously inducing seizures for attention or pleasure. This belief created a stigma around the disorder. As a result, people have adopted the belief that individuals with Sunflower syndrome can control their hand waving episodes.

Although some case studies provide anecdotal evidence to support this, the findings in scientific literature are not consistent. In fact, EEG studies have found that the misfiring of neurons in the brain or epileptiform activity start at the same time as the hand waving behavior. This suggests that the hand waving may in fact be part of the seizure, not the cause.

How Can I Help?

The Pediatric Epilepsy Program at the Massachusetts General Hospital is currently working to identify funding sources for current and future projects designed to understand and improve clinical care for children with Sunflower syndrome and are in the process of establishing a dedicated multidisciplinary Sunflower syndrome clinical program. If you are interested in donating, please visit our Sunflower syndrome fundraiser page or email bfleming2@mgh.harvard.edu.

Current Projects

Under the direction of Elizabeth Thiele, MD, PhD, the Pediatric Epilepsy Program at MGH has initiated several projects to develop a better understanding of Sunflower syndrome. 

Gene Identification: Because of the highly stereotyped characteristics of Sunflower syndrome, it is possible that there is a genetic component to the disorder. Efforts are currently underway to identify the specific gene/s that may be involved in Sunflower syndrome.

Clinical and EEG characterization: Sunflower syndrome is not well understood. The Pediatric Epilepsy Program at MGH is currently working to characterize the clinical features and EEG patterns of children with Sunflower Syndrome.

Scientific Literature:  Geenen KR, Patel S, Thiele EA. Sunflower syndrome: a poorly understood photosensitive epilepsy. Dev Med Child Neurol. 2020 Oct 31. doi: 10.1111/dmcn.14723. Epub ahead of print. PMID: 33135153.ture

Aicardi, J., & Gastaut, H. (1985). Treatment of self-induced photosensitive epilepsy with fenfluramine. The New England journal of medicine, 313(22), 1419-1419.

Ames, F. R. (1971). “Self-induction” in photosensitive epilepsy. Brain, 94(4), 781-798.

Ames, F. R., & Saffer, D. (1983). The sunflower syndrome: a new look at “self-induced” photosensitive epilepsy. Journal of the neurological sciences, 59(1), 1-11

Belcastro, V., & Striano, P. (2014). Self?induction seizures in sunflower epilepsy: a video?EEG report. Epileptic Disorders, 16(1), 93-95.

Livingston, S., & Torres, I. C. (1964). Photic epilepsy: report of an unusual case and review of the literature. Clinical pediatrics, 3(5), 304-307.

Singhi, P. D., & Bansal, D. (2004). Self induced photosensitive epilepsy. Indian journal of pediatrics, 71(7), 649-651.

https://www.massgeneral.org/children/sunflower-syndrome

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Geenen KR, Patel S, Thiele EA. Sunflower syndrome: a poorly understood photosensitive epilepsy. Dev Med Child Neurol. 2020 Oct 31. doi: 10.1111/dmcn.14723. Epub ahead of print. PMID: 33135153.

Abstract

Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome's natural history and to identify more effective treatment options.

Barnett JR, Fleming BM, Geenen KR, Sourbron J, Freedman JH, Bruno PL, Thiele EA. Characterizing Sunflower syndrome: a clinical series. Epileptic Disord. 2020 Jun 1;22(3):273-280. doi: 10.1684/epd.2020.1161. PMID: 32554362.

Abstract

To characterize the clinical phenotype of Sunflower syndrome. Sunflower syndrome is a rare photosensitive epilepsy syndrome characterized by highly stereotyped seizures, photosensitivity, and heliotropism. We retrospectively reviewed the medical records of patients seen in the Massachusetts General Hospital for Children (MGHfC) pediatric epilepsy program with a history of Sunflower syndrome. Twenty-four patients were identified; 18 were female. At the time of initial MGHfC evaluation, patients' ages ranged from 6.4 to 25 years, with a median age of 11.5 years. All patients presented with hand-waving episodes (HWEs), although one patient no longer demonstrates this, but now has eye blinking episodes on exposure to light. Four have associated eye fluttering as a component of their most prevalent light-induced seizures. The average age at onset of HWEs was six years. Seventeen developed other symptoms prior to the onset of HWEs. The most prevalent symptom was an attraction to light and possible absence seizures. Light-induced seizures were generally refractory to broad-spectrum antiepileptic drugs (AEDs). Only three patients had a reduction of HWEs with the use of AEDs. Several non-pharmacological strategies reduced seizure frequency, however, efficacy varied. These non-pharmacological strategies included avoiding stimulus, focusing on other tasks, and occupying or restraining the hand that was involved in hand-waving. The use of tinted glasses reduced seizure frequency in 17 patients, however, no patient achieved seizure freedom. Twenty-two patients had available EEGs, 20 of which showed interictal epileptiform discharges. Additionally, many of the patients experienced a negative impact on their self-concept due to anxiety, depression, or negative interactions with peers. Sunflower syndrome is a generalized, pharmacoresistant epilepsy with childhood onset and remains poorly understood. To improve clinical care and scientific understanding, long-term prospective research exploring the natural history, etiology, and effective treatments for Sunflower syndrome should be conducted. [Published with video sequence].

Baumer FM, Porter BE. Clinical and electrographic features of sunflower syndrome. Epilepsy Res. 2018 May;142:58-63. doi: 10.1016/j.eplepsyres.2018.03.002. Epub 2018 Mar 3. PMID: 29555355; PMCID: PMC6051521.

Abstract

Background: Sunflower Syndrome describes reflex seizures - typically eyelid myoclonia with or without absence seizures - triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients. 

Methods: Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings. 

Results: Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia ± absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4 Hz spike waves ± polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy. 

Conclusions: Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective.

Neutropenia in children treated With ketogenic diet therapy

Munro K, Keller AE, Lowe H, Ferrara E, Whitney R, Liu CYM, Zak M, Chan V, Kobayashi J, Donner EJ. Neutropenia in Children Treated With Ketogenic Diet Therapy. J Child Neurol. 2021 Jan 4:883073820984067. doi: 10.1177/0883073820984067. Epub ahead of print. PMID: 33393840.

Abstract

Objectives: The objectives were to investigate the relationship between ketogenic diet therapy and neutropenia in children with epilepsy. 

Methods: A retrospective chart review of children who initiated ketogenic diet at the Hospital for Sick Children between January 1, 2000, and May 1, 2018 was performed. Factors associated with the development of neutropenia during ketogenic diet therapy were evaluated and the relationship between development of a significant or suspected infection and neutrophil count was analyzed. 

Results: One hundred two children met inclusion criteria and were followed on the diet for up to 24 months. Thirteen of 102 (13%) children were neutropenic at diet initiation. In the remaining 89 children, 27 developed neutropenia. Developing neutropenia was significantly associated with the ketogenic diet at 6 (13%), 12 (23%), and 24 (25%) months follow-up. Developing neutropenia was associated with higher urinary ketones (OR = 4.26, 95% CI: 1.27, 14.15) and longer duration of ketogenic diet therapy (OR = 3.29, 95% CI: 1.42, 7.96). There was no significant association between development of a clinically significant infection and neutropenia. 

Conclusion: Ketogenic diet therapy is associated with neutropenia in children with epilepsy, however, it does not have a significant clinical impact. Concern regarding neutropenia should not discourage the use of the ketogenic diet in children.

https://www.mdlinx.com/journal-summary/neutropenia-in-children-treated-with-ketogenic-diet-therapy/5k4EuPBBgfRAYxU58Cp5aW

Language after childhood hemispherectomy

Nahum AS, Liégeois FJ. Language after childhood hemispherectomy: A systematic review. Neurology. 2020 Dec 8;95(23):1043-1056. doi: 10.1212/WNL.0000000000011073. Epub 2020 Oct 21. PMID: 33087498.

Abstract

Objective: To conduct a systematic review on language outcomes after left and right hemispherectomy in childhood, a surgical procedure that involves removing or disconnecting a cerebral hemisphere. 

Methods: We searched MEDLINE, Embase, and PsycInfo for articles published between January 1, 1988, and May 16, 2019. We included (1) all types of observational studies; (2) studies in which hemispherectomy was performed before age 18 years; and (3) studies with standardized scores measuring receptive vocabulary, expressive vocabulary, sentence comprehension, and/or sentence production. We calculated mean z scores after left and right hemispherectomy in the whole group and within etiology-specific subgroups. 

Results: Our search identified 1,096 studies, of which 17 were eligible. The cohort added up to 205 individuals (62% left hemispherectomy) assessed 1 to 15 years after surgery. In the left surgery group, all language skills were impaired (z scores <-1.5) except sentence comprehension. In the right surgery group, language performance was in the borderline range (z scores ∼ -1.5). Children with cortical dysplasia showed the worst outcomes irrespective of surgery side (z scores <-2.5). Individuals with left vascular etiology and right-sided Rasmussen syndrome showed the best outcomes. 

Conclusion: Evidence based on the largest patient cohort to date (205 participants) suggests that the risk of language impairment after hemispherectomy is high, with few exceptions. Etiology plays a major role in postsurgical plasticity. We recommend specialist evaluation of language skills soon after surgery to identify intervention targets. Large-scale studies examining outcomes in consecutive cases are still needed.

Electroclinical features and outcome of ANKRD11-related KBG syndrome

 Nardello R, Mangano GD, Antona V, Fontana A, Striano P, Giorgio E, Brusco A, Mangano S, Salpietro V, Electroclinical features and outcome of ANKRD11-related KBG syndrome: a novel report and literature review, Seizure: European Journal of Epilepsy (2020), doi: https://doi.org/10.1016/j.seizure.2020.12.017

Introduction

KBG syndrome (OMIM #148050) is a rare autosomal dominant disorder, typically characterized by macrodontia of the upper central incisors, distinct craniofacial findings, short stature, and skeletal anomalies associated with neurological involvement including intellectual disability, behaviour difficulties, and epilepsy. KBG syndrome is associated with mutations in ANKRD11 gene that plays a chromatin regulator role of histone acetylation and gene expression during neurogenesis in the embryonic brain. A systemic review of epilepsy and EEG anomalies in subjects with KBG syndrome is missing. Samanta first described in a patient an intermittent bisynchronous temporo-occipital rhythmic delta activity and episodes of staring spells with no EEG changes suggesting that these findings may be specific to KBG syndrome. 

Here, we report a patient with a severe neurological phenotype of KBG syndrome associated with a novel heterozygous frame-shift de novo variant in the ANKRD11 (NM_013275.6) gene, to contribute to identify a specific electroclinical pattern of KBG syndrome.

Extent of leptomeningeal capillary malformation is associated with severity of epilepsy in Sturge-Weber syndrome

Sugano H, Iimura Y, Igarashi A, Nakazawa M, Suzuki H, Mitsuhashi T, Nakajima M, Higo T, Ueda T, Nakanishi H, Niijima S, Karagiozov K, Arai H, Extent of leptomeningeal capillary malformation is associated with severity of epilepsy in Sturge-Weber syndrome, Pediatric Neurology (2021), doi: https://doi.org/10.1016/j.pediatrneurol.2020.12.012.

Abstract

Background

Sturge-Weber syndrome (SWS) patients have risks of intractable epilepsy and cognitive decline. We hypothesized that leptomeningeal capillary malformation (LCM) extent related to severity of neurological affection in SWS. This study tested the hypothesis in a cross-sectional study of seizure severity and electroencephalography (EEG) findings and a retrospective cohort study for surgical indications related to extent of LCM. 

Methods

We enrolled 112 patients and classified them according to LCM distribution: (1) Bilateral, (2) Hemispheric, (3) Multilobar, and (5) Single lobe. Seizure onset age, semiology and frequency, and EEG findings were compared. Surgical indications were antiepileptic drug resistance, progressive cerebral atrophy, and cognitive decline, and evaluated in each group by Fisher’s exact test, while predictors for surgery by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-neurological score (SWS-NS). 

Results

Bilateral and Hemispheric groups had early-onset age (4.0-months and 3.0-months), frequent seizures (88.9% and 80.6% had more than once-a-month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). Groups did not differ significantly in EEG findings. Surgical indications were present in 77.8% of Bilateral, 88.1% of Hemispheric, and 46.8% of Multilobar groups. Seizure more than once monthly were a surgical treatment predictor. Seizure sub-score improved significantly postoperatively in Hemispheric and Multilobar groups. Even after the surgical treatment, Bilateral and Hemispheric groups SWS-NSs were higher than those of other groups. 

Conclusion

Our study demonstrated a strong association between extensive LCM and epileptic severity. Surgical intervention improved seizure outcome in SWS patients with large LCMs. (248)