Gene therapy and tazarotene/bexarotene therapy for multiple sulfatase deficiency

Promising results from research at The Jackson Laboratory (JAX) and University of Texas Southwestern Medical Center (UTSW) on a gene therapy for the ultra-rare genetic disorder, Multiple Sulfatase Deficiency (MSD), will be presented today during the WORLDSymposium, an annual research conference dedicated to lysosomal diseases. The data paves the way for a gene therapy approach for MSD patients, a very important and exciting step forward for the MSD community.

MSD is an ultra-rare genetic disorder which is often described as “Alzheimer’s in a child,” and leads to premature death, normally before 10 years of age. MSD is caused by mutations in the gene responsible for making formylglycine-generating enzyme, an essential enzyme needed by cells for normal function and to break down cellular waste products, encoded by the SUMF1 gene.

With funding provided by the United MSD Foundation, a parent-led patient advocacy organization that funds research grants for MSD studies, JAX and UTSW partnered to study the SUMf1 gene in mouse models of MSD. The research team utilized a mouse model with the SUMF1 gene “knocked out,” which has similar traits to human MSD patients. While many of the mice die soon after birth, mirroring the short lives of many children with MSD, some of the mice survived past two weeks, providing sufficient time to test possible treatments.

“The experiments were challenging given the early mortality of the mouse model and need to explore several routes of administration and doses,” said Maximiliano Presa , Ph.D., study director at The Jackson Laboratory. “These were big experiments that required a lot of effort, skill and planning by the entire team. The data are encouraging, and we are beyond delighted with the results.”

The researchers used an engineered virus (AAV9) to deliver working copies of the SUMF1 gene into the mouse cells. They tried different delivery methods, locations and time points and found that delivery of the gene through a spinal tap at seven days of age alleviated MSD symptoms. The treated mice showed wide distribution of the SUMF1 gene, no signs of toxicity or neuropathy, improved vision and cardiac function, and no behavioral deficits.

“We are thrilled with these impressive and promising results, and grateful to the scientists and supporters who made them possible,” said Amber Olsen, executive director and founder of the United MSD Foundation. “The United MSD Foundation’s mission is simple: to cure MSD, and this work represents incredible progress toward that cure. Our efforts are now focused on the critical next steps necessary to get gene therapy to children suffering and dying from MSD.”

The data supports that gene replacement therapy could be a therapeutic approach for pediatric subjects, who currently lack any treatment options, and represents a huge milestone for the MSD community.

“We are excited about the results showing successful treatment of mice with MSD, which was the result of a strong collaborative effort between investigators at UTSW, JAX and the United MSD Foundation,” said Steven Gray, Ph.D., associate professor at the University of Texas Southwestern Medical Center.

“MSD is a devastating disease and there are currently no effective treatments for patients. We are highly encouraged by the positive therapeutic response in mice and look forward to further exploring the possible use of this treatment for MSD,” said Rachel Bailey, assistant professor at the University of Texas Southwestern Medical Center.

Through the collaboration with The Jackson Laboratory, UT Southwestern and United MSD Foundation, the MSD community is one step closer to saving the lives of children impacted by this devastating disorder.

https://www.jax.org/news-and-insights/2022/february/promising-data-supports-gene-therapy-for-msd

Schlotawa L, Tyka K, Kettwig M, Ahrens-Nicklas RC, Baud M, Berulava T, Brunetti-Pierri N, Gagne A, Herbst ZM, Maguire JA, Monfregola J, Pena T, Radhakrishnan K, Schröder S, Waxman EA, Ballabio A, Dierks T, Fischer A, French DL, Gelb MH, Gärtner J. Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. EMBO Mol Med. 2023 Mar 8;15(3):e14837. doi: 10.15252/emmm.202114837. Epub 2023 Feb 15. PMID: 36789546; PMCID: PMC9994482.

Abstract

Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

Strict rest should be avoided after a concussion

Patricios JS, Schneider KJ, Dvorak J, Ahmed OH, Blauwet C, Cantu RC, Davis GA, Echemendia RJ, Makdissi M, McNamee M, Broglio S, Emery CA, Feddermann-Demont N, Fuller GW, Giza CC, Guskiewicz KM, Hainline B, Iverson GL, Kutcher JS, Leddy JJ, Maddocks D, Manley G, McCrea M, Purcell LK, Putukian M, Sato H, Tuominen MP, Turner M, Yeates KO, Herring SA, Meeuwisse W. Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport-Amsterdam, October 2022. Br J Sports Med. 2023 Jun;57(11):695-711. doi: 10.1136/bjsports-2023-106898. PMID: 37316210.

Abstract

For over two decades, the Concussion in Sport Group has held meetings and developed five international statements on concussion in sport. This 6th statement summarises the processes and outcomes of the 6th International Conference on Concussion in Sport held in Amsterdam on 27-30 October 2022 and should be read in conjunction with the (1) methodology paper that outlines the consensus process in detail and (2) 10 systematic reviews that informed the conference outcomes. Over 3½ years, author groups conducted systematic reviews of predetermined priority topics relevant to concussion in sport. The format of the conference, expert panel meetings and workshops to revise or develop new clinical assessment tools, as described in the methodology paper, evolved from previous consensus meetings with several new components. Apart from this consensus statement, the conference process yielded revised tools including the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), as well as a new tool, the Sport Concussion Office Assessment Tool-6 (SCOAT6, Child SCOAT6). This consensus process also integrated new features including a focus on the para athlete, the athlete's perspective, concussion-specific medical ethics and matters related to both athlete retirement and the potential long-term effects of SRC, including neurodegenerative disease. This statement summarises evidence-informed principles of concussion prevention, assessment and management, and emphasises those areas requiring more research.

_______________________________________________________________________________

Strict rest should be avoided after a concussion, but light-intensity physical activity, such as walking, can help recovery. Screen use should also be limited in the first 48 hours following the injury, according to a new statement released by the Concussion in Sport Group published in the British Journal of Sports Medicine. The new guidelines come following the organization’s 6th International Conference on Concussion in Sport, held in Amsterdam from October 27 to 30, 2022.

The new guidelines also updated the definition of concussion, though “work continues toward a unified conceptual and operational definition.” The consensus statement also highlighted sport-specific strategies for prevention, including policy changes to reduce collisions (such as suggesting disallowing body-checking in hockey), neuromuscular training, and the implementation of optimal concussion management strategies to decrease recurrent concussion rates.

The conference also produced updated versions of the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), designed for use within the first 72 hours (and up to 1 week) following injury. Additionally, new office tools, the Sport Concussion Office Assessment Tool-6 (SCOAT6) and Child SCOAT6, were developed for post-72-hour evaluations and subsequent weeks.

The statement updated return-to-learn and return-to-sport strategies, and underscored the benefits of physical activity and aerobic exercise as early interventions. For athletes experiencing neck pain, headaches, dizziness, and/or balance issues, cervicovestibular rehabilitation was recommended.

For individuals with persisting symptoms lasting more than 4 weeks, a multimodal clinical assessment using standardized symptom rating scales was proposed.

The potential long-term effects of sports-related concussions and repetitive head impacts, sex-based differences in concussion prevention and management, concussion diagnosis and management in para-athletes, and concussions in children aged 5 to 12 years were acknowledged as areas requiring dedicated research, the Concussion in Sport Group noted.

https://www.hmpgloballearningnetwork.com/site/neuro/news/no-strict-rest-after-concussion-and-other-new-guidelines-released

Euthanasia for autism and intellectual handicaps

Netherlands programs have euthanized otherwise healthy individuals with autism and intellectual handicaps in recent years, researchers have found. 

Five individuals under the age of 30, who cited autism as a factor in their decision to seek legal euthanasia, are among the cases reviewed by specialists at the U.K.'s Kingston University. 

"Factors directly associated with intellectual disability and/or ASD were the sole cause of suffering described in 21% of cases and a major contributing factor in a further 42% of cases," Kingston University's report on the issue found. 

The study noted that in many cases, doctors determined there was "no prospect of improvement" for intellectually challenged individuals because there is no treatment for their handicap.

"Reasons for the EAS [euthanasia and physician-assisted suicide] request included social isolation and loneliness (77%), lack of resilience or coping strategies (56%), lack of flexibility (rigid thinking or difficulty adapting to change) (44%) and oversensitivity to stimuli (26%). In one-third of cases, physicians noted there was ‘no prospect of improvement’ as ASD and intellectual disability are not treatable," the study reads.

Palliative care specialist Irene Tuffrey-Wijne — one of the lead authors of the Kingston University report — found Dutch doctors were legally killing patients who sought their own euthanasia because their intellectual disability or mental condition prevented them from leading a normal life, according to The Associated Press.

One record includes the case of a Dutch woman in her 30s with autism and borderline personality disorder. Doctors determined her afflictions prevented her from maintaining relationships and made forming connections with others "too difficult."

"There’s no doubt in my mind these people were suffering," Tuffrey-Wijne said. "But is society really OK with sending this message, that there’s no other way to help them, and it’s just better to be dead?"

Dutch psychologist Dr. Bram Sizoo expressed horror at the trend of autistic youths seeking assisted suicide and euthanasia's expanding acceptance.

"Some of them are almost excited at the prospect of death," Sizoo said. "They think this will be the end of their problems and the end of their family’s problems."

The Royal Dutch Medical Association has left the decision of who qualifies for assisted suicide up to medical professionals with few hard guidelines or rules.

https://www.foxnews.com/world/netherlands-euthanizing-autistic-intellectually-handicapped-people-researcher-finds

The ironically named Court of Protection. More end-of-life humanity in the UK

A UK court has ruled a 19-year-old critically ill female patient with a rare disorder cannot make her own decisions about continuing her medical care, as her family battles her doctors' desire to stop treatment and pursue end-of-life care.

The teen, whose identity has been anonymized as "ST" by the court, has a rare genetic mitochondrial disease that is progressively degenerative, according to court documents. Her condition is similar to that of Charlie Gard, the infant whose story drew global headlines in 2017. Charlie's parents lost a bid to bring him to the U.S. for an experimental treatment for his critical condition and he died after the hospital withdrew life-saving care after a months-long high profile legal battle.

Despite previously being a student studying for her A-levels (short for advanced levels), the 19-year-old girl has spent the past year in the ICU, dependent on a ventilator and a feeding tube. She requires regular dialysis due to chronic kidney damage from her disease. "ST" is currently fighting the hospital to be allowed to travel to Canada for an experimental treatment to treat her disease.

The Christian Legal Centre, which is advocating for the patient, argues her case is different than Gard's because she is conscious and able to communicate and argue in her defense.

But her doctor believe "ST" is "actively dying" and has no hope of a cure to resume life outside intensive care. They are asking the court to end her dialysis treatments and pursue palliative care instead. The hospital told the court the 19-year-old is incapable of making decisions about her future medical care because she is under the "delusion" that her death is not imminent.

The teen, who comes from a strong Christian family, confessed she realizes the treatment may not help extend her life but wants to keep fighting.

"This is my wish. I want to die trying to live. We have to try everything," she told clinicians, according to court documents.

Her family has spent their entire life savings to treat the girl, the Christian Legal Centre said, and wants to go to the public to raise funds for the expensive treatment, but cannot due to a "transparency order" requested by the hospital which bars reporting any information which might identify "ST", her family, or the hospital.

The girl's family described the long battle with the hospital as "a year of continuous torture" for them.

"Not only are we anxious about our beloved daughter’s fight for survival, but we have also been cruelly gagged from being able to speak about her situation. We are not allowed to ask people for prayers or for help which she desperately needs. It is a matter of life and death for our daughter to raise money for treatment in Canada, so these arbitrary reporting restrictions are literally killing her," they said via legal representation.

In court this week, a judge determined the teen "is able to communicate reasonably well with her doctors with assistance from her mother and, on occasion, speech therapists." Two psychiatrists assessed the teen was capable of making decisions about her future care for herself.

However, the judge said that, "ST" was mentally incapable of making decisions for herself because "she does not believe the information she has been given by her doctors." The judge ruled that decisions about ST's further care should be determined by the Court of Protection based on an assessment of her best interests.

"We are shocked to be told by the judge that our daughter does not have capacity to make decisions for herself after all the experts have said that she does. We are very distressed by this injustice, and we hope that, by Jesus’s grace, this will be corrected on appeal," the family of the patient said. 

Andrea Williams, the Chief Executive of Christian Legal Centre, blasted the transparency order and called the case "profoundly disturbing."

"This profoundly disturbing case demonstrates the urgent need for an overhaul into how end-of-life decisions are made in the NHS and the Courts," she said.

"What can be more natural or rational for a seriously ill 19-year-old than to leave no stone unturned and to take every chance of survival? ST has wanted to tell her story to the world in order to try and access further treatment but has been prevented from doing so by the ironically named Court of Protection," she said in a statement.

The NHS did not respond to a request for comment.

https://www.foxnews.com/media/uk-court-rules-teen-rare-disorder-incapable-making-decisions-care-begging-live

See the video, Charlie Gard's father: So sorry we couldn't save you. https://www.foxnews.com/video/5519176818001

Clinical spectrum and treatment outcomes of patients with developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep

Tchah N, Yang D, Kim HD, Lee JS, Kim SH, Kang HC. Clinical Spectrum and Treatment Outcomes of Patients with Developmental and/or Epileptic Encephalopathy with Spike-and-Wave Activation in Sleep. Ann Child Neurol. 2022;30(4):189-196.

Abstract

Purpose
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) is a spectrum of conditions characterized by various phenotypes of cognitive, linguistic, and behavioral regression associated with spike-and-wave activation in sleep. We aimed to investigate the phenotypic spectrum and treatment outcomes of pediatric patients with D/EE-SWAS.

Methods
We retrospectively analyzed the medical records of pediatric patients diagnosed with D/EE-SWAS and treated at Severance Children’s Hospital from 2006 to 2022. We extracted information from their medical records on electroencephalography before and after treatment, types of treatment, seizure frequency, and developmental profiles. The primary outcome was reduction of the spike-wave index on electroencephalography after treatment.

Results
Twenty-one patients with a median age of 5.3 years (interquartile range, 4.1 to 6.6) at diagnosis were included. Ten patients had delayed development. The patients received various anti-seizure medications. Fourteen received long-term, high-dose steroid therapy, 10 were placed on a ketogenic diet, four received intravenous steroid pulse therapy, and one each was treated with intravenous immunoglobulin and cannabidiol. The most effective treatments were steroid therapy and a ketogenic diet, which were also effective in reducing seizures and improving cognition. Side effects during treatment were transient and treatable.

Conclusion
We described the clinical spectrum of pediatric patients with D/EE-SWAS. Steroid therapy and a ketogenic diet can be considered effective therapeutic options for patients with D/EE SWAS.

Iron and tic disorders

Inspired by a patient

Avrahami M, Barzilay R, HarGil M, Weizman A, Watemberg N. Serum Ferritin Levels Are Lower in Children With Tic Disorders Compared with Children Without Tics: A Cross-Sectional Study. J Child Adolesc Psychopharmacol. 2017 Mar;27(2):192-195. doi: 10.1089/cap.2016.0069. Epub 2016 Aug 22. PMID: 27548271.

Abstract

Objectives: Alteration in peripheral iron indices has been reported in a number of movement disorders, particularly Parkinson's disease. We hypothesized that iron stores may be diminished in children at an early stage of tic disorder.

Methods: Using data retrieved from electronic medical records, we compared serum ferritin levels, an indicator of body iron store balance, in drug-naive children diagnosed for the first time with tic disorder (study group; N = 47, 32 boys/15 girls, aged 8.66 ± 3.17 years) compared to age- and sex-matched children with headaches (comparison group, n = 100, 62 boys/38 girls, aged 9.51 ± 3.15 years) treated in the same pediatric neurological clinic.

Results: Mean serum ferritin levels were significantly lower (-32%, p = 0.01) in the tic disorder group compared to the headache group. No significant differences were detected in circulatory hemoglobin, iron, transferrin, and platelet count between the two groups.

Conclusion: Our findings suggest that body iron stores may be reduced in children with recent-onset tic disorder.

Ghosh D, Burkman E. Relationship of serum ferritin level and tic severity in children with Tourette syndrome. Childs Nerv Syst. 2017 Aug;33(8):1373-1378. doi: 10.1007/s00381-017-3424-z. Epub 2017 May 3. PMID: 28470381.

Abstract

Purpose: Tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS). Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in Tourette syndrome (TS). The purpose of this study was to evaluate the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS.

Methods: Children <18 years, diagnosed with TS during 2009-2015, were reviewed. Only those with serum ferritin testing were included. The following data were collected: tic severity, impact on life, medication, comorbidities, blood count, and serum ferritin at diagnosis and follow-up.

Results: In fifty-seven patients, M:F = 2:1, serum ferritin was 48.0 ± 33.28 ng/mL, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6. Serum ferritin was not influenced by comorbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (P > 0.16). Thirty-eight percent with low serum ferritin (≤50 ng/mL) (n = 37) had severe tics (>5 composite score), compared with 25% in normal ferritin group (n = 20). Over 6-12 months, tic severity score improved in both iron treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron.

Conclusions: Our data suggest iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. Iron supplementation showed a trend towards improvement of tic severity upon follow-up. We suggest a double-blind, placebo-controlled prospective study to reach a definite conclusion.

Kanaan AS, Yu D, Metere R, Schäfer A, Schlumm T, Bilgic B, Anwander A, Mathews CA, Scharf JM, Müller-Vahl K, Möller HE. Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome. Neurobiol Dis. 2023 Aug 2;185:106252. doi: 10.1016/j.nbd.2023.106252. Epub ahead of print. PMID: 37536382.

Abstract

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Tang CY, Wen F. Serum ferritin levels in children with attention deficit hyperactivity disorder and tic disorder. World J Clin Cases. 2022 Aug 6;10(22):7749-7759. doi: 10.12998/wjcc.v10.i22.7749. PMID: 36158507; PMCID: PMC9372851.

Abstract

Background: Iron plays an important role in neurodevelopmental functions in the brain. Serum ferritin levels are different in children with attention deficit hyperactivity disorder and tic disorder than in healthy children.

Aim: To explore the current status of iron deficiency in children with neurodevelopmental disorders and its sex and age effects.

Methods: A total of 1565 children with attention deficit hyperactivity disorder (ADHD), 1694 children with tic disorder (TD), 93 children with ASD and 1997 healthy control children were included between January 1, 2020, and December 31, 2021 at Beijing Children's Hospital. We describe the differences in age levels and ferritin levels between different disease groups and their sex differences. The differences between the sexes in each disease were analyzed using the t test. The incidence rate of low serum ferritin was used to describe the differences between different diseases and different age groups. A chi-square test was used to analyze the difference in the incidence of low serum ferritin between the disease group and the control group. Analysis of variance was used for comparisons between subgroups, and regression analysis was used for confounding factor control.

Results: A total of 1565 ADHD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 36.82 ± 20.64 μg/L and 35.64 ± 18.56 μg/L, respectively. A total of 1694 TD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 35.72 ± 20.15 μg/L and 34.54 ± 22.12 μg/L, respectively. As age increased, the incidence of low serum ferritin in ADHD and TD first decreased and then increased, and 10 years old was the turning point of rising levels. The incidence of ADHD with low serum ferritin was 8.37%, the incidence of TD with low serum ferritin was 11.04%, and the incidence of the healthy control group with low serum ferritin was 8.61%, among which male children with TD accounted for 9.25% and female children with TD accounted for 11.62%. There was a significant difference among the three groups (P < 0.05). In addition, there were 93 children with ASD with an average serum ferritin level of 30.99 ± 18.11 μg/L and a serum ferritin incidence of 15.05%.

Conclusion: In conclusion, low serum ferritin is not a risk factor for ADHD or TD. The incidence of low serum ferritin levels in children with ADHD and TD between 5 and 12 years old decreases first and then increases with age.

Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Bai YM. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry. 2013 Jun 4;13:161. doi: 10.1186/1471-244X-13-161. PMID: 23735056; PMCID: PMC3680022.

Abstract

Background: A great deal of evidence has shown that iron is an important component in cognitive, sensorimotor, and social-emotional development and functioning, because the development of central nervous system processes is highly dependent on iron-containing enzymes and proteins. Deficiency of iron in early life may increase the risk of psychiatric morbidity.

Methods: Utilizing the National Health Insurance Database from 1996 to 2008, children and adolescents with a diagnosis of IDA were identified and compared with age and gender-matched controls (1:4) in an investigation of the increased risk of psychiatric disorders.

Results: A total of 2957 patients with IDA, with an increased risk of unipolar depressive disorder (OR = 2.34, 95% CI = 1.58 ~ 3.46), bipolar disorder (OR = 5.78, 95% CI = 2.23 ~ 15.05), anxiety disorder (OR = 2.17, 95% CI = 1.49 ~ 3.16), autism spectrum disorder (OR = 3.08, 95% CI = 1.79 ~ 5.28), attention deficit hyperactivity disorder (OR = 1.67, 95% CI = 1.29 ~ 2.17), tic disorder (OR = 1.70, 95% CI = 1.03 ~ 2.78), developmental delay (OR = 2.45, 95% CI = 2.00 ~ 3.00), and mental retardation (OR = 2.70, 95% CI = 2.00 ~ 3.65), were identified. A gender effect was noted, in that only female patients with IDA had an increased OR of bipolar disorder (OR = 5.56, 95% CI = 1.98 ~ 15.70) and tic disorder (OR = 2.95, 95% CI = 1.27 ~ 6.86).

Conclusion: Iron deficiency increased the risk of psychiatric disorders, including mood disorders, autism spectrum disorder, attention deficit hyperactivity disorder, and developmental disorders. Further study is required to clarify the mechanism in the association between IDA and psychiatric disorder.

Efficiency of brivaracetam in a tertiary referral epilepsy center.

Steinhoff BJ, Bacher M, Bucurenciu I, Hillenbrand B, Intravooth T, Kornmeier R, Kurth C, Stockinger J, Staack AM. Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-A monocenter survey. Seizure. 2017 May;48:11-14. doi: 10.1016/j.seizure.2017.03.010. Epub 2017 Mar 18. PMID: 28364655.

Abstract

Purpose: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center.

Methods: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV.

Results: Data of 101 patients (mean age 42 years, range 18-81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2-18). The initial dose of BRV was at least 50mg per day, the mean maintenance dose at cut-off was 168.6mg (median 200mg, range 50-400mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n=28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%.

Conclusion: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy.