Critical incidents, nocturnal supervision, and caregiver knowledge on SUDEP in patients with Dravet syndrome: A prospective multicenter study in Germany.

OBJECTIVE: The aim was to investigate the monitoring, interventions, and occurrence of critical, potentially life-threatening incidents in patients with Dravet syndrome (DS) and caregivers' knowledge about sudden unexpected death in epilepsy (SUDEP). METHODS: This multicenter, cross-sectional study of patients with DS and their caregivers in Germany consisted of a questionnaire and prospective diary querying the disease characteristics and demographic data of patients and caregivers. RESULTS: Our analysis included 108 questionnaires and 82 diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 (SD ± 10.0 years) and primary caregivers were 92.6% (n = 100) female, with a mean age of 44.7 (SD ± 10.6 years). Monitoring devices were used regularly by 75.9% (n = 82) of caregivers, and most monitored daily/nightly. Frequently used devices were pulse oximeters (64.6%), baby monitors (64.6%), thermometers (24.1%), and Epi-Care (26.8%). Younger caregiver and patient age and history of status epilepticus were associated with increased use of monitoring, and 81% of monitor users reported having avoided a critical incident with nocturnal monitoring. The need for resuscitation due to cardiac or respiratory arrest was reported by 22 caregivers (20.4%), and most cases (72.7%) were associated with a seizure. Caregivers reported frequently performing interventions at night, including oropharyngeal suction, oxygenation, personal hygiene, and change of body position. Most caregivers were well informed about SUDEP (n = 102; 94%) and monitored for a lateral or supine body position; however, only 39.8% reported receiving resuscitation training, whereas 52.8% (n = 57) knew what to do in case the child's breathing or heart activity failed. SIGNIFICANCE: Critical incidents and the need for resuscitation are reported frequently by caregivers and may be related to high mortality and SUDEP rates in DS. Resuscitation training is welcomed by caregivers and should be continuously provided. Oxygen monitoring devices are frequently used and considered useful by caregivers.

Applicability and clinical utility of the German rivermead post-concussion symptoms questionnaire in proxies of children after traumatic brain injury: an instrument validation study.

BACKGROUND: The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. METHODS: In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8-12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects' sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. RESULTS: Good internal consistency was demonstrated regarding Cronbach's α (0.81-0.90) and McDonald's ω (0.84-0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50-0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49-0.65) and the GAD-7 (ϱ = 0.44-0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. CONCLUSIONS: The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI.

Bilateral Foramina Parietalia Permagna - A Calvarial Defect Caused by Haploinsufficiency of the Msh Homeobox 2 Gene: A Case Report and Current Literature Review.

Foramina parietalia permagna (FPP) is a rare anatomical defect that affects the parietal bones of the human skull. FPP is characterized by symmetric perforations on either side of the skull, which are caused by insufficient ossification during embryogenesis. These openings are typically abnormally large and can range from a few millimeters to several centimeters in diameter. Enlarged foramina are often discovered incidentally during anatomical or radiological examinations and in most cases left untreated unless symptoms develop. Although this calvarial defect is usually asymptomatic, it may be accompanied by neurological or vascular conditions that can have clinical significance in certain cases. FPP is an inherited disorder and arises due to mutations in either Msh homeobox 2 (MSX2) or aristaless-like homeobox 4 (ALX4) genes. In almost all cases, one parent is affected. Clinical findings and diagnostic imaging typically contribute to determine the diagnosis.

A short scale to measure health-related quality of life after traumatic brain injury in children and adolescents (QOLIBRI-OS-KID/ADO): psychometric properties and German reference values.

PURPOSE: The impact of pediatric traumatic brain injury (pTBI) on health-related quality of life (HRQoL) in children and adolescents remains understudied. Short scales have some advantages in terms of economy and administration over longer scales, especially in younger children. The aim of the present study is to psychometrically evaluate the six-item German version of the QOLIBRI-OS-KID/ADO scale for children and adolescents. In addition, reference values from a general German pediatric population are obtained to assist clinicians and researchers in the interpretation of HRQoL after pTBI. METHODS: A total of 297 individuals after TBI and 1997 from a general population sample completed the questionnaire. Reliability, validity, and comparability of the assessed construct were examined. RESULTS: The questionnaire showed satisfactory reliability (α = 0.75 and ω = 0.81 and α = 0.85 and ω = 0.86 for the TBI and general population samples, respectively). The QOLIBRI-OS-KID/ADO was highly correlated with its long version (R2 = 67%) and showed an overlap with disease-specific HRQoL (R2 = 55%) in the TBI sample. The one-dimensional factorial structure could be replicated and tested for measurement invariance between samples, indicating a comparable HRQoL construct assessment. Therefore, reference values and cut-offs indicating clinically relevant impairment could be provided using percentiles stratified by factors significantly associated with the total score in the regression analyses (i.e., age group and gender). CONCLUSION: In combination with the cut-offs, the QOLIBRI-OS-KID/ADO provides a cost-effective screening tool, complemented by interpretation guidelines, which may help to draw clinical conclusions and indications such as further administration of a longer version of the instrument to gain more detailed insight into impaired HRQoL domains or omission of further steps in the absence of an indication.

Peripheral polyneuropathy in children and young adults with ataxia-telangiectasia.

BACKGROUND AND PURPOSE: Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T. METHODS: In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed. RESULTS: In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001). CONCLUSIONS: In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.

Intrafamilial variability in six family members with ERF-related craniosynostosis syndrome type 4.

ERF-related craniosynostosis syndrome type 4 (CRS4, OMIM #600775) is a rare autosomal dominant malformation syndrome, caused by pathogenic variants in the ERF gene and characterized by craniosynostosis, developmental delay, and dysmorphic features such as hypertelorism, exophthalmos, depressed nasal bridge, and retrognathia. So far, there are mostly individual reports and only a few descriptions of families with more than two affected patients, allowing statements about the penetrance of a certain variant and its variability only to a limited extent. In this study, we report an in-depth analysis of the clinical course of six family members from three generations with the novel heterozygous nonsense variant c.286A>T (p.Lys96*) in the ERF gene. At the time of examination, all of the six patients showed mild dysmorphic features and brachydactyly, five were overweight/obese and had delayed speech development, and four were short in stature. Hyperactivity, a short concentration span and a history of learning difficulties were found in half of the affected family members. To this day, none of the patients developed increased intracranial hypertension that would require surgical intervention. This work provides further information on the expressive variability of an ERF variant in six members of one family and focuses on the need for close neuropediatric surveillance.

The incidence and type of cancer in patients with ataxia-telangiectasia via a retrospective single-centre study.

Ataxia-telangiectasia (A-T) is a hereditary immune system disorder with neurodegeneration. Its first neurologic symptoms include ataxic gait in early childhood, with slowly progressive cerebellar ataxia, oculomotor apraxia, oculocutaneous telangiectasia, and progressive muscle weakness. Neonatal screening for severe T-cell deficiency was recently found to diagnose A-T patients with a significantly reduced naïve T-cell pool. Our study includes 69 A-T patients between 8 January 2002 and 1 December 2019. Nineteen cases of cancer were diagnosed in 17 patients (25%), with a median overall survival [OS; 95% cumulative indcidence (CI)] of 26·9 years for the entire cohort. The 15-year OS of 82·5% (72-95%) was significantly decreased among A-T patients with malignancies, who had a median OS of 2·11 years, with a two-year-estimated OS of 50·7% (31-82%). Haematological malignancies were the major causes of death within the initial years of life with a 15 times increased risk for death [HR (95% CI): 6·9 (3·1-15.2), P < 0·001] upon malignancy diagnosis. Male patients with A-T are at a higher cancer risk than their female counterparts. This manuscript highlights the need for cancer surveillance and prevention, as well as optimal treatment in this cohort.

Abusive head trauma: experience improves diagnosis.

PURPOSE: The diagnosis of abusive head trauma (AHT) is complex and neuroimaging plays a crucial role. Our goal was to determine whether non-neuroradiologists with standard neuroradiology knowledge perform as well as neuroradiologists with experience in pediatric neuroimaging in interpreting MRI in cases of presumptive AHT (pAHT). METHODS: Twenty children were retrospectively evaluated. Patients had been diagnosed with pAHT (6 patients), non-abusive head trauma-NAHT (5 patients), metabolic diseases (3 patients), and benign enlargement of the subarachnoid spaces (BESS) (6 patients). The MRI was assessed blindly, i.e., no clinical history was given to the 3 non-neuroradiologists and 3 neuroradiologists from 2 different institutions. RESULTS: Blindly, neuroradiologists demonstrated higher levels of sensitivity and positive predictive value in the diagnosis of pAHT (89%) than non-neuroradiologists (50%). Neuroradiologists chose correctly pAHT as the most probable diagnosis 16 out of 18 times; in contrast, non-neuroradiologists only chose 9 out of 18 times. In our series, the foremost important misdiagnosis for pAHT was NAHT (neuroradiologists twice and non-neuroradiologists 5 times). Only victims of motor vehicle accidents were blindly misdiagnosed as pAHT. No usual household NAHT was not misdiagnosed as pAHT. Neuroradiologists correctly ruled out pAHT in all cases of metabolic diseases and BESS. CONCLUSION: MRI in cases of suspected AHT should be evaluated by neuroradiologists with experience in pediatric neuroimaging. Neuroradiologists looked beyond the subdural hemorrhage (SDH) and were more precise in the assessment of pAHT and its differential diagnosis than non-neuroradiologists were. It seems that non-neuroradiologists mainly assess whether or not a pAHT is present depending on the presence or absence of SDH.

Retrospectively diagnosing congenital cytomegalovirus infections in symptomatic infants is challenging.

AIM: Our aim was to analyse the diagnostic workup of hospitalised infants with symptoms of congenital cytomegalovirus (CMV) infections. METHODS: This retrospective study was carried out at the University Hospital Frankfurt, Germany, from 2008 to 2017 on infants aged 4 weeks to 12 months presenting with neurological symptoms consistent with congenital CMV infections. RESULTS: We studied 117 infants, and workup data for CMV infections were available for 84%. Of these, 54% were immunoglobulin G- and immunoglobulin M-seronegative for CMV or immunoglobulin G-seropositive with no viral shedding. Congenital CMV infection was excluded in these cases. In 16%, the CMV workup was incomplete, precluding a definitive diagnosis. Dried blood spots (DBS) were requested from 30%. CMV polymerase chain reaction was negative in 19 of these 29 infants, and CMV deoxyribonucleic acid detection confirmed congenital CMV infections in six patients. DBS had been destroyed in line with German law in four cases. Congenital CMV infections were diagnosed (5%) or excluded (62%) in 67% of patients and unanswered in the remaining 33%. CONCLUSION: Diagnoses of congenital CMV infections were widely considered and found in 5%. CMV was not stringently investigated in all patients or remained elusive due to German law on destroying DBS.

[Diagnostics and Significance Evaluation in Cases of Suspected Child Sexual Assault - An Analysis of 210 Cases]. / Diagnostik und Signifikanzbeurteilung bei Verdacht auf sexuelle Gewalt im Kindes- und Jugendalter.

BACKGROUND: Child sexual abuse is difficult to diagnose in children and it is a challenging task for all involved medical disciplines of a medical child protection unit. The present study describes the factors that led patients to be presented to a child protection unit under the suspicion of sexual abuse and the diagnostic instruments which were used in order to substantiate or prove suspicious fact. PATIENTS AND METHOD: This study was conducted retrospectively on the basis of 210 children and adolescents ranged in age between 4 months and 18 years, who were presented to the medical child protection unit of Frankfurt am Main with suspected sexual abuse in the period from 2010 to 2015. 173 cases were analyzed in more detail. The cases were analyzed with the help of standardized documentation sheet and suspicious facts were evaluated with regard to their significance. RESULTS: A total of 173 patient records were analyzed in more detail containing cases of suspected child sexual abuse. The majority of the children and teenager were female and younger than 10. Often the father was accused of sexual abuse and parents were separated or in custody battle. The patient's statements were crucial for substantiation of suspicious fact in 60% of the cases. The assessment was more certain if the alleged perpetrator was not part of the close family and if other forms of physical violence were associated. CONCLUSION: The study shows that gynecological respectively anogenital findings do not represent the key evidence for the substantiation of sexual abuse allegations. Instead, it underlines the significance of further diagnostic methods, in particular the psychological and anamnestic evaluation.

[Acceptance of Binding Preventive Examinations: A Survey of Parents in Hessen]. / Akzeptanz verbindlicher Vorsorgeuntersuchungen ­ Ergebnisse einer Elternbefragung in Hessen.

OBJECTIVE: In 2008, the Child Health Protection Act (Kindergesundheitsschutz-Gesetz) became effective in Hesse. Since then, participation in the early screening examinations U1 to U9 in Hesse is obligatory. The implementation of the law is part of the responsibility of the Hessian Children's Preventive Healthcare Centre (Hessisches Kindervorsorgezentrum (HKVZ)), which invites parents and legal guardians to each examination from U4 up to and including U9. To obtain information on the acceptance of the law, the HKVZ carried out for the first time a survey of parents and legal guardians as part of their quality management. The following questions were raised: How well accepted are obligatory check-ups by Hessian parents? What is the degree of popularity and the limitation of such a law? METHOD: Along with the letter of invitation to participate in U7a, all parents and legal guardians received an anonymous survey questionnaire to be filled out and returned to the HKVZ. The evaluation took place in the HKVZ. RESULTS: Especially noteworthy are 3 results of the survey: When asked if health problems were detected during the check-ups, 8.94% of the parents and legal guardians answered the question with a "yes". Almost every ninth child examined was found to have health problems during the check-up. The reasons for a missed check-up were comparatively trivial. 96.53% of the respondents had not missed a check-up, only 2.88% answered this question with a "yes" and 0.59% did not give any information here. The most frequent reason for a missed examination with 1.59% was that it was simply "forgotten". In the category "other", 1.12% mentioned a disease of the child or a stay abroad as the most frequent reason for a missed check-up. Difficulty in making an appointment with the pediatrician (0.35% was another reason. The high level of awareness of the Hessian Child Health Protection Act (94.12% of respondents) and the positive ratings of the letters sent by the HKVZ (84.06% good to very good) reflect its acceptance. Further research is needed to confirm the effectiveness of such preventive health care examinations.

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

OBJECTIVE: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. METHODS: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). RESULTS: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). SIGNIFICANCE: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.

The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: Current evidence and future perspectives.

Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Mutations in the TSC1 or TSC2 genes lead to the dysregulation of the mechanistic target of rapamycin (mTOR) pathway. This mTOR pathway hyperactivation is associated with several processes resulting in epileptic conditions. The occurrence of seizures and their treatment outcomes seem to play a crucial role in cognitive and behavioral developments in patients with TSC. Mechanistic target of rapamycin inhibitors have been proven to be effective in epilepsy treatment in individuals with TSC. Specifically, because of their disease-modifying mechanism of action, they have the capability to prevent epileptogenesis in patients with TSC. This article will provide an overview of the current evidence of and delineate future perspectives for mTOR inhibitors and their role in preventing epileptogenesis.

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature.

OBJECTIVE: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. METHODS: Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. RESULTS: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. SIGNIFICANCE: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.

Ataxia telangiectasia alters the ApoB and reelin pathway.

Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2 months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.

Growth hormone treatment in patients with ataxia telangiectasia.

INTRODUCTION: Ataxia telangiectasia (A-T) is a devastating autosomal recessive disorder with chromosomal instability and growth failure. Low levels of growth hormone (GH) and growth factors may be related to advanced neurological deterioration, wasting syndrome and more pronounced immunodeficiency. OBJECTIVE: The objective of this study is to study safety and effectiveness of GH therapy in patients with A-T and evaluate the effect of GH on ataxia and lymphocyte subsets. METHODS: Three patients with classical A-T were treated with GH (0.3 mg/kg/d) for 1 year. Growth rate, ataxia score and lymphocyte subsets were monitored. RESULTS: GH treatment was well tolerated. All patients showed a significant increase of height SDS of +1.3 (mean height SDS -1.994), a mean increase of 8 (6-11) cm/12 months. Lymphocytes subsets and ataxia were not altered before and after GH treatment. CONCLUSIONS: Treatment with GH is feasible and effective in A-T patients with severe growth arrest, but no effect on ataxia and lymphocytes could be recorded.

Predictors of and attitudes toward counseling about SUDEP and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians.

OBJECTIVE: To examine the attitudes toward counseling about sudden unexpected death in epilepsy (SUDEP) and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians, and to determine factors associated with not discussing SUDEP. METHODS: Questionnaires were sent to approximately 5,000 neurologists and neuropediatricians in 2014 regarding respondents' demographics, their working environments, and how often they discussed SUDEP, suicidal ideations on anticonvulsive medication, driving restrictions, and risks in daily life activities. RESULTS: In total, 519 surveys were completed (respondents' mean age: 45.5 years, 41.6% female, 66.9% adult neurologists, 31.0% neuropediatricians). A minority of 2.7% reported that they counseled all of their patients on SUDEP, 8.7% counseled most of the time (50-90%), 20.8% sometimes (10-49%), 44.5% rarely (1-9%), and 23.3% reported not counseling about SUDEP at all. In contrast, 92.9% reported that they counseled all patients about driving restrictions and 81.5% about risks in daily life activities. Suicidal ideations were discussed in 59.0% for some and in 3.3% for all patients, whereas 35.1% of respondents reported never discussing suicidal ideations. Independent predictors of not discussing SUDEP were no additional epilepsy training, no or uncertain SUDEP cases in the past, <10 years in practice, <25 epilepsy patients seen per quarter, and the opinion of a lack of consequences in SUDEP prevention. The opinion that SUDEP is a risk factor in particular patient groups and the attitude that all risks should be discussed predicted counseling on SUDEP. SIGNIFICANCE: Our findings show a discrepancy between guidelines and practice regarding the discussion of premature mortality due to SUDEP or suicidality. Both are not discussed at all by a substantial proportion of neurologists and neuropediatricians. This is in contrast to ubiquitous education about driving restrictions. Dissemination of knowledge among physicians about potential preventive strategies might increase the likelihood of discussion. Clinical practice guidelines are welcomed by the majority of physicians in this process.

Frontal and thalamic changes of GABA concentration indicate dysfunction of thalamofrontal networks in juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) has been considered to be a frontal variant of thalamocortical network dysfunction in epilepsy. Changes of γ-aminobutyric acid (GABA)ergic neurotransmission may play a key role in this dysfunction. Magnetic resonance spectroscopy (MRS) is the only noninvasive method to measure GABA concentrations in different brain regions. We measured GABA and other metabolite concentrations in the thalamus and frontal lobe of patients with JME. METHODS: A specific protocol was used for determining GABA concentrations in the thalamus, frontal lobe, and motor cortex contralateral to the handedness in 15 patients with JME and 15 age-matched controls. In addition, we measured concentrations of glutamate and glutamine, N-acetyl-aspartate (NAA), myoinositol, creatine, and choline using MRS with short echo time. JME-related concentration changes were analyzed comparing patients to controls, also considering potential effects of antiepileptic drugs. RESULTS: In patients with JME, GABA and NAA were reduced in the thalamus (p = 0.03 and p = 0.02), whereas frontal GABA and glutamine were elevated (p = 0.046 and p = 0.03). MRS revealed reduced NAA in the thalamic gray matter contralateral to the handedness (p = 0.04 each). These changes were found consistently in patients treated with new antiepileptic drugs and with valproate, although the extent of metabolic changes differed between these treatments. SIGNIFICANCE: Decreased thalamic and increased frontal GABA suggest a dysfunction of GABAergic neurotransmission in these brain regions of patients with JME. The NAA decrease in the gray matter of the thalamus may hint to a damage of GABAergic neurons, whereas frontal increase of GABA and its precursor glutamine may reflect increased density in GABAergic neurons due to subtle cortical disorganization in the thalamofrontal network.

Odontoid infiltration and spinal compression in Farber Disease: reversal by haematopoietic stem cell transplantation.

Farber disease (FD) is a lysosomal storage disorder caused by accumulation of ceramide in various organs and tissues, most notably the central nervous system, subcutaneous tissues and respiratory tract. We report a girl who developed major destructive bone involvement, which affected the odontoid process and produced spinal compression at 9 years of age. Bone involvement was proven histologically but resolved, as assessed by serial MRI scanning, following matched unrelated donor haematopoietic stem cell transplantation. This transplant resulted in only partial donor chimerism (less than 10 % donor cells in peripheral blood), yet this was sufficient to almost normalize acid ceramidase levels in leukocytes and to produce dramatic improvements in subcutaneous nodules and joint mobility as well as the beneficial effect on the involved bone. Unfortunately, the transplant was rejected after 2 years but the patient was rescued from an aplastic state by successful haploidentical peripheral blood stem cell transplantation and remained a full donor chimera without recurrence of the bone involvement and with steadily improving mobility at the age of 17 years. We describe an FD patient who presented with severe destruction of the odontoid by inflammatory tissue which was reversed after long-term control achieved by allogeneic hematopoietic stem cell transplantation. After extensive literature search, we believe that this is the first report of bony involvement in Farber disease.