The spectrum of intermediate SCN8A-related epilepsy.

OBJECTIVE: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. METHODS: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. RESULTS: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. SIGNIFICANCE: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

Current Status of Pediatric Ventricular Assist Device Support.

The last decade has witnessed significant advancement in the field of ventricular assist device (VAD) support. Although device options for pediatric patients were previously severely limited because of body size constraints, this frustrating situation has gradually been changing, owing to ongoing device miniaturization. Recognition of the superiority of VAD support compared with conventional extracorporeal membrane oxygenation support has spurred enthusiasm for VAD support in children. In this article, we discuss the current status of pediatric VAD support; where do we stand now and where will we be heading? Because this field is rapidly changing, it is anticipated that this article will provide a general overview of what is currently occurring in the field of pediatric VAD support.

Larger Centers May Produce Better Outcomes: Is Regionalization in Congenital Heart Surgery a Superior Model?

Efforts to correlate outcomes of children undergoing heart surgery with center volume and characteristics are not novel. In the current era, outcomes are defined as, and in many cases limited to, mortality rates. Over the past two decades, several investigators have explored various aspects of the volume-mortality relationship. The association between center volume and mortality, although not uniform, is highly implicated by the current literature. Notwithstanding, varied population densities in the United States makes regionalization of specialized services, such as pediatric cardiac surgery, undeniably challenging. There may be an unfortunate reality that larger centers have some advantage in achieving, at the very least, timely measures. However, as pediatric cardiac surgery progresses as a specialty, the definition of 'outcomes' must be expanded beyond simplified, dichotomous parameters. While mortality has been our historical primary focus, as it should be, it is reasonable to propose that our focus should be increasingly refined towards patient- and family-centric measures, including morbidity, cost/value ratio, and overall hospital experience.

Acute ischemic stroke in children versus young adults.

OBJECTIVE: The aim of this study was to compare children and young adults with acute ischemic stroke (AIS) in 2 large registries. METHODS: We compared clinical characteristics, stroke etiology, workup, and outcome (modified Rankin scale score [mRS] at 3-6 months) in children (1 month-16 years) and young adults (16.1-45 years) with AIS. Data of children were collected prospectively in the nationwide Swiss NeuroPediatric Stroke Registry, young adults in the Bernese stroke database. Outcome (mRS) and stroke severity (pediatric adaptation of the National Institutes of Health stroke scale [PedNIHSS]) in children were calculated retrospectively. RESULTS: From January 2000 to December 2008, 128 children and 199 young adults suffered from an AIS. Children were more likely to be male than young adults (62%/49%, p = 0.023) and less frequently had hypertension (p = 0.001), hypercholesterolemia (p = 0.003), and a family history of stroke (p = 0.048). Stroke severity was similar in children and young adults (median PedNIHSS/NIHSS 5/6; p = 0.102). Stroke etiology (original TOAST classification) was more likely to be "other determined cause" in children than in young adults (51%/29%; p < .001). Cervicocerebral artery dissections were less frequent in children than in young adults (10%/23%; p = 0.005). Outcome at 3 to 6 months did not differ between children and young adults (p = 0.907); 59% of children and 60% of young adults had a favorable outcome (mRS 0-1). Mortality was similar among children and young adults (4%/6%; p = 0.436). In multivariate analysis, low PedNIHSS/NIHSS was the most important predictor of favorable outcome (p < 0.001). INTERPRETATION: Although stroke etiology and risk factors in children and young adults are different, stroke severity and clinical outcome were similar in both groups.

Targeted next generation sequencing as a diagnostic tool in epileptic disorders.

PURPOSE: Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient's epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks. METHODS: To overcome these diagnostic restrictions, we composed a panel of genes for Next Generation Sequencing containing the most relevant epilepsy genes and covering the most relevant epilepsy phenotypes known so far. With this method, 265 genes were analyzed per patient in a single step. We evaluated this panel on a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a severe but unspecific seizure disorder covering both sporadic and familial cases. KEY FINDINGS: We identified presumed disease-causing mutations in 16 of 33 patients comprising sequence alterations in frequently as well as in less commonly affected genes. The detected aberrations encompassed known and unknown point mutations (SCN1A p.R222X, p. E289V, p.379R, p.R393H; SCN2A p.V208E; STXBP1 p.R122X; KCNJ10 p.L68P, p.I129V; KCTD7 p.L108M; KCNQ3 p.P574S; ARHGEF9 p.R290H; SMS p.F58L; TPP1 p.Q278R, p.Q422H; MFSD8 p.T294K), a putative splice site mutation (SCN1A c.693A> p.T/P231P) and small deletions (SCN1A p.F1330Lfs3X [1 bp]; MFSD8 p.A138Dfs10X [7 bp]). All mutations have been confirmed by conventional Sanger sequencing and, where possible, validated by parental testing and segregation analysis. In three patients with either Dravet syndrome or myoclonic epilepsy, we detected SCN1A mutations (p.R222X, p.P231P, p.R393H), even though other laboratories had previously excluded aberrations of this gene by Sanger sequencing or high-resolution melting analysis. SIGNIFICANCE: We have developed a fast and cost-efficient diagnostic screening method to analyze the genetic basis of epilepsies. We were able to detect mutations in patients with clear and with unspecific epilepsy phenotypes, to uncover the genetic basis of many so far unresolved cases with epilepsy including mutation detection in cases in which previous conventional methods yielded falsely negative results. Our approach thus proved to be a powerful diagnostic tool that may contribute to collecting information on both common and unknown epileptic disorders and in delineating associated phenotypes of less frequently mutated genes.

On-Hours Compared to Off-Hours Pediatric Extracorporeal Life Support Initiation in the United States Between 2009 and 2018-An Analysis of the Extracorporeal Life Support Organization Registry.

We aimed to investigate whether there are differences in outcome for pediatric patients when extracorporeal life support (ECLS) is initiated on-hours compared with off-hours. DESIGN: Retrospective cohort study. SETTING: Ten-year period (2009-2018) in United States centers, from the Extracorporeal Life Support Organization registry. PATIENTS: Pediatric (>30 d and <18 yr old) patients undergoing venovenous and venoarterial ECLS. INTERVENTIONS: The primary predictor was on versus off-hours cannulation. On-hours were defined as 0700-1859 from Monday to Friday. Off-hours were defined as 1900-0659 from Monday to Thursday or 1900 Friday to 0659 Monday or any time during a United States national holiday. The primary outcome was inhospital mortality. The secondary outcomes were complications related to ECLS and length of hospital stay. MEASUREMENTS AND MAIN RESULTS: In a cohort of 9,400 patients, 4,331 (46.1%) were cannulated on-hours and 5,069 (53.9%) off-hours. In the off-hours group, 2,220/5,069 patients died (44.0%) versus 1,894/4,331 (44.1%) in the on-hours group (p = 0.93). Hemorrhagic complications were lower in the off-hours group versus the on-hours group (hemorrhagic 18.4% vs 21.0%; p = 0.002). After adjusting for patient complexity and other confounders, there were no differences between the groups in mortality (odds ratio [OR], 0.95; 95% CI, 0.85-1.07; p = 0.41) or any complications (OR, 1.02; 95% CI, 0.89-1.17; p = 0.75). CONCLUSIONS: Survival and complication rates are similar for pediatric patients when ECLS is initiated on-hours compared with off-hours. This finding suggests that, in aggregate, the current pediatric ECLS infrastructure in the United States provides adequate capabilities for the initiation of ECLS across all hours of the day.

Predicting Language Outcome After Left Hemispherotomy: A Systematic Literature Review.

OBJECTIVE: Hemidecortication is a therapeutic option in patients with drug-resistant structural epilepsy. If surgery is performed early enough in left-hemispheric pathology, the plasticity of the developing brain may enable the right hemisphere to take over language-if this has not occurred before surgery. A systematic overview of potential predictors of language outcome after left hemidecortication in children is warranted. METHODS: In a systematic literature review, we analyzed 58 studies on language lateralization after congenital or postneonatally acquired left-hemispheric pathology, and on language outcome after left-sided hemidisconnection, such as hemispherotomy. Single-subject data were pooled to determine the distribution of lateralization across etiologies in congenital lesions and across age groups in acute postneonatal lesions. A hierarchical linear regression assessed the influence of age at surgery, lesion type, age at seizure onset, and presurgery language function on language outcome after left hemidecortication. RESULTS: In acute postneonatal lesions, younger age at injury was significantly associated with right-sided language lateralization (Cramér V = 0.458; p = 0.039). In patients with hemidecortication, age at surgery was not significantly associated with language outcome (Cramér V = -0.056; p = 0.584). Presurgical language function was the most powerful predictor for postsurgical language outcome (F 4,47 = 7.35, p < 0.0001), with good presurgical language bearing the risk of postsurgical deterioration. In congenital pathology, right-sided language lateralization was most frequent in pre-/perinatal stroke (Cramér V = 0.357; p < 0.0001). CONCLUSIONS: We propose a presurgical decision algorithm with age, presurgical language function, language lateralization, and left-hemispheric structural pathology as decision points regarding surgery.

Sotos syndrome: a pitfall in the presurgical workup of temporal lobe epilepsy.

Tumour-associated epilepsy accounts for a quarter of paediatric patients undergoing epilepsy surgery with the vast majority achieving long-term seizure and drug freedom. We report the case of an eight-year-old patient who presented with developmental delay and overgrowth, followed by temporal lobe seizures that were attributed to a mesio-temporal brain tumour, and who was eventually treated with epilepsy surgery. Histopathology revealed a diffuse astrocytoma but its gross total resection surprisingly failed to control the temporal lobe seizures. Genetic testing identified a de novo pathogenic variant in the NSD1 gene, thus establishing the diagnosis of Sotos syndrome. Sotos syndrome is a rare overgrowth syndrome with an increased incidence of malignancy, including the very rare occurrence of brain tumours. Seizures are frequent in patients with Sotos syndrome, often occurring with temporal lobe semiology and ictal EEG patterns in the absence of a brain lesion, and usually responding to anti-seizure medication. Our case highlights Sotos syndrome as a rare but important pitfall in the presurgical workup of temporal lobe epilepsy that should be considered particularly in MRI-negative cases but also in the presence of a focal lesion that does not fully explain the clinical picture. Most importantly, our observations underline the value of thorough presurgical diagnostics including genetic testing, even in apparently straightforward cases of lesional epilepsy, to rule out an underlying genetic aetiology that may not be treated by surgery. Finally, our findings emphasize the need to re-evaluate our less successful epilepsy surgery cases and offer informed counselling and prognostication.

Delineating Pathways to Death by Multisystem Organ Failure in Patients With a Left Ventricular Assist Device.

BACKGROUND: This study delineates the sequences of adverse events (AEs) preceding mortality attributed to multisystem organ failure (MSOF) in patients with a left ventricular assist device (LVAD). METHODS: We analyzed 3765 AEs after 536 LVAD implants recorded in The Society of Thoracic Surgeons Intermacs data registry between 2006 and 2015 that resulted in MSOF death. Hierarchical clustering identified and visualized quantitatively unique clusters of patients with similar AE profiles. Markov modeling was used to illustrate the AE sequences that led to MSOF death within the clusters. Cox proportional hazard models determined the risk-adjusted, preimplant predictors of MSOF. RESULTS: We identified 2 distinct MSOF clusters based on their proportion of AE types and survival time. The early-death cluster (418 patients, 2304 AEs) had a median survival of 1 month (interquartile range, 3-6 months), whereas the late-death cluster (118 patients, 1,461 AEs) had a median survival of 11 months (interquartile range, 6-22 months). The predominant AE sequences in the early-death and late-death clusters were renal failure, to respiratory failure, to death (62%) and bleeding, to infection, to respiratory failure, to death (45%), respectively. Significant risk-adjusted preimplant predictors of MSOF included line sepsis (hazard ratio [HR] 3.0; 95% confidence interval [CI], 1.1-8.2), extracorporeal membrane oxygenation (HR, 2.2; 95% CI, 1.2-3.9), and dialysis or ultrafiltration (HR, 2.1; 95% CI, 1.5-3.0). CONCLUSIONS: This analysis identified 2 AE clusters and the predominant sequences that result in MSOF-associated mortality. MSOF develops in 1 cluster of patients after chronic bleeding and repeated infections but has prolonged survival, while another group dies early after renal and respiratory complications.

Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway.

Lung cancer is one of the most prevalent malignancies world-wide with non-small cell lung cancer (NSCLC) comprising nearly 80% of all cases. Unfortunately, many lung cancer patients are diagnosed at advanced stages of the disease with an associated poor prognosis. Recently, the Chinese herb root extract Triptolide/Minnelide (TL) has shown significant promise as a therapeutic agent for NSCLC treatment both in vitro and in vivo. The aim of this study was to investigate the underlying mechanism(s) of action regarding TL-induced cytotoxicity in NSCLC. We demonstrate that triptolide treatment of A549 and H460 NSCLC cells decreases Caveolin-1 (CAV-1) mRNA/protein expression, resulting in activation of the Akt/Bcl-2-mediated mitochondrial apoptosis pathway. CAV-1 down-regulation was triggered by Micro-RNA 204-5p (miR204-5p) up-regulation and could be significantly blocked by pre-treatment with both Sirt-1/Sirt-3 specific siRNA and SIRT-1/SIRT-3 enzyme inhibitors, EX-527 and nicotinamide. Overall, our results provide evidence for a novel mechanism by which TL exerts its cytotoxic effects on NSCLC via CAV-1 down-regulation. Furthermore, these findings demonstrate a pivotal role for TL induction of the Akt/Bax pathway in apoptosis of human lung cancer.

Impact of triptolide during ex vivo lung perfusion on grafts after transplantation in a rat model.

OBJECTIVE: Ex vivo lung perfusion creates a proinflammatory environment leading to deterioration in graft quality that may contribute to post-transplant graft dysfunction. Triptolide has been shown to have a therapeutic potential in various disease states because of its anti-inflammatory properties. On this basis, we investigated the impact of triptolide on graft preservation during ex vivo lung perfusion and associated post-transplant outcomes in a rat transplant model. METHODS: We performed rat normothermic ex vivo lung perfusion with acellular Steen solution containing 100 nM triptolide for 4 hours and compared the data with untreated lungs. Orthotopic single lung transplantation after ex vivo lung perfusion was performed. RESULTS: Physiologic and functional parameters of lung grafts on ex vivo lung perfusion with triptolide were better than those without treatment. Graft glucose consumption was significantly attenuated on ex vivo lung perfusion with triptolide via inhibition of hypoxia signaling resulting in improved mitochondrial function and reduced oxidative stress. Also, intragraft inflammation was markedly lower in triptolide-treated lungs because of inhibition of nuclear factor-κB signaling. Furthermore, post-transplant graft function and inflammatory events were significantly improved in the triptolide group compared with the untreated group. CONCLUSIONS: Treatment of lung grafts with triptolide during ex vivo lung perfusion may serve to enhance graft preservation and improve graft protection resulting in better post-transplant outcomes.

Iodine bioavailability from cow milk: a randomized, crossover balance study in healthy iodine-replete adults.

BACKGROUND: Milk and dairy products are considered important dietary sources of iodine in many countries. However, to our knowledge, iodine bioavailability from milk has not been directly measured in humans. OBJECTIVE: The aim of this study was to compare iodine bioavailability in iodine-replete adults from: 1) cow milk containing a high concentration of native iodine; 2) milk containing a low concentration of native iodine, with the addition of potassium iodide (KI) to assess a potential matrix effect; and 3) an aqueous solution of KI as a comparator; with all 3 containing equal amounts of total iodine (263 µg/250 mL). We also speciated iodine in milk. DESIGN: We conducted a 3-wk, randomized, crossover balance study in adults (n = 12) consuming directly analyzed, standardized diets. During the 3 test conditions - high intrinsic iodine milk (IIM), extrinsically added iodine in milk (EIM), and aqueous iodine solution (AIS) - subjects collected 24-h urine over 3 d and consumed the test drink on the second day, with 3- or 4-d wash-out periods prior to each treatment. Iodine absorption was calculated as the ratio of urinary iodine excretion (UIE) to total iodine intake. Milk iodine speciation was performed using ion chromatography-mass spectrometry. RESULTS: Iodine intake from the standardized diet was 195 ± 6 µg/d for males and 107 ± 6 µg/d for females; the test drinks provided an additional 263 µg. Eleven subjects completed the protocol. There was a linear relation between iodine intake and UIE (ß = 0.89, SE = 0.04, P < 0.001). There were no significant differences in UIE among the 3 conditions (P = 0.24). Median (range) fractional iodine absorption across the 3 conditions was 91 (51-145), 72 (48-95), and 98 (51-143)% on days 1, 2, and 3, respectively, with day 2 significantly lower compared with days 1 and 3 (P < 0.001). In milk, 80-93% of the total iodine was inorganic iodide. CONCLUSION: Nearly all of the iodine in cow milk is iodide and although fractional iodine absorption from milk decreases with increasing dose, its bioavailability is high. The trial was registered at clinicaltrials.gov as NCT03590431.

Prevalence of Anemia and Iron Deficiency in Pediatric Patients on Ventricular Assist Devices.

The prevalence and characteristics of anemia and iron deficiency in children supported by a ventricular assist device (VAD) are unknown. Patients <21 years of age on durable VAD support for ≥7 days at Texas Children's Hospital from 2006 to 2015 were retrospectively reviewed. Red blood cell (RBC) and iron deficiency indices in pulsatile VAD (P-VAD) and continuous-flow VAD (CF-VAD) were evaluated. Anemia, iron deficiency, and iron therapy regimens were identified. Seventy-six VAD implants in 74 patients were included: 45 P-VAD and 31 CF-VAD. Overall, 48% (36/75) of patients were anemic at VAD implant, with 67% of CF-VAD and 34% of P-VAD affected. Iron deficiency was seen in 52% (39/75) of patients at implant (similar in both groups). At explant, 71% (53/75) had anemia (similar in both groups). No patients had microcytosis. Iron supplementation was given to 20 patients, with four receiving target replacement therapy (2-6 mg/kg/d × 90 days). Red blood cell transfusion volumes were higher for P-VAD versus CF-VAD. We concluded that anemia and iron deficiency are common in pediatric VAD patients. Pulsatile VAD patients tend to develop anemia over the course of VAD support. Lack of microcytosis, likely masked by high RBC transfusions, suggests that specific iron studies are necessary to identify iron deficiency.

Pediatric ventricular assist devices: current challenges and future prospects.

The field of mechanical circulatory support has made great strides in the preceding 2 decades. Although pediatric mechanical circulatory support has lagged behind that of adults, the gap between them is expected to close soon. The only device currently approved by the US Food and Drug Administration for use in children is the Berlin Heart EXCOR ventricular assist device (VAD). The prospective Berlin Heart Investigational Device Exemption Trial demonstrated good outcomes, such as bridge to transplantation or recovery, in ~90% of children supported with this device. However, a high incidence of hemorrhagic and thrombotic complications was also noted. As a result, pediatric centers have just started implanting adult intracorporeal continuous-flow devices in children. This paradigm shift has opened a new era in pediatric mechanical circulatory support. Whereas children on VAD were previously managed exclusively in hospital, therapeutic options such as outpatient management and even destination therapy have been becoming a reality. With continued miniaturization and technological refinements, devices currently in development will broaden the range of options available to children. The HeartMate 3 and HeartWare MVAD are two such compact VADs, which are anticipated to have great potential for pediatric use. Additionally, a pediatric-specific continuous-flow VAD, the newly redesigned Jarvik Infant 2015, is currently undergoing preclinical testing and is expected to undergo a randomized clinical trial in the near future. This review aims to discuss the challenges posed by the use of intracorporeal adult continuous-flow devices in children, as well as to provide our perspective on the future prospects of the field of pediatric VADs.

The miniaturized pediatric continuous-flow device: Preclinical assessment in the chronic sheep model.

BACKGROUND: The Infant Jarvik 2015 is an implantable axial-flow ventricular assist device (VAD) that has undergone the major evolutionary design modifications to improve hemocompatibility. This study was conducted in anticipation of data submission to the US Food and Drug Administration to obtain Investigational Device Exemption approval. METHODS: The VAD was implanted via a left thoracotomy in Barbado sheep (n = 10, 26 (19-34] kg). Anticoagulation was maintained with coumadin, with a target international normalized ratio of greater than the individual sheep's baseline values. The VAD was managed at the highest possible speed as clinically tolerable. Complete necropsy was performed at the end of the study. RESULTS: There were 2 early mortalities: tension pneumothorax (n = 1) and shower emboli of the fragmented myocardium (n = 1). The remaining 8 sheep (2 with 30-day and 6 with 60-day protocols) completed the anticipated study duration in excellent condition, with the 6 completing 60-day sheep showing appropriate weight gain during support. There were no signs of clinically significant hemolysis, with the final plasma-free hemoglobin of 2 (1-17) mg/dL. Necropsy showed old renal infarction in 7 sheep. Although thromboembolism can be the potential etiology, given the mild anticoagulation regimen, other sources of emboli were identified in 2 sheep (graft coating material and fragmented myocardium). Flow study demonstrated favorable increase in flow (up to 3.0 L/min) in proportion to change in pump speed. CONCLUSIONS: This study has demonstrated that the Infant Jarvik 2015 VAD is capable of maintaining its functionality for an extended period of time with minimal hemolysis.

Pediatric ventricular assist devices.

The domain of pediatric ventricular assist device (VAD) has recently gained considerable attention. Despite the fact that, historically, the practice of pediatric mechanical circulatory support (MCS) has lagged behind that of adult patients, this gap between the two groups is narrowing. Currently, the Berlin EXCOR VAD is the only pediatric-specific durable VAD approved by the U.S Food and Drug Administration (FDA). The prospective Berlin Heart trial demonstrated a successful outcome, either bridge to transplantation (BTT), or in rare instances, bridge to recovery, in approximately 90% of children. Also noted during the trial was, however, a high incidence of adverse events such as embolic stroke, bleeding and infection. This has incentivized some pediatric centers to utilize adult implantable continuous-flow devices, for instance the HeartMate II and HeartWare HVAD, in children. As a result of this paradigm shift, the outlook of pediatric VAD support has dramatically changed: Treatment options previously unavailable to children, including outpatient management and even destination therapy, have now been becoming a reality. The sustained demand for continued device miniaturization and technological refinements is anticipated to extend the range of options available to children-HeartMate 3 and HeartWare MVAD are two examples of next generation VADs with potential pediatric application, both of which are presently undergoing clinical trials. A pediatric-specific continuous-flow device is also on the horizon: the redesigned Infant Jarvik VAD (Jarvik 2015) is undergoing pre-clinical testing, with a randomized clinical trial anticipated to follow thereafter. The era of pediatric VADs has begun. In this article, we discuss several important aspects of contemporary VAD therapy, with a particular focus on challenges unique to the pediatric population.

Cognitive outcome in children with rhombencephalosynapsis.

PURPOSE: Rhombencephalosynapsis is a rare congenital cerebellar malformation increasingly recognized by prenatal and neonatal neuroimaging. Cognitive outcome seems to be variable but is not well documented. AIMS AND METHODS: To study neurological, behavioural, and cognitive functions of patients with non-syndromic rhombencephalosynapsis, five patients (three female and two male, mean age at the time of this study 8.9 years, range 4.3-17.3 years) were assessed by neurological examination and several tests of behaviour and cognitive functions. RESULTS: Ataxia was present in all patients, but daily life activities were partly restricted in only one. Other symptoms were muscular hypotonia, abnormal eye movements, and head stereotypies. Three patients had pathological scores on both attention and hyperactivity/impulsivity scales. Only two patients had normal full-scale IQ (IQ value of 109 and 114, respectively). Verbal and/or performance IQ were impaired in three. CONCLUSION: In non-syndromic rhombencephalosynapsis the clinical presentation is variable. Attention deficit and hyperactivity disorders are frequent behavioural problems. Cognitive functions are mostly impaired, as mild intellectual impairment without a typical cognitive profile. However, rhombencephalosynapsis is compatible with normal cognitive functions. No definitive correlation between cognitive impairment and additional supratentorial abnormalities could be established.