Proceedings of the first global meeting of the Posterior Fossa Society: state of the art in cerebellar mutism syndrome.

PURPOSE: The Posterior Fossa Society, an international multidisciplinary group, hosted its first global meeting designed to share the current state of the evidence across the multidisciplinary elements of pediatric post-operative cerebellar mutism syndrome (pCMS). The agenda included keynote talks from world-leading speakers, compelling abstract presentations and engaging discussions led by members of the PFS special interest groups. METHODS: This paper is a synopsis of the first global meeting, a 3-day program held in Liverpool, England, UK, in September 2022. RESULTS: Topics included nosology, patient and family experience, cerebellar modulation of cognition, and cerebellar cognitive affective syndrome. In addition, updates from large-scale studies were shared as well as abstracts across neuroradiology, neurosurgery, diagnosis/scoring, ataxia, and rehabilitation. CONCLUSIONS: Based on data-driven evidence and discussions, each special interest group created research priorities to target before the second global meeting, in the spring of 2024.

The underlying etiology of infantile spasms (West syndrome): Information from the International Collaborative Infantile Spasms Study (ICISS).

OBJECTIVE: To determine the underlying etiologies in a contemporary cohort of infants with infantile spasms and to examine response to treatment. METHODS: Identification of the underlying etiology and response to treatment in 377 infants enrolled in a clinical trial of the treatment of infantile spasms between 2007 and 2014 using a systematic review of history, examination, and investigations. They were classified using the pediatric adaptation of International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: A total of 219 of 377 (58%) had a proven etiology, of whom 128 (58%) responded, 58 of 108 (54%) were allocated hormonal treatment, and 70 of 111 (63%) had combination therapy. Fourteen of 17 (82%, 95% confidence interval [CI] 59% to 94%) infants with stroke and infarct responded (compared to 114 of 202 for the rest of the proven etiology group (56%, 95% CI 48% to 62%, chi-square 4.3, P = .037): the better response remains when treatment allocation and lead time are taken into account (odds ratio 5.1, 95% CI 1.1 to 23.6, P = .037). Twenty of 37 (54%, 95% CI 38% to 70%) infants with Down syndrome had cessation of spasms compared to 108 of 182 (59%, 95% CI 52% to 66%, chi-square 0.35, P = .55) for the rest of the proven etiology group. The lack of a significant difference remains after taking treatment modality and lead-time into account (odds ratio 0.8, 95% CI 0.4 to 1.7, P = .62). In Down syndrome infants, treatment modality did not appear to affect response: 11 of 20 (55%) allocated hormonal therapy responded, compared to 9 of 17 (53%) allocated combination therapy. SIGNIFICANCE: This classification allows easy comparison with other classifications and with our earlier reports. Stroke and infarct have a better outcome than other etiologies, whereas Down syndrome might not respond to the addition of vigabatrin to hormonal treatment.

The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth.

Our knowledge of the effect of metformin on human health is increasing. In addition to its ability to improve the control of hyperglycaemia, metformin has been shown to reduce the burden o,f ageing via effects on damaged DNA and the process of apoptosis. Studies have shown that metformin may reduce the risk of cardiovascular disease through influences on body weight, blood pressure, cholesterol levels and the progression of atherosclerosis. Studies also suggest that metformin may be beneficial for neuro-psychiatric disorders, cognitive impairment and in reducing the risk of dementia, erectile dysfunction and Duchenne muscular dystrophy. In vivo and in vitro studies have shown that metformin has anti-cancer properties, and population studies have suggested that metformin may reduce the risk of cancer or improve cancer prognosis. It is thought that it exerts its anti-cancer effect through the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. Because of its effect on the mTOR pathway, there may be a role for metformin in slowing or reversing growth of life-threatening hamartomas in tuberous sclerosis complex.

'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

AIM: To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. METHOD: In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. RESULTS: Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. INTERPRETATION: MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody-associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. WHAT THIS PAPER ADDS: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second-line immunotherapy.

Causes of mortality in individuals with tuberous sclerosis complex.

AIM: The causes of death in patients with tuberous sclerosis complex (TSC) have rarely been studied, with only one published account, which was reported from the Mayo Clinic in 1991. We aimed to investigate mortality in a large cohort of patients with TSC from one of two national referral clinics in the UK. METHOD: We identified 284 patients who attended Bath TSC clinic between 1981 and 2015, and ascertained causes of death by reviewing medical records, death certificates, and postmortem reports. RESULTS: Sixteen patients died from complications of TSC: eight from TSC kidney diseases; four from sudden unexpected death in epilepsy (SUDEP); two from lymphangioleiomyomatosis; one from a subependymal giant cell astrocytoma; and one from a pancreatic malignancy. The median age of death was 33 years (interquartile range [IQR] 26-46). Mortality was significantly more common in patients with learning disabilities than in those without (13/135 [9%] vs 3/131 [2%]; two-tailed Fisher exact test p=0.020). INTERPRETATION: Renal disease is a major cause of mortality in TSC. Lifelong surveillance and early intervention is warranted. SUDEP is also an important cause of mortality. Patients with learning disabilities are at significantly greater risk of early mortality and this implies the need for greater vigilance for TSC-related complications in this group. Female patients are vulnerable to pulmonary and renal disease. Pancreatic lesions are a rare but potentially treatable cause of mortality.

Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.

INTRODUCTION: Confusion has surrounded the description of post-operative mutism and associated morbidity in pediatric patients with cerebellar tumors for years. The heterogeneity of definitions and diagnostic features has hampered research progress within the field, and to date, no international guidelines exist on diagnosis, prevention, treatment, or follow-up of this debilitating condition. An international group of clinicians and researchers from multiple relevant disciplines recently formed a cohesive panel to formulate a new working definition and agree upon standardized methods for diagnosis and follow-up. METHODS: Consensus was obtained using the modified nominal group technique, involving four rounds of online Delphi questionnaires interspersed with a structured consensus conference with lectures, group work, and open discussion sessions. RESULTS: A new, proposed definition of "post-operative pediatric CMS" was formed, preliminary recommendations for diagnostic and follow-up procedures were created, two working groups on a new scoring scale and risk prediction and prevention were established, and areas were identified where further information is needed. DISCUSSION: The consensus process was motivated by desire to further research and improve quality of life for pediatric brain tumor patients. The Delphi rounds identified relevant topics and established basic agreement, while face-to-face engagement helped resolve matters of conflict and refine terminology. The new definition is intended to provide a more solid foundation for future clinical and research work. It is thought as a consensus for moving forward and hopefully paves the way to developing a standard approach to this challenging problem with the advent of better scoring methods and ultimate goal of reducing the risk of CMS.

SGCE mutations cause psychiatric disorders: clinical and genetic characterization.

Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.

Latest American and European updates on infantile spasms.

Infantile spasms remain a challenging condition to study and treat, and although they form the commonest epilepsy syndrome with onset in infancy, the challenge is broadened by the wide range of potential underlying causes. The field of study remains dynamic, with debates relating to case definitions and organising structures for classification of seizures and epilepsies in general, and a newly proposed genetic and biologic classification specifically for infantile spasms. There have been recent consensus statements, a Delphi process eliciting prioritised quality-of-care indicators, systematic reviews of treatment, and a survey of clinical practice in the USA. There is increasing evidence that longer duration of spasms is associated with poorer neurodevelopmental outcomes. It has taken many years to develop an animal model that reasonably represents infantile spasms, but there are now several animal models, and they are leading to innovative and valuable studies that suggest novel treatments.

An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms.

AIM: We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. METHOD: Retrospective review and brain MRI analysis of children enrolled in the International Collaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. RESULTS: Ten of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls. INTERPRETATION: It is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder.

Prednisolone or tetracosactide depot for infantile epileptic spasms syndrome? A prospective analysis of data embedded within two randomised controlled trials.

OBJECTIVE: To report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS). METHODS: Individual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13-14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14-42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks. RESULTS: 126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13-14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14-42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = -0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33). SIGNIFICANCE: With hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.

PURPOSE: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. METHODS: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. KEY FINDINGS: Age of onset ranged (77 infants) from <1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8-14 days in 16, 15 days to 1 month in 8, 1-2 months in 15, >2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64-5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3-0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p=0.004). SIGNIFICANCE: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.

Hereditary geniospasm in a mother and son treated with botulinum toxin injection: A case report.

Hereditary geniospasm is a rare and benign disorder that can cause distress and social embarrassment to patients. There are only a handful of possible treatment options available. Due to the rarity of the condition, practices differ across the world and the results are varied. These include beta-blockers, benzodiazepines and anti-epileptics. These treatments can have significant side-effects when used long term. However, botulinum toxin injections have been successfully used in a handful of cases. We report a successful botulinum treatment of hereditary geniospasm in a mother and son, with the injection protocols.

The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification.

PURPOSE: To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10. METHODS: Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification. RESULTS: Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic-ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies. DISCUSSION: Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis.

Recurrence of First Afebrile Unprovoked Seizure and Parental Consanguinity: A Hospital-Based Study.

PURPOSE: The aim of the current study was to determine the incidence, clinical characteristics, and risk factors associated with the recurrence of first unprovoked seizure in children. METHODS: A retrospective, observational study was conducted at King Abdullah University Hospital in Jordan. Children aged from 1 month to 16 years old who attended the hospital between January 2013 to December 2017 were evaluated on the basis of medical records, from the first visit and for a 1-year follow-up period. RESULTS: During the study period, a total of 290 cases with first unprovoked seizure were included. The incidence of first unprovoked seizure was 441 cases per 100 000 patient visits to the pediatric clinic. More than half of the cases developed a second attack (55.3%). Children with parental consanguinity were almost 3 times more likely to develop a second attack of seizure compared to those without parental consanguinity (odds ratio [OR] = 2.785, 95% confidence interval [CI] = 1.216-6.378, P = .015) and patients who had a history of focal type of seizure were almost twice as likely to develop seizure recurrence (OR = 1.798, 95% CI = 1.013-3.193, P = .045). CONCLUSIONS: The current results showed a high incidence of first unprovoked seizure among children in Jordan. Parental consanguinity and focal seizure were associated with the increased risk of recurrent attack. This finding highlights the need for public education regarding the outcomes of parental consanguinity to improve the patient's quality of life.

Quality of life in patients with Tuberous Sclerosis Complex (TSC).

BACKGROUND: The quality of life (QoL) of patients with Tuberous Sclerosis Complex (TSC) has not been studied before. We aimed to investigate the impact of the disease on QoL. We studied the QoL of 91 TSC patients who have attended the Bath TSC clinic, UK over 6 months. QoL was evaluated using the PedsQL for children, and SF-36 for adults. RESULTS: Impaired QoL is found in all patients with TSC regardless of the presence of epilepsy and learning disabilities (LD). Total mean self-reported score for children was 71 out of 100, compared to a UK norm of 84, p < 0.000. The proxy mean score was 48, (UK norm 85, p < 0.000). Physical Functioning score for adults with TSC was 70, compared to a UK norm of 94, p < 0.000. The Social Functioning score for adults with TSC was 71, (UK norm 88, p < 0.000). CONCLUSIONS: Impaired QoL is found in all patients with TSC regardless of the presence of epilepsy and learning disabilities. The psychosocial domain is most affected. The quality of life of children with TSC is lower than children who suffer from asthma, diabetes, cancer and inflammatory bowel disease. To improve health related quality of life in TSC, a focus on patient's physical health, educational performances, and overall quality of life is crucial. In order to achieve this, coordinated medical care across disciplines, and psychosocial and social support is necessary.

A case report: Paediatric surfer's myelopathy.

Surfer's myelopathy was first described by Thompson et al., in 2004.1 It is a rare cause of sudden spinal cord injury that occurs in the absence of direct trauma to the spinal area in novice healthy surfers. We present the case of the youngest patient we are aware of to be diagnosed with surfer's myelopathy following actual surfing. A clear aetiology for surfer's myelopathy has not previous been described. However, the hypothesis that there is ischaemia to the lower spinal cord is supported by our case, where we present the first clear angiographic evidence of the occlusion of the great anterior radicular artery of Adamkiewicz in a patient diagnosed with surfer's myelopathy.