Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2019
Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-... more Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, inclu...
The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transf... more The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain
classical description. The Multiple Sleep Latency Test (MSLT) was grossly abnormal in all them. H... more classical description. The Multiple Sleep Latency Test (MSLT) was grossly abnormal in all them. Hypocretin was absent in the one child investigated. Autoimmune screen was negative in all. One child was treated for H1N1 and 2 had the H1N1 vaccine prior to onset of symptoms. Conclusion The key to early diagnosis and treatment is recognition of the condition. The videos highlight the facial features and other symptoms that are clues to narcolepsy (Pentad of narcolepsy). Rapid progression is possible related to H1N1 exposure.
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in human... more Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. ...
Objective-Neuromyelitis optica (NMO) is a rare antibody-mediated CNS disease characterised by dis... more Objective-Neuromyelitis optica (NMO) is a rare antibody-mediated CNS disease characterised by disabling relapses leading to high morbidity and mortality. Understanding relapse activity and severity is important for treatment decisions and clinical trial design. We assessed (1) whether clinical and demographic factors associate with different relapse rates and (2) the relative impact of immunosuppressive treatments on relapse rates and on attack-related residual disability. Methods-Clinical, demographic and treatment data were prospectively collected from 79 consecutive aquaporin 4 antibody positive patients seen in the nationally commissioned Oxford NMO service. The influence of clinical features on annualised relapse rates (using multiple regression) and the effect of immunosuppression on relapse-associated residual disability for transverse myelitis and optic neuritis attacks (using a mixed effect model) were analysed. Results-The mean annualised relapse rate was 0.93. Relapse rates were significantly higher in Afro-Caribbeans, children and in those of shorter disease duration. Relapse rates reduced on treatment (from 0.87 to 0.42). Delay to first treatment did not influence eventual ontreatment relapse rate. Immunosuppressive treatment significantly reduced the residual disability from ON (p<0.01), and TM (p=0.029) attacks. Conclusions-Relapse rates in NMO are influenced by multiple factors, including age, ethnicity and disease duration. Current immunosuppressive treatments reduce but do not
To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies ... more To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders. Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated. THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved follow...
Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory... more Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n 5 39), opsoclonus myoclonus ataxia syndrome (n 5 32), neuromyelitis optica spectrum disorders (n 5 20), neuropsychiatric systemic lupus erythematosus (n 5 18), and other neuroinflammatory disorders (n 5 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1-8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an offlabel use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections. Neurology ® 2014;83:142-150 GLOSSARY AE 5 adverse events; CMV 5 cytomegalovirus; CTCAE 5 Common Terminology Criteria for Adverse Events; DoD 5 duration of disease; mRS 5 modified Rankin Scale; NMDAR 5 NMDA receptor; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorders; OMAS 5 opsoclonus myoclonus ataxia syndrome; PML 5 progressive multifocal leukoencephalopathy. Rituximab is an anti-CD20 chimeric monoclonal antibody that results in B-cell depletion. Initially used to treat B-cell neoplasms such as non-Hodgkin lymphoma, 1 rituximab has more recently been licensed for use in autoimmune disorders such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitides. 2,3 In a double-blind placebo-controlled trial, rituximab reduced disease activity in relapsing-remitting multiple sclerosis, 4 and open-label studies have described benefit in NMDA receptor (NMDAR) encephalitis, neuromyelitis optica (NMO) spectrum disorders (NMOSD), and opsoclonus myoclonus ataxia syndrome (OMAS). 5-7 From the Neuroimmunology Group (R.C.D., F.B.
American journal of medical genetics. Part A, 2015
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1,... more Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, h...
Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a mult... more Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a multi-centre retrospective observational study of the efficacy, tolerability and retention rate in 105 children, aged 0-17.5 years (mean 10.1) over a 14 year period. The median age of epilepsy onset was 2.5 years (range 0-14.6). 72% started GAB as at least the 3rd AED, with 43% having been withdrawn from at least 2 AEDs. 77% had focal and 52% symptomatic epilepsies. The maintenance doses for GAB ranged 6.0-87.3 mg/kg/day (mean 43.7). The study comprised 157 person-treatment years for GAB. GAB was well tolerated with 55% remaining on treatment beyond 1 year. No serious adverse events were reported whilst on GAB, but 39% reported possibly and probably related adverse events. Seizure improvement (<50% seizure frequency compared to baseline) at more than 12 months of treatment, was reported in 35% of patients starting GAB, including 6% who remained seizure free. The results demonstrated the efficacy and tolerability of GAB in children with difficult to treat epilepsies, and a good response to treatment beyond 12 months, in both focal and generalised epilepsies.
We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clin... more We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clinical features associated with cerebellar hypoplasia. We then studied children presenting with any likely associated clinical feature of cerebellar hypoplasia previously observed or reported. Two hundred fifty-one children, with one or more of these features, exhibited no cerebellar hypoplasia on imaging. We compared the children with cerebellar hypoplasia with those without cerebellar hypoplasia. Logistic regression and Pearson's 2 test were used. Of the 45 children with cerebellar hypoplasia, 39 exhibited developmental delay; 24, speech delay; 25, seizures; nine, microcephaly; 22, hypotonia; 22, ataxia and impaired coordination; four, abnormal movements (tremor or titubation); 13, hypertonia; eight, autistic features; and 18, ocular signs (nystagmus, strabismus, and abnormal ocular movements). Statistically significant clinical features of children with cerebellar hypoplasia compared with those without were development and speech delay, microcephaly, abnormal movements, ataxia and impaired coordination, autistic features, hypotonia, and ocular signs. The regression combination of speech delay, ataxia, hypotonia, autistic features, and ocular signs correctly predicted 86% of those with cerebellar hypoplasia. Main clinical features of cerebellar hypoplasia are developmental or speech delay, autistic features, ataxia, hypotonia, and ocular signs.
Objective: Pediatric studies for new biological agents are mandated by recent legislation, necess... more Objective: Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research. Methods: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions. Results: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge. Conclusion: Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.
New therapies are being evaluated by clinical trials and, if efficacious, introduced for the trea... more New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool....
The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We a... more The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We aimed to assess the utility of McDonald 2010 criteria in comparison with 2007 International Paediatric Multiple Sclerosis Study Group (IPMSSG)-recommended criteria for PMS diagnosis. Retrospective analysis of 38 PMS cases from three UK demyelination clinics was conducted. Dissemination in space (DIS) and time (DIT) for both McDonald and IPMSSG criteria were noted on initial and follow-up magnetic resonance imaging (MRI). At first MRI scan, IPMSSG DIS criteria were fulfilled in 68% of scans and McDonald DIS criteria in 84%. In total, 11/18 children given gadolinium contrast fulfilled both McDonald DIS and DIT criteria on initial scan. The 2010 McDonald criteria appear more sensitive than IPMSSG and may allow PMS diagnosis at first presentation of CIS in at least a half of cases.
Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the c... more Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 re...
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Introduction It is frustrating for patients, families and clinicians when a unifying diagnosis fo... more Introduction It is frustrating for patients, families and clinicians when a unifying diagnosis for the constellations of neurological signs and symptoms remains elusive. Two recent reports, working independently, have hypothesised that KCNJ10 mutations on Chrosome 1q23.2 are responsible for Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy (EAST syndrome/ SeSAME syndrome). We present a series of six patients with ages ranging from 3-22 years from three families. Case series We describe three Asian siblings, two Caribbean siblings, and one Caucasian child who have epilepsy, ataxia, sensorineural hearing loss, and tubulopathy. Consanguinity was present only in the Asian family. Seizures were a presenting symptom in four with onset as early as 3–7 months of age. Development delay and learning difficulties were present in all of the cases. Ataxia was evident from early on. Sensorineural hearing loss was identified at different ages and in some cases was asymptomatic. In some cases, tubulopathy was an incidental finding. In the five children who have been extensively investigated, metabolic and mitochondrial investigations, magnetic resonance images, and electroencephalograms were normal. All six children had biochemical evidence of a tubulopathy with hypokalaemia, hypomagnesaemia, and alkalosis. KCNJ10 DNA mutations have since been identified in all of them. Conclusion This condition does not seem to be life limiting as is evident from the early reports and our own experience. Three patients from our series have moved on to the adult services. We hypothesise that there are adult patients with similar findings who are still waiting for a closure.
Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been l... more Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been linked to a variety of neuropsychiatric disorders, particularly attention deficit hyperactivity disorder. In addition, the homozygous Slc6a3 knockout mouse displays a hyperactivity phenotype. Here, we analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense SLC6A3 mutations (p.L368Q and p.P395L) in both families. Functional studies demonstrated that both mutations were loss-of-function mutations that severely reduced levels of mature (85-kDa) DAT while having a differential effect on the apparent binding affinity of dopamine. Thus, in humans, loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder. Identification of the molecular basis of IPD suggests SLC6A3 as a candidate susceptibility gene for other movement disorders associated with parkinsonism and/or dystonic features.
S15 tous growths in various organs, including renal angiomyolipoma (AML). CNS manifestations incl... more S15 tous growths in various organs, including renal angiomyolipoma (AML). CNS manifestations include tubers, subependymal nodules and subependymal giant cell astrocytoma (SEGA). Up to 90% of TSC patients suffer from epilepsy, with 50% of patients intractable to anti-epileptic drugs. Recent clinical trials have shown a decrease in AML and SEGA volume upon treatment with mTOR inhibiting drugs. In animal models of TSC, mTOR inhibitors decrease seizures and improve EEG findings. Rapamycin (sirolimus) is an inhibitor of the mTOR pathway, and has been used in various animal and patient studies. In the TSC clinic of the ENCORE expertise center for neurodevelopmental disorders at the Erasmus MC-Sophia Children's Hospital, we are currently performing a randomized clinical trial into the effect of rapamycin on epilepsy in TSC patients. Eligible children, with a definite diagnosis of TSC and intractable epilepsy, participate in the trial during one year, and are randomised to receive add-on oral rapamycin treatment during the first or second six months of trial participation. Primary outcome of the trial is seizure frequency, assessed by an epilepsy diary kept by the parents. EEG and developmental examination are secondary outcomes, and are performed upon inclusion and after the first and second six months. Developmental examination includes mental, motor and behavioural functioning. To monitor safety, blood samples to determine rapamycin trough levels, renal and liver function and blood cell counts are taken regularly. Currently, 20 patients have been included in the RATE trial. Design, progression and preliminary results of the trial will be presented. O46-1548 Long term follow-up of clinical and neurographical abnormalities in eight Croatian patients with triple A syndrome
We present a family with mild neurological symptoms and intra-cerebral subcortical cysts on magne... more We present a family with mild neurological symptoms and intra-cerebral subcortical cysts on magnetic resonance imaging (MRI). Common clinical features are microcephaly, learning difficulties, spasticity, dyspraxia and restricted movements of the neck and shoulder. The family has features in common with vacuolating leukoencephalopathy of van de Knaap and Olivier and may represent a new variant.
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2019
Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-... more Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, inclu...
The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transf... more The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain
classical description. The Multiple Sleep Latency Test (MSLT) was grossly abnormal in all them. H... more classical description. The Multiple Sleep Latency Test (MSLT) was grossly abnormal in all them. Hypocretin was absent in the one child investigated. Autoimmune screen was negative in all. One child was treated for H1N1 and 2 had the H1N1 vaccine prior to onset of symptoms. Conclusion The key to early diagnosis and treatment is recognition of the condition. The videos highlight the facial features and other symptoms that are clues to narcolepsy (Pentad of narcolepsy). Rapid progression is possible related to H1N1 exposure.
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in human... more Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. ...
Objective-Neuromyelitis optica (NMO) is a rare antibody-mediated CNS disease characterised by dis... more Objective-Neuromyelitis optica (NMO) is a rare antibody-mediated CNS disease characterised by disabling relapses leading to high morbidity and mortality. Understanding relapse activity and severity is important for treatment decisions and clinical trial design. We assessed (1) whether clinical and demographic factors associate with different relapse rates and (2) the relative impact of immunosuppressive treatments on relapse rates and on attack-related residual disability. Methods-Clinical, demographic and treatment data were prospectively collected from 79 consecutive aquaporin 4 antibody positive patients seen in the nationally commissioned Oxford NMO service. The influence of clinical features on annualised relapse rates (using multiple regression) and the effect of immunosuppression on relapse-associated residual disability for transverse myelitis and optic neuritis attacks (using a mixed effect model) were analysed. Results-The mean annualised relapse rate was 0.93. Relapse rates were significantly higher in Afro-Caribbeans, children and in those of shorter disease duration. Relapse rates reduced on treatment (from 0.87 to 0.42). Delay to first treatment did not influence eventual ontreatment relapse rate. Immunosuppressive treatment significantly reduced the residual disability from ON (p<0.01), and TM (p=0.029) attacks. Conclusions-Relapse rates in NMO are influenced by multiple factors, including age, ethnicity and disease duration. Current immunosuppressive treatments reduce but do not
To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies ... more To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders. Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated. THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved follow...
Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory... more Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n 5 39), opsoclonus myoclonus ataxia syndrome (n 5 32), neuromyelitis optica spectrum disorders (n 5 20), neuropsychiatric systemic lupus erythematosus (n 5 18), and other neuroinflammatory disorders (n 5 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1-8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an offlabel use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections. Neurology ® 2014;83:142-150 GLOSSARY AE 5 adverse events; CMV 5 cytomegalovirus; CTCAE 5 Common Terminology Criteria for Adverse Events; DoD 5 duration of disease; mRS 5 modified Rankin Scale; NMDAR 5 NMDA receptor; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorders; OMAS 5 opsoclonus myoclonus ataxia syndrome; PML 5 progressive multifocal leukoencephalopathy. Rituximab is an anti-CD20 chimeric monoclonal antibody that results in B-cell depletion. Initially used to treat B-cell neoplasms such as non-Hodgkin lymphoma, 1 rituximab has more recently been licensed for use in autoimmune disorders such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitides. 2,3 In a double-blind placebo-controlled trial, rituximab reduced disease activity in relapsing-remitting multiple sclerosis, 4 and open-label studies have described benefit in NMDA receptor (NMDAR) encephalitis, neuromyelitis optica (NMO) spectrum disorders (NMOSD), and opsoclonus myoclonus ataxia syndrome (OMAS). 5-7 From the Neuroimmunology Group (R.C.D., F.B.
American journal of medical genetics. Part A, 2015
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1,... more Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, h...
Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a mult... more Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a multi-centre retrospective observational study of the efficacy, tolerability and retention rate in 105 children, aged 0-17.5 years (mean 10.1) over a 14 year period. The median age of epilepsy onset was 2.5 years (range 0-14.6). 72% started GAB as at least the 3rd AED, with 43% having been withdrawn from at least 2 AEDs. 77% had focal and 52% symptomatic epilepsies. The maintenance doses for GAB ranged 6.0-87.3 mg/kg/day (mean 43.7). The study comprised 157 person-treatment years for GAB. GAB was well tolerated with 55% remaining on treatment beyond 1 year. No serious adverse events were reported whilst on GAB, but 39% reported possibly and probably related adverse events. Seizure improvement (<50% seizure frequency compared to baseline) at more than 12 months of treatment, was reported in 35% of patients starting GAB, including 6% who remained seizure free. The results demonstrated the efficacy and tolerability of GAB in children with difficult to treat epilepsies, and a good response to treatment beyond 12 months, in both focal and generalised epilepsies.
We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clin... more We reviewed 45 children with cerebellar hypoplasia on magnetic resonance imaging to identify clinical features associated with cerebellar hypoplasia. We then studied children presenting with any likely associated clinical feature of cerebellar hypoplasia previously observed or reported. Two hundred fifty-one children, with one or more of these features, exhibited no cerebellar hypoplasia on imaging. We compared the children with cerebellar hypoplasia with those without cerebellar hypoplasia. Logistic regression and Pearson's 2 test were used. Of the 45 children with cerebellar hypoplasia, 39 exhibited developmental delay; 24, speech delay; 25, seizures; nine, microcephaly; 22, hypotonia; 22, ataxia and impaired coordination; four, abnormal movements (tremor or titubation); 13, hypertonia; eight, autistic features; and 18, ocular signs (nystagmus, strabismus, and abnormal ocular movements). Statistically significant clinical features of children with cerebellar hypoplasia compared with those without were development and speech delay, microcephaly, abnormal movements, ataxia and impaired coordination, autistic features, hypotonia, and ocular signs. The regression combination of speech delay, ataxia, hypotonia, autistic features, and ocular signs correctly predicted 86% of those with cerebellar hypoplasia. Main clinical features of cerebellar hypoplasia are developmental or speech delay, autistic features, ataxia, hypotonia, and ocular signs.
Objective: Pediatric studies for new biological agents are mandated by recent legislation, necess... more Objective: Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research. Methods: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions. Results: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge. Conclusion: Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.
New therapies are being evaluated by clinical trials and, if efficacious, introduced for the trea... more New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool....
The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We a... more The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We aimed to assess the utility of McDonald 2010 criteria in comparison with 2007 International Paediatric Multiple Sclerosis Study Group (IPMSSG)-recommended criteria for PMS diagnosis. Retrospective analysis of 38 PMS cases from three UK demyelination clinics was conducted. Dissemination in space (DIS) and time (DIT) for both McDonald and IPMSSG criteria were noted on initial and follow-up magnetic resonance imaging (MRI). At first MRI scan, IPMSSG DIS criteria were fulfilled in 68% of scans and McDonald DIS criteria in 84%. In total, 11/18 children given gadolinium contrast fulfilled both McDonald DIS and DIT criteria on initial scan. The 2010 McDonald criteria appear more sensitive than IPMSSG and may allow PMS diagnosis at first presentation of CIS in at least a half of cases.
Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the c... more Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 re...
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Introduction It is frustrating for patients, families and clinicians when a unifying diagnosis fo... more Introduction It is frustrating for patients, families and clinicians when a unifying diagnosis for the constellations of neurological signs and symptoms remains elusive. Two recent reports, working independently, have hypothesised that KCNJ10 mutations on Chrosome 1q23.2 are responsible for Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy (EAST syndrome/ SeSAME syndrome). We present a series of six patients with ages ranging from 3-22 years from three families. Case series We describe three Asian siblings, two Caribbean siblings, and one Caucasian child who have epilepsy, ataxia, sensorineural hearing loss, and tubulopathy. Consanguinity was present only in the Asian family. Seizures were a presenting symptom in four with onset as early as 3–7 months of age. Development delay and learning difficulties were present in all of the cases. Ataxia was evident from early on. Sensorineural hearing loss was identified at different ages and in some cases was asymptomatic. In some cases, tubulopathy was an incidental finding. In the five children who have been extensively investigated, metabolic and mitochondrial investigations, magnetic resonance images, and electroencephalograms were normal. All six children had biochemical evidence of a tubulopathy with hypokalaemia, hypomagnesaemia, and alkalosis. KCNJ10 DNA mutations have since been identified in all of them. Conclusion This condition does not seem to be life limiting as is evident from the early reports and our own experience. Three patients from our series have moved on to the adult services. We hypothesise that there are adult patients with similar findings who are still waiting for a closure.
Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been l... more Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been linked to a variety of neuropsychiatric disorders, particularly attention deficit hyperactivity disorder. In addition, the homozygous Slc6a3 knockout mouse displays a hyperactivity phenotype. Here, we analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense SLC6A3 mutations (p.L368Q and p.P395L) in both families. Functional studies demonstrated that both mutations were loss-of-function mutations that severely reduced levels of mature (85-kDa) DAT while having a differential effect on the apparent binding affinity of dopamine. Thus, in humans, loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder. Identification of the molecular basis of IPD suggests SLC6A3 as a candidate susceptibility gene for other movement disorders associated with parkinsonism and/or dystonic features.
S15 tous growths in various organs, including renal angiomyolipoma (AML). CNS manifestations incl... more S15 tous growths in various organs, including renal angiomyolipoma (AML). CNS manifestations include tubers, subependymal nodules and subependymal giant cell astrocytoma (SEGA). Up to 90% of TSC patients suffer from epilepsy, with 50% of patients intractable to anti-epileptic drugs. Recent clinical trials have shown a decrease in AML and SEGA volume upon treatment with mTOR inhibiting drugs. In animal models of TSC, mTOR inhibitors decrease seizures and improve EEG findings. Rapamycin (sirolimus) is an inhibitor of the mTOR pathway, and has been used in various animal and patient studies. In the TSC clinic of the ENCORE expertise center for neurodevelopmental disorders at the Erasmus MC-Sophia Children's Hospital, we are currently performing a randomized clinical trial into the effect of rapamycin on epilepsy in TSC patients. Eligible children, with a definite diagnosis of TSC and intractable epilepsy, participate in the trial during one year, and are randomised to receive add-on oral rapamycin treatment during the first or second six months of trial participation. Primary outcome of the trial is seizure frequency, assessed by an epilepsy diary kept by the parents. EEG and developmental examination are secondary outcomes, and are performed upon inclusion and after the first and second six months. Developmental examination includes mental, motor and behavioural functioning. To monitor safety, blood samples to determine rapamycin trough levels, renal and liver function and blood cell counts are taken regularly. Currently, 20 patients have been included in the RATE trial. Design, progression and preliminary results of the trial will be presented. O46-1548 Long term follow-up of clinical and neurographical abnormalities in eight Croatian patients with triple A syndrome
We present a family with mild neurological symptoms and intra-cerebral subcortical cysts on magne... more We present a family with mild neurological symptoms and intra-cerebral subcortical cysts on magnetic resonance imaging (MRI). Common clinical features are microcephaly, learning difficulties, spasticity, dyspraxia and restricted movements of the neck and shoulder. The family has features in common with vacuolating leukoencephalopathy of van de Knaap and Olivier and may represent a new variant.
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Papers by E. Wassmer