Efficacy and safety of ketamine for neonatal refractory status epilepticus: case report and systematic review

BackgroundEvidence-based data on treatment of neonatal status epilepticus (SE) are scarce. We aimed to collect data on the efficacy and safety of ketamine for the treatment of neonatal SE and to assess its possible role in the treatment of neonatal SE.MethodsWe described a novel case and conducted a systematic literature review on neonatal SE treated with ketamine. The search was carried out in Pubmed, Cochrane, Clinical Trial Gov, Scopus and Web of Science.ResultsSeven published cases of neonatal SE treated with ketamine were identified and analyzed together with our novel case. Seizures typically presented during the first 24 h of life (6/8). Seizures were resistant to a mean of five antiseizure medications. Ketamine, a NMDA receptor antagonist, appeared to be safe and effective in all neonates treated. Neurologic sequelae including hypotonia and spasticity were reported for 4/5 of the surviving children (5/8). 3/5 of them were seizure free at 1–17 months of life.DiscussionNeonatal brain is more susceptible to seizures due to a shift towards increased excitation because of a paradoxical excitatory effect of GABA, a greater density of NMDA receptors and higher extracellular concentrations of glutamate. Status epilepticus and neonatal encephalopathy could further enhance these mechanisms, providing a rationale for the use of ketamine in this setting.ConclusionsKetamine in the treatment of neonatal SE showed a promising efficacy and safety profile. However, further in-depth studies and clinical trials on larger populations are needed

Sleep spindles across youth affected by schizophrenia or anti-N-methyl-D-aspartate-receptor encephalitis

BackgroundSleep disturbances are intertwined with the progression and pathophysiology of psychotic symptoms in schizophrenia. Reductions in sleep spindles, a major electrophysiological oscillation during non-rapid eye movement sleep, have been identified in patients with schizophrenia as a potential biomarker representing the impaired integrity of the thalamocortical network. Altered glutamatergic neurotransmission within this network via a hypofunction of the N-methyl-D-aspartate receptor (NMDAR) is one of the hypotheses at the heart of schizophrenia. This pathomechanism and the symptomatology are shared by anti-NMDAR encephalitis (NMDARE), where antibodies specific to the NMDAR induce a reduction of functional NMDAR. However, sleep spindle parameters have yet to be investigated in NMDARE and a comparison of these rare patients with young individuals with schizophrenia and healthy controls (HC) is lacking. This study aims to assess and compare sleep spindles across young patients affected by Childhood-Onset Schizophrenia (COS), Early-Onset Schizophrenia, (EOS), or NMDARE and HC. Further, the potential relationship between sleep spindle parameters in COS and EOS and the duration of the disease is examined.MethodsSleep EEG data of patients with COS (N = 17), EOS (N = 11), NMDARE (N = 8) aged 7–21 years old, and age- and sex-matched HC (N = 36) were assessed in 17 (COS, EOS) or 5 (NMDARE) electrodes. Sleep spindle parameters (sleep spindle density, maximum amplitude, and sigma power) were analyzed.ResultsCentral sleep spindle density, maximum amplitude, and sigma power were reduced when comparing all patients with psychosis to all HC. Between patient group comparisons showed no differences in central spindle density but lower central maximum amplitude and sigma power in patients with COS compared to patients with EOS or NMDARE. Assessing the topography of spindle density, it was significantly reduced over 15/17 electrodes in COS, 3/17 in EOS, and 0/5 in NMDARE compared to HC. In the pooled sample of COS and EOS, a longer duration of illness was associated with lower central sigma power.ConclusionsPatients with COS demonstrated more pronounced impairments of sleep spindles compared to patients with EOS and NMDARE. In this sample, there is no strong evidence that changes in NMDAR activity are related to spindle deficits

Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.

Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders

Sleep spindles across youth affected by schizophrenia or anti-N-methyl-D-aspartate-receptor encephalitis

BackgroundSleep disturbances are intertwined with the progression and pathophysiology of psychotic symptoms in schizophrenia. Reductions in sleep spindles, a major electrophysiological oscillation during non-rapid eye movement sleep, have been identified in patients with schizophrenia as a potential biomarker representing the impaired integrity of the thalamocortical network. Altered glutamatergic neurotransmission within this network via a hypofunction of the N-methyl-D-aspartate receptor (NMDAR) is one of the hypotheses at the heart of schizophrenia. This pathomechanism and the symptomatology are shared by anti-NMDAR encephalitis (NMDARE), where antibodies specific to the NMDAR induce a reduction of functional NMDAR. However, sleep spindle parameters have yet to be investigated in NMDARE and a comparison of these rare patients with young individuals with schizophrenia and healthy controls (HC) is lacking. This study aims to assess and compare sleep spindles across young patients affected by Childhood-Onset Schizophrenia (COS), Early-Onset Schizophrenia, (EOS), or NMDARE and HC. Further, the potential relationship between sleep spindle parameters in COS and EOS and the duration of the disease is examined.MethodsSleep EEG data of patients with COS (N = 17), EOS (N = 11), NMDARE (N = 8) aged 7–21 years old, and age- and sex-matched HC (N = 36) were assessed in 17 (COS, EOS) or 5 (NMDARE) electrodes. Sleep spindle parameters (sleep spindle density, maximum amplitude, and sigma power) were analyzed.ResultsCentral sleep spindle density, maximum amplitude, and sigma power were reduced when comparing all patients with psychosis to all HC. Between patient group comparisons showed no differences in central spindle density but lower central maximum amplitude and sigma power in patients with COS compared to patients with EOS or NMDARE. Assessing the topography of spindle density, it was significantly reduced over 15/17 electrodes in COS, 3/17 in EOS, and 0/5 in NMDARE compared to HC. In the pooled sample of COS and EOS, a longer duration of illness was associated with lower central sigma power.ConclusionsPatients with COS demonstrated more pronounced impairments of sleep spindles compared to patients with EOS and NMDARE. In this sample, there is no strong evidence that changes in NMDAR activity are related to spindle deficits

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ?75% agreement).Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

A registry for Dravet syndrome: The Italian experience

Objectives: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. / Methods: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. / Results: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0–9) while at last follow-up was 11 years (IQR 5–18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). / Significance: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes

Treatments and outcomes among patients with Sydenham chorea

Importance: Sydenham chorea is the most common acquired chorea of childhood worldwide; however, treatment is limited by a lack of high-quality evidence. Objectives: To evaluate historical changes in the clinical characteristics of Sydenham chorea and identify clinical and treatment factors at disease onset associated with chorea duration, relapsing disease course, and functional outcome. Data Sources: The systematic search for this meta-analysis was conducted in PubMed, Embase, CINAHL, Cochrane Library, and LILACS databases and registers of clinical trials from inception to November 1, 2022 (search terms: [Sydenham OR Sydenham’s OR rheumatic OR minor] AND chorea). Study Selection: Published articles that included patients with a final diagnosis of Sydenham chorea (in selected languages). Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Individual patient data on clinical characteristics, treatments, chorea duration, relapse, and final outcome were extracted. Data from patients in the modern era (1945 through 2022) were entered into multivariable models and stratified by corticosteroid duration for survival analysis of chorea duration. Main Outcomes and Measures: The planned study outcomes were chorea duration at onset, monophasic course (absence of relapse after ≥24 months), and functional outcome (poor: modified Rankin Scale score 2-6 or persisting chorea, psychiatric, or behavioral symptoms at final follow-up after ≥6 months; good: modified Rankin Scale score 0-1 and no chorea, psychiatric, or behavioral symptoms at final follow-up). Results: In total, 1479 patients were included (from 307 articles), 1325 since 1945 (median [IQR] age at onset, 10 [8-13] years; 875 of 1272 female [68.8%]). Immunotherapy was associated with shorter chorea duration (hazard ratio for chorea resolution, 1.51 [95% CI, 1.05-2.19]; P = .03). The median chorea duration in patients receiving 1 or more months of corticosteroids was 1.2 months (95% CI, 1.2-2.0) vs 2.8 months (95% CI, 2.0-3.0) for patients receiving none (P = .004). Treatment factors associated with monophasic disease course were antibiotics (odds ratio [OR] for relapse, 0.28 [95% CI, 0.09-0.85]; P = .02), corticosteroids (OR, 0.32 [95% CI, 0.15-0.67]; P = .003), and sodium valproate (OR, 0.33 [95% CI, 0.15-0.71]; P = .004). Patients receiving at least 1 month of corticosteroids had significantly lower odds of relapsing course (OR, 0.10 [95% CI, 0.04-0.25]; P &lt; .001). No treatment factor was associated with good functional outcome. Conclusions and Relevance: In this meta-analysis of treatments and outcomes in patients with Sydenham chorea, immunotherapy, in particular corticosteroid treatment, was associated with faster resolution of chorea. Antibiotics, corticosteroids and sodium valproate were associated with a monophasic disease course. This synthesis of retrospective data should support the development of evidence-based treatment guidelines for patients with Sydenham chorea

Clinical and therapeutic decision making in paediatric autoimmune and inflammatory neurological disease

ABSTRACT 1. Background. Paediatric neuroimmunology is a rapidly evolving field both as regards clinical-radiological phenotyping, biomarker development, and therapeutic possibilities. In this latter aspect, while a growing armamentarium of treating agents is becoming available, this is not mirrored by quality evidence and definite recommendations on treatment strategies, drugs’ efficacy and tolerability. This is especially true in paediatric age, where most data is derived from adult studies. Objective. To investigate clinical and therapeutic aspects of decision making in paediatric autoimmune and immune-mediated inflammatory conditions. In particular, the aims of this work include: exploring the available immune therapeutic agents and their mechanisms of action; investigating the use of immune therapy in autoimmune encephalitis; investigating the use, efficacy and tolerability of individual immune therapeutic agents in different clinical situations in paediatric neurology (intravenous immunoglobulin in Sydenham’s chorea; intravenous immunoglobulin in paediatric neurology; therapeutic plasma exchange in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis; rituximab in neuromyelitis optica spectrum disorders; mycophenolate mofetil, azathioprine and methotrexate in anti-NMDAR encephalitis; mycophenolate mofetil in paediatric autoimmune and immune-mediated central nervous system (CNS) conditions). 2. Methods. The present PhD thesis is articulated into sub-projects carried out at the Department of Women's and Children's Health in Padua, Italy, and at the Children's Hospital at Westmead, Sydney, Australia. Study designs include six literature reviews (available immune therapeutic agents and their mechanisms of action; immune therapy in autoimmune encephalitis; immune therapy in herpes simplex virus-induced anti-NMDAR encephalitis; intravenous immunoglobulin in Sydenham’s chorea; therapeutic plasma exchange in paediatric anti-NMDAR encephalitis; mycophenolate mofetil, azathioprine and methotrexate in paediatric anti-NMDAR encephalitis) and four original studies with observational retrospective design (immune therapy in paediatric anti-NMDAR encephalitis; intravenous immunoglobulin in paediatric neurology; rituximab in neuromyelitis optica spectrum disorders; mycophenolate mofetil in paediatric autoimmune and immune-mediated CNS conditions). Of these latter original studies, one includes an Italian population (immune therapy in paediatric anti-NMDAR encephalitis), one a single-center Australian population (intravenous immunoglobulin in paediatric neurology), and two include an international cohort of paediatric patients (rituximab in neuromyelitis optica spectrum disorders; mycophenolate mofetil in paediatric autoimmune and immune-mediated CNS conditions). Most of the projects have been concluded, whereas two are in their final phases (mycophenolate mofetil, azathioprine and methotrexate in paediatric anti-NMDAR encephalitis; mycophenolate mofetil in paediatric autoimmune and immune-mediated CNS conditions). 3. Results. Key findings are presented for the main study objectives. 3.1 Immune therapeutic agents and their mechanisms of action. 3.1.1 Immune therapeutic agents and their mechanisms of action (literature review). First-line treatments typically include corticosteroids, intravenous immunoglobulin, and plasmapheresis, while for severe disease second-line ‘induction’ agents such as rituximab or cyclophosphamide are used. Steroid-sparing agents such as mycophenolate mofetil, azathioprine or methotrexate are often used in potentially relapsing or corticosteroid-dependent diseases. Lessons from adult neuroimmunology and rheumatology could be translated into pediatric autoimmune CNS disease in the future, including the potential utility of monoclonal antibodies targeting lymphocytes, adhesion molecules for lymphocytic migration, cytokines or their receptors, or complement. Finally, many agents used in other fields have multiple mechanisms of action, including immunomodulation, with potential utility in neuroimmunology, such as antibiotics, psychotropic drugs, probiotics, gut health, and ketogenic diet. 3.2 Immune therapy in autoimmune encephalitis. 3.2.1 Autoimmune encephalitis with antibodies targeting neuronal surface antigens (systematic literature review). Most studies on immune therapy in autoimmune encephalitis associated with antibodies to cell surface antigens are retrospective cohorts, and there are no randomised controlled trials. Most clinicians use first-line therapy (steroids, intravenous immunoglobulin, plasma exchange), and if severe or refractory, second-line therapy (rituximab, cyclophosphamide). When present, tumours should be removed. There are common therapeutic themes emerging. Firstly, patients given immune therapy do better and relapse less than patients given no treatment. Secondly, patients given early treatment do better. And thirdly, when patients fail first-line therapy, second-line therapy improves outcomes and reduces relapses. Given the retrospective uncontrolled data, the literature has inherent bias, including severity and reporting bias. 3.2.2 Clinical and therapeutic aspects of the Italian cohort of paediatric anti-NMDAR encephalitis (national retrospective observational study). We described a new case series of 20 children (50% females), with anti-NMDAR encephalitis referred by 13 Italian centers (mean age at onset 8 years, range 3-17). Onset was with neurological symptoms in 70%, and with behavioral/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had modified Rankin Scale (mRS) 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. 3.2.3 Herpes simplex virus-induced anti-NMDAR encephalitis (systematic literature review). 43 patients with herpes simplex encephalitis (HSE) followed by anti-NMDAR encephalitis were identified in the literature (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs. 40.5 days; p=0.0057). Compared to the HSE phase, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% in HSE, vs. 75% in anti-NMDAR encephalitis; p<.0001), and by significantly lower rate of seizures (70% in HSE, vs. 30% in anti-NMDAR encephalitis; p=0.0011). Compared to adults, during anti-NMDAR encephalitis children had significantly more movement disorder (86.7% in children, vs. 40% in adults; p=0.0064) and less psychiatric symptoms (41.9% in children, vs. 90% in adults; p=0.0251). Children also had a slightly higher median mRS than adults during the acute phase of anti-NMDAR encephalitis (5 vs. 4; p=0.0146). During anti-NMDAR encephalitis, 84.6% patients received acyclovir (for ≤7 days in 22.7%; long-term antivirals in 18% only), and 92.7% immune therapy, but none had recurrence of HSE clinically or using CSF HSV-PCR (median follow-up 7 months). 3.3 Modes of use, efficacy and tolerability of individual immune therapeutic agents in different clinical situations in paediatric neurology. 3.3.1 Intravenous immunoglobulin in Sydenham’s chorea (systematic literature review). The studies reviewed on intravenous immunoglobulin in Sydenham’s chorea demonstrate a short-term benefit in symptomatic improvement. However, they do not clarify an optimum timing and duration for use of intravenous immunoglobulin, and do not provide data on the effect on long-term neurological and psychiatric complications. 3.3.2 Intravenous immunoglobulin in paediatric neurology (single-center retrospective observational study). 196 children received intravenous immunoglobulin for neuroimmunological indications at the Children’s Hospital at Westmead, Australia, between 2000 and 2014 (28.1% had Guillain-Barré syndrome) (15.5% of all hospital indications). In total, 1669 intravenous immunoglobulin courses were administered (total 57221 g, median 78 g/patient, range 12-5748 g). Highest median number of courses was in chronic inflammatory demyelinating polyneuropathies, opsoclonus-myoclonus-ataxia, suspected immune-mediated epilepsies and Rasmussen’s encephalitis. Adverse reactions occurred in 25.5%, mostly minor. Outcome at follow-up was best in anti-NMDAR encephalitis, Guillain-Barré syndrome and myasthenia gravis, and worst in Rasmussen’s encephalitis and epilepsies. The total cost for intravenous immunoglobulin was 2,595,907 American dollars (median $3,538/patient, range$544-260,766). 45.4%-57.1% patients received intravenous immunoglobulin for ‘weak’ indications or ‘not listed’ in international guidelines. Some entities frequently treated with intravenous immunoglobulin in current practice, such as anti-NMDAR encephalitis and transverse myelitis, are not listed in most guidelines. 3.3.3 Therapeutic plasma exchange in anti-NMDAR encephalitis (systematic literature review). 71 articles were identified (mostly retrospective), reporting a total of 242 children treated with therapeutic plasma exchange for anti-NMDAR encephalitis (73.2%, 93/127 females; median age at onset 12 years, range 1-18). Median time to immunotherapy was 21 days (range 0-190). In most cases, therapeutic plasma exchange was given with steroids and intravenous immunoglobulin (69.5%, 89/128), or steroids only (18%, 23/128); in a minority, it was associated with intravenous immunoglobulin only (7%, 9/128), or was the only first-line treatment (5.5%, 7/128). In 54.5% (65/119), therapeutic plasma exchange was the third treatment after steroids and intravenous immunoglobulin, in 31.1% (37/119) the second after steroids or intravenous immunoglobulin; only in 14.3% (17/119) was it the first treatment. Second-line immunotherapies were administered in 71.9% (100/139). Higher rates of full/substantial recovery at follow-up were observed with immunotherapy given ≤30 days from onset (69.4%, 25/36) compared to later (59.2%, 16/27), and when therapeutic plasma exchange was associated with steroids (66.7%, 70/105) rather than not (46.7%, 7/15). Significant adverse reactions to therapeutic plasma exchange were reported in 6 patients. 3.3.4 Rituximab in paediatric neuromyelitis optica spectrum disorders (international retrospective observational study). 16 patients treated with at least two courses of rituximab for neuromyelitis optica were included (14 females; mean age 9.6 years, range 1.8-15.3). The patients had a mean of 6.1 events (range 1-11) during a mean follow-up of 6.1 years (range 1.6-13.6), and received a total of 76 rituximab courses (mean 4.7, range 2-9) in 42.6-year cohort treatment. Before rituximab, 62.5% received azathioprine, mycophenolate mofetil or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months respectively, with large inter-patient variability. Earliest repopulations (2.7 and 2.9 months) occurred with the lowest rituximab doses. Significant reduction between pre and post rituximab annualized relapse rate (ARR) was observed (p=0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 ‘repopulation’, 3 ‘depletion’, and 4 ‘depletion failure-related relapses’. Of the 13 ‘repopulation relapses’, 4 had CD19 10-50x106cells/L, 10 inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 delayed re-dosing ≥10 days after repopulation detection. 3.3.5 Mycophenolate mofetil, azathioprine and methotrexate in anti-NMDAR encephalitis (systematic literature review). 76 patients treated with mycophenolate mofetil/azathioprine/methotrexate for paediatric-onset anti-NMDAR encephalitis were included (age range at onset 0.8-18 years; 69.7% females; 49.1% had ≥1 relapse), reported in 37 articles. Mycophenolate mofetil was used in 53.9%, azathioprine in 25%, methotrexate in 15.8%; an additional 5.3% received two among mycophenolate mofetil/azathioprine/methotrexate. Mycophenolate mofetil/azathioprine/methotrexate were not preceded by any second-line therapy (rituximab/cyclophosphamide) in 47.7%, and were administered only after relapses in 46.8%. Among the subgroup treated with mycophenolate mofetil/azathioprine/methotrexate after the first event, relapses occurred in 8.3% only. Time on mycophenolate mofetil/azathioprine/methotrexate was median 9 months (range 1-48). Median annualised relapse rate was 0.45 (mean 1, range 0-6.67) before mycophenolate mofetil/azathioprine/methotrexate (excluding onset), and 0 (mean 0.06, range 0-1.3) during/after mycophenolate mofetil/azathioprine/methotrexate. Adverse reactions were reported only for mycophenolate mofetil (cytomegalovirus colitis and respiratory infection; grade 3 Common Terminology Criteria for Adverse Events v4.0). Relapse rate was significantly higher in patients started on first immune therapy (any) >30 days after onset (85.7%) compared to those treated early (31.2% (p=0.0272). 3.3.6 Mycophenolate mofetil in paediatric autoimmune and immune-mediated central nervous system conditions (international retrospective observational study). 44 children were included (30/44, 68.2% females). 43.2% (19/44) had proven or suspected autoimmune encephalitis, 31.8% (14/44) autoimmune inflammatory demyelinating CNS diseases, and 25% (11/44) other autoimmune/immune-mediated CNS conditions. Worst mRS was median 4 (range 2-6). Disease course was relapsing in 52.3% (23/44), monophasic in 38.6% (17/44), and chronic/chronic-progressive in 9.1% (4/44). Before mycophenolate mofetil, all patients received first-line (steroids: 44/44, 100%; intravenous immunoglobulin: 23/44, 52.3%; plasma exchange: 14/44, 31.8%) and 38.6% (17/44) second-line immune therapies (cyclophosphamide: 12/44, 27.3%; rituximab: 6/44, 13.6%). Median age at mycophenolate mofetil commencement was 9.3 years (range 1.4-16.4). Mycophenolate mofetil was started at median 9.5 months from onset (range 1-127; ≤6 months in 31.8%, 14/44). In 55% (22/40) of patients, mycophenolate mofetil was started only after ≥2 events had occurred. Median duration of treatment with mycophenolate mofetil was 18 months (mean 23.2, range 0.3-73). Median annualised relapse rate (excluding patients with chronic/chronic-progressive disease) was 0.52 (mean 0.86, range 0-3) before mycophenolate mofetil (excluding first events), and 0 (mean 0.36, range 0-4.64) during mycophenolate mofetil. 20.5% (8/39) patients relapsed during mycophenolate mofetil; compared to patients who did not relapse (31/49, 79.5%), these patients were younger (median age at onset 4.2 years versus 7.6), were more frequently females (8/8, 100% versus 21/31, 67.7%), had lower rate of second-line treatments before mycophenolate mofetil (1/8, 12.5% versus 15/31, 48.4%), a later commencement of mycophenolate mofetil (>6 months after onset in 7/8, 87.5% versus 22/35, 58.1%), and more frequently they were started on mycophenolate mofetil only after ≥2 events had occurred (7/8, 87.5% versus 14/35, 45.2%). Adverse reactions to mycophenolate mofetil occurred in 18.2% (8/44) of cases (6/8: grade 2, 2/8: grade 3 Common Terminology Criteria for Adverse Events v4.0). 4. Conclusion. The present thesis is a collection of ten works exploring several aspects of the clinical and therapeutic decision-making in paediatric autoimmune and immune-mediated inflammatory conditions. A growing array of immune therapies are becoming available in paediatric neurology, also derived from the experience in immune modulation from other fields of paediatrics and in adult patients. While quality data and definite recommendations are generally lacking, there are common themes emerging, such as the utility of early and aggressive immune therapy in certain clinical situations, such as in autoimmune encephalitis. The use of immune therapy is still characterised by a great heterogeneity between physicians in many neurological conditions, for examples as regards therapeutic plasma exchange and steroid sparers in anti-NMDAR encephalitis, reflecting not only the lack of definite recommendations, but also different treating habits and potential practical difficulties, such as with therapeutic plasma exchange in children and uncooperative patients. Even when recommendations do exist, such as for the use of intravenous immunoglobulin in neurology, current practice is not always adherent to the guidelines, suggesting both the need for greater adherence to existing recommendations and the need for recommendations to be updated to accommodate emerging indications. In other cases, finally, the utility and safety of treatments such as steroid sparing agents warrants further investigations in several fields of paediatric neurology, such as in anti-NMDAR encephalitis. In all cases, both currently accepted and future potential agents have adverse effects, which can be severe. A comprehensive understanding of the therapeutic aspects should not go without the ability to understand each clinical situation in all its facets, taking into considerations not only potential effects, adverse reactions and mechanisms of treatment agents, but also the pathophysiology, the severity of the acute disease, the risk of relapses and of permanent disability, in a complex ‘risk-versus-benefit’ determination and a tailored approach

Neuropsychological and Psychopathological Profile of Anti-NMDAR Encephalitis: A Possible Pathophysiological Model for Pediatric Neuropsychiatric Disorders

Objective: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a severe, but treatable, autoimmune disorder, characterized by autoantibodies causing hypofunction of blocking NMDA receptors leading to a unique constellation of cognitive, motor, and psychiatric symptoms. Neuropsychological and psychopathological outcome has not been fully explored, particularly in children. Aim of this study was to investigate pediatric anti-NMDAR encephalitis as a model of impairment of the complex frontal-subcortical circuits who are implicated in several of the childhood neuropsychiatric disorders. Method: Seven children diagnosed with anti-NMDAR encephalitis at our department underwent an evaluation of the global mental functioning before discharge, a neuropsychological and psychological/behavioral standardized examination within one month after discharge and subsequently were followed up longitudinally for mean 35 months (range 24-48 months). Collected neuropsychological data were evaluated retrospectively. Results: Deficits in attention, executive functions and/or visual motor functions involving executive functions were seen in all children within one month after discharge. These deficits were long lasting in about a half of the patients. In addition, four patients developed persistent psychopathological dysfunctions: difficulties to regulate their own behavior, impulsivity, hyperactivity, irritability, apathy, and obsessive-compulsive symptoms. Conclusions: Our data are in line with research suggesting a crucial role of the executive functions impairments in cognitive outcome disturbance of anti-NMDAR encephalitis. We found also behavioral and psychological deficits pointing to a more comprehensive framework of frontal-subcortical dysfunction, in which the NMDA mediated transmission appear to have a role, as suggested by neurobiological, pharmacological, and neuroimaging studies