An open-label trial of JAK 1/2 blockade in progressive IFIH1 -associated neuroinflammation

IFIH1 gain-of-function causes a spectrum of neuroinflammatory phenotypes associated with enhanced type I interferon production and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation.1,2 Patients most often present in infancy, variably exhibiting spasticity, dystonia, seizures, and acquired microcephaly. We report the use of ruxolitinib, a JAK 1/2 blocker, in the treatment of early-onset, progressive neurologic disease due to an IFIH1 mutation

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

Correlation of autism with temporal tubers in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an inherited genetic disorder commonly associated with neuropsychiatric complications like epilepsy, mental retardation, autism and other behavioral problems and constitutes about 1-4% of the autistic population. Mental retardation and seizures, particularly infantile spasms are significant risk factors for the development of autism. Patients of TSC with autism are more likely to have temporal tubers than those cases without autism. We describe clinical and neuroimaging features of two such cases of tuberous sclerosis with autism

Use of thrombolytic therapy in cerebral venous sinus thrombosis with ulcerative colitis

Cerebral venous thrombosis developing concurrently with active ulcerative colitis poses a therapeutic dilemma. We report the case of a 31-year-old woman who developed dural venous sinus thrombosis during the course of active ulcerative colitis in whom we accomplished clot lysis using intrasinus urokinase. The success of the procedure was assessed by improvement in the patient's neurological condition and resolution of imaging features without any bleeding complications. We also reviewed literature on various modalities of treatment of sinus venous thrombosis in patients with ulcerative colitis and outcome

Rapid onset functional tic_like behaviours in children and adolescents during COVID-19: Clinical features, assessment and biopsychosocial treatment approach

AIM: To report the prevalence and clinical characteristics of children with rapid onset functional tic-like behaviours during the COVID-19 pandemic. METHODS: Single centre, retrospective cohort study of children (<18_years) referred to the tic clinic from January 2018 to July 2021. We calculate the prevalence of newly diagnosed functional tics, and compare the clinical features to chronic tic disorder/Tourette syndrome (CTD/TS). RESULTS: A total of 185 new patients were referred to the tic clinic between 2018 and 2021. There was a significant increase in the percentage of functional tics in 2020 and 2021 (2% in 2018, 5.6% in 2019, 10.6% in 2020 and 36% in 2021). Differences between functional tics (n=22) and CTD/TS (n=163) include female predominance (100 vs. 28%,

B cell, Th17, and neutrophil related cerebrospinal fluid cytokine/chemokines are elevated in MOG antibody associated demyelination

Background: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. Aim: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and-negative (NEG) groups. Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM=8), transverse myelitis (TM=2) n=10] and serum MOG Ab NEG (ADEM=5, TM=4, n=9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. Results: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. Conclusion: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.16 page(s

Acute hemorrhagic leukoencephalopathy: pathological features and cerebrospinal fluid cytokine profiles

Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic central nervous system demyelination with high mortality. It is unclear whether acute hemorrhagic leukoencephalopathy is an entirely distinct entity from acute disseminated encephalomyelitis.We report two patients with rapidly progressive neurological illness resulting in raised intracranial pressure and coma, with biopsy-proven acute hemorrhagic leukoencephalopathy (perivascular hemorrhages and demyelination, predominantly neutrophil infiltrates).Acute cerebrospinal fluid showed pronounced T cell-associated cytokine elevation (interleukins 6, 8, and 17A) and CCL2 or CCL3, higher than in patients with acute disseminated encephalomyelitis, but no B cell-associated cytokine elevation.Improved understanding of the immune process may provide rationale for use of anticytokine biologic agents

Herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis: A systematic literature review with analysis of 43 cases

IM To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar\u2019s test, Fisher\u2019s test, and Wilcoxon rank sum test were used (two-tailed signi\ufb01cance level set at 5%). RESULTS Forty-three patients with biphasic disease were identi\ufb01ed (31 children). Latency between HSE and anti-NMDAR encephalitis was signi\ufb01cantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by signi\ufb01cantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and signi\ufb01cantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had signi\ufb01cantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modi\ufb01ed Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for 647d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal \ufb02uid HSV polymerase chain reaction (median follow-up 7mo). INTERPRETATION Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV- induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence