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ObjectiveTo describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs).MethodsIn this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment.ResultsWe included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age ConclusionsAge at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

BackgroundAquaporin-4 (AQP4) antibody associated neuromyelitis optica spectrum disorder (NMOSD) requires long-term immunomodulation. In refractory cases rituximab can be used, however the optimal regime is not established.MethodsWe retrospectively examined different rituximab regimes in AQP4-NMOSD. Standard mono- therapy (SM; 6 monthly infusions), SM plus oral steroids (SM+S), extended interval dosing (EID; with retreat- ment at CD19 >1%) and EID with oral steroids (EID+S) were compared. The primary outcome was time to first clinical relapse. Potential confounders including age, gender, number of previous relapses, and onset phenotype were included.Results77 patients were included: 67 females, mean age 34.6, median DSS at rituximab initiation 5.0. 40 were on SM+S, 19 on SM, 8 on EID, and 10 on EID+S, with mean follow-up 38.5 months. 25/77 patients relapsed on rituximab. Median time to first relapse was 39 months (SM+S), 46 months (SM), 54 months (EID) and 42 months (EID+S). Adjusted Cox proportional hazard model revealed no significant difference between rituximab regimes (SM+S as reference; hazard ratio for SM 1.39, 95%CI 0.49–4.1, p=0.55; hazard ratio for EID 0.70, 95%CI 0.15–3.3, p=0.65; hazard ratio for EID+S 1.63, 95%CI 0.48–5.5, p=0.43). 9 significant infections were recorded, 3 in the SM group and 6 in SM+S.ConclusionsThis provides initial evidence that EID could be used for long term treatment of NMOSD. This may improve patient experience and consolidate use of hospital resources.

BackgroundVaccination is a recognised trigger of ADEM and approximately 50% paediatric cases have antibodies to MOG. The SARS-CoV-2 mass vaccination programme could therefore trigger cases of MOGAD. Neuromyelitis optica (NMO) is an autoimmune inflammatory condition of the CNS associ- ated with antibodies to AQP4.MethodTen patients (ages 22 – 65 years) with antibodies to MOG or AQP4 were referred to the NHS England NMO service having developed acute onset CNS inflammation within 8 weeks of vaccination.ResultsEight patients had MOGAD, seven of whom received the AstraZeneca vaccine (AZV) and one the Pfizer vaccine (PV). Only the post-PV MOGAD patient presented with typical adult-onset phenotype of isolated ON. All post-AZV MOGAD patients presented atypically; 85.7% had LETM and 71.4% had intrac- erebral lesions, resembling ADEM more commonly seen in paediatric MOGAD. The atypical presentation supports a causative role of AZV, but the role of PV is less convincing.Two patients had AQP4-NMOSD with typical demographic features. Both received AZV. Less typically, one young adult presented with LETM rather than characteristic young adult ON, the other had a silent short segment myelitis, which is rarely seen in AQP4-NMOSD. Both patients achieved good outcomes.ConclusionWe discuss the potential causation and pathophysiological mechanisms.

We describe a man with an intracranial dural arteriovenous fistula that presented as a subacute longitudinally extensive cervical myelopathy. The uncommon location of the fistula and the absence of specific radiological signs resulted in initial misdiagnosis as longitudinally extensive transverse myelitis. Neurologists should have a high index of suspicion for dural arteriovenous fistula in older men, especially those with subacute or chronic symptoms, acellular cerebrospinal fluid and, particularly, if there is neurological deterioration soon after corticosteroid treatment. Patients need early angiography to identify this treatable cause of myelopathy.

BackgroundA standard cut-off of ≥2 CSF-specific OCBs is used in multiple sclerosis but some studies suggest ≥3 CSF OCBs maybe more specific.AimTo determine if a cut-off of ≥2 or ≥3 CSF OCBs should be used in MSMaterials and MethodsOligoclonal bands were tested using standardised methods incorporating iso- electric focussing. Samples sent between July 2018-June 2019 were included. CSF OCB number (1, ≥2,≥3, or unclear) was assessed by two blinded raters and case records were reviewed.ResultsCSF OCBs were detected in 196/746 (26%) samples (CSF OCB=1; 14/196 (7%), ≥2=182/196 (93%), ≥3=169/196 (86%). Clinical data were available in 157 patients (MS=101, other inflammatory=37, unclear significance=19). Excluding CSF OCB results, 68/101 (67%) cases fulfilled MS diagnostic criteria. Of patients with 1, ≥2 and ≥3 CSF OCBs, 1/8 (12%), 100/182 (55%) and 98/169 (58%) had MS respectively. The positive predictive value of 1, ≥2, and ≥3 OCBs was 0.35, 0.89 and 0.92 respectively in CNS inflammatory disease.ConclusionDetection of CSF OCBs was necessary to fulfil MS diagnostic criteria in approximately 30% of cases. Detection of ≥3 OCBs marginally improved the likelihood of an MS diagnosis. Overall measures of sensitivity, specificity and receiver operator curves will be presented.giovanna.campagna@thewaltoncentre.nhs.uk

BackgroundNeuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune inflammatory disorder of the central nervous system (CNS), and in most cases is associated with Aquaporin-4 antibodies (AQP4- IgG). Severe optic neuritis, longitudinally extensive myelitis and brain involvement is characteristic. Similarly presenting patients may not have detectable AQP4-IgG (seronegative NMOSD) or have Myelin Oligo- dendrocyte Glycoprotein IgG (MOG-IgG).MethodA retrospective study of AQP4-IgG, MOG-IgG, and seronegative NMOSD patients attending the highly specialised NMOSD service between September 2010-August 2019 was performed. In particular, the presence of coexistent autoimmunity was assessed.ResultsCoexistent autoimmunity in AQP4-IgG patients was higher as compared to MOG-IgG and seron- egative NMOSD (30% vs. 8% vs. 8%). Some AQP4-IgG patients had 2nd and 3rd autoimmune diseases (7% and 1% respectively). In contrast no patients with MOG-IgG or seronegative NMOSD had 2 or more other autoimmune diseases.ConclusionCoexistent autoimmunity in AQP4-IgG NMOSD is more common that in seronegative NMOSD and patients with MOG-IgG. It is reasonable to periodically assess for coexistent autoimmunity in AQP4-IgG NMOSD as it is present in almost a third of patients. Finally the detection of ≥2 autoimmune diseases in newly presenting cases provides a useful clue to AQP4-IgG NMOSD whilst antibody results are awaited.giovanna.campagna@thewaltoncentre.nhs.uk

ObjectiveTo evaluate causes of death in Aquaporin-4 antibody positive Neuromyelitis Optica Spectrum Disorder (AQP4-IgG NMOSD) patients treated in the National NMOSD service.MethodRetrospective review of Liverpool and Oxford patient databases (NMOSD national referral centres) between January 2010–2020.ResultsAQP4-IgG NMOSD=414 patients attended the NMOSD Service and 34 died. Of these, 32/34(94%) were female with a median disease duration of 10 years (0.5–19.1). The median age at death was 67.1(45.1–88.3) years. Median EDSS score prior to death was 8(2–9.5). The median number of relapses from disease onset to death was 3(0–10), with 94% of patients experiencing at least 1 relapse. All but one patient was immunosuppressed (Azathioprine=15, Mycophenolate=3, Rituximab=7, Methotrexate=4, IVIg=1, Ciclosporin=1, Eculizumab=1, Prednisolone=1). Causes of death were available in 31/34 patients; infections=18, coronary artery disease=5, malignancy=4, bowel obstruction=1 and respiratory failure=2. Only one patient died from an acute brain stem relapse.ConclusionApproximately 1 in 10 AQP4-NMOSD patients died over a 10-year period. The majority of patients had significant disability, suggesting possible association with NMOSD mortality. Infection was the leading cause of death, suggesting a possible relationship with immunosuppression. Striking a balance between disease suppression and mitigation of side effects poses a significant challenge in autoimmune neurological conditions.emily.gibbons@doctors.org.uk

BackgroundMost but not all cases of Neuromyelitis Optica Spectrum Disorder (NMOSD) are associated with Aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibodies.ObjectiveTo determine the clinical characteristics of seronegative NMOSDMethodRetrospective review of seronegative NMOSD in Liverpool and Oxford between January 2010–2020ResultsOf NMOSD=727, 49(7%) were seronegative. The male to female ratio was 1:2.5 and median age at onset was 36(5–57) years. In 2/3 of patients the index presentation was myelitis=22 or myelitis+optic neuritis=11. In 26/33 (79%), longitudinally extensive myelitis was present. Optic neuritis=9 (4 bilateral) and brain involvement=7 were also seen. Relapsing disease was observed in 39/49(80%) of patients. The median annualised attack rate was 0.58 over a median disease duration of 78 (3–258) months. Unmatched CSF oligoclonal bands (CSF-OCBs) were detected in 4/38(11%) and 31/49(63%) fulfilled multiple sclerosis (MS) diagnostic criteria. Immunosuppression (typically Mycophenolate and Rituximab) was used in 34/49(69%). Median last EDSS was 4 (1–10) with death recorded in 5/49 (10%) patients.ConclusionSeronegative NMOSD is uncommon. Longitudinal myelitis with/without optic neuritis is a common initial presentation. Similar to AQP4-IgG, NMOSD disability and mortality rates are high. Absence of unmatched CSF-OCB and typical brain lesions help to distinguish this disease from MS.emily.gibbons@doctors.org.uk

A 28 year-old Caucasian woman was found to have reduced visual acuity during routine optician checks and was referred to ophthalmology and then neurology. Examination revealed acuities of 6/12 in both eyes, pale optic discs and reduced colour perception. MRI brain did not show any lesions. Routine bloods were normal as were serum ACE, B1, B12, folate, HIV, syphilis, Lyme serology, AQP4-IgG and MOG-IgG. Leber’s and AD optic atrophy screens were negative. CSF protein was 0.41, WBC 7 (100% lymphocytes), elevated IgG Index 1.4 (normalG p. (Glu2020Gly); c.874C>T p.(Pro292Ser) leading to diagnosis of‘Wolfram’Syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) with an isolated optic atrophy phenotype. This case is unusual given the late age of presentation, lack of classical associ- ated features, suggestion of CSF inflammation and apparent steroid responsiveness. It also highlights the importance of expanded genetic testing in atypical optic atrophy cases.emily.gibbons@doctors.org.uk

IntroductionMS patients who have their first symptom onset after 50 years of age are defined as Late onset Multiple Sclerosis (LOMS). Our study analyses the clinical profile of patients with LOMS in North Wales region of United KingdomMethods and materialsA retrospective medical record review of all patients attending regional MS clinic in North Wales, based at Glan Clwyd Hospital (2007–2018) was done.ResultsOf 648 patients with MS, 60 (9.2%) had LOMS. Mean age at onset was 55.3 years and the M: F ratio was 1:1.85. 63% and 28% of LOMS were progressive and relapsing types respectively.At a mean of 7.8 years follow up, 31% of relapsing patients converted to SPMS. Majority of LOMS presented with gait difficulties-67% (97% in Progressive MS and 23% in relapsing).Only 15% of the relapsing MS patients were eligible or chose DMT.ConclusionsLOMS forms at least 9% of this MS cohort with majority presenting with a progressive course at diagnosis. The high proportion of LOMS in this cohort may reflect, delayed reporting of symptoms or slower access to care.

Recreational use of nitrous oxide as a ‘legal high’ is increasing in the UK. Physicians should be ‘street wise’ to this increasing prevalence and aware of the potential neurological complications which may result from misuse. We describe a 17-year-old male patient who presented to neurology with a severe myelopathy following prolonged recreational use of nitrous oxide. MRI demonstrated characteristic changes affecting the dorsal columns and blood tests demonstrated a ‘functional’ B12 deficiency. Clinical and radiological improvement was noted following initiation of vitamin B12 replacement.

AimsTo analyse the MRI abnormalities of myelin oligodendrocyte glycoprotein-antibody (MOG-Ab) associated demyelinating disease.MethodsClinical records and 165 MRIs from 56 patients with MOG-Abs were reviewed.ResultsThe median age was 29(8–71) years and 52% percent were female. Common phenotypes included isolated optic neuritis (ON)=17, or transverse myelitis (TM)=16, ON+TM =12, and combinations of above groups with cerebral and/or brainstem involvement=11. Seventeen patients (30%) fulfilled NMOSD 2015 diagnostic criteria.All patients had brain imaging and 89% (50/56) had spinal imaging. Common areas of MRI brain abnormality involved brainstem(32%), hemispheric white matter(29%), corticospinal tracts(21%), and U-fibres(20%). Dawson’s fingers were not detected in any patients.Cord imaging showed longitudinally extensive myelitis in 69% (20/29) and atrophy in 4% (2/47). Optic nerve imaging was abnormal in 69% (18/26) of patients, with bilateral lesions in 33% and long lesions (orbital and/or canalicular) in 83%. On serial MRI, radiological improvement was observed in 76% (22/29; median interval- 14 months) and importantly asymptomatic new lesions were absent in 13 untreated patients after a median of 16.5 months.ConclusionsApart from optic nerve and spinal cord changes, brainstem and hemispheric white matter abnormalities are common in MOG-antibody disease. Irrespective of treatment, asymptomatic accrual of brain and/or spinal lesions is uncommon.

BackgroundThe association of N-methyl d-aspartate receptor-antibodies (NMDAR-Abs) and encephalitis is now well recognised. MethodsRetrospective review of frequency of diagnosis and outcomes in encephalitis with NMDAR-Abs identified at the Walton Centre between 2012–2017.ResultsNMDAR-Abs were detected in 29/1131 (3%) of sera and/or CSF samples. Of 20 (69%) patients with encephalitis, 50% were identified in the last two years. Median onset age was 34(17–75) years and 60% (12/20) were female. Median symptom duration before diagnosis was 24(2–720) weeks between 2012–2015, improving to 14(1–96) weeks between 2015–2016. Five patients (25%) had an infectious prodrome (one prior HSV-1 encephalitis). Psychiatric/cognitive symptoms, seizures, and movement disorders were present in 80% (16/20), 70% (14/20), and 55% (11/20) of patients respectively. Three patients had ovarian teratomas.Electroencephalograms were abnormal in 65% (15/23) and MRI brain in 37% (7/19) patients. Unmatched intrathecal oligoclonal bands and CSF pleocytosis were present in 31% (5/16) and 60% (15/25) of samples respectively. Immunotherapy was beneficial in 73% (11/15) of patients. Two patients died (sepsis and multi-organ failure) and two improved spontaneously. At a median follow-up of 9 (5–180) months, 69% (11/16) of patients had an mRS ≤2. ConclusionAlthough the recognition of NMDAR-Ab encephalitis has improved, there is still a significant delay to diagnosis. The majority of patients have good outcomes.

Background Myasthenia gravis with muscle-specific kinase (MuSK) antibodies (Abs) typically causes cranial and bulbar muscle weakness with frequent respiratory crises. MuSK-Abs compromise neuromuscular transmission through disruption of MuSK/LRP4 interaction, inhibiting agrin-dependent acetylcholine receptor (AChR) clustering. MuSK phosphorylation is a key step in this pathway. Modulation of signalling pathways downstream of MuSK/LRP4 disruption may represent a novel therapeutic strategy. Aims To assess if inhibition of SHP2, a tyrosine phosphatase alleviates the in vitro effects of MuSK-Abs Methods MuSK phosphorylation was assessed in C2C12 myotubes incubated with agrin, the SHP2 inhibitor- NSC-87877 (Tocris) and purified IgG1–3, IgG4 and IgG fractions from MuSK-MG plasmas (n=2). The effects of NSC-87877 on agrin-dependent formation, dispersal, and re-clustering of AChR’s was assessed in myotubes incubated with MuSK-MG sera (total n=32). Agrin-independent clustering was assessed using Docking Protein-7 overexpressing myotubes. Results NSC-87877 increased MuSK phosphorylation and AChR clustering in myotubes. IgG4 from MuSK-MG plasmas inhibited agrin-dependent MuSK phosphorylation, which was rescued with NSC-87877. Importantly NSC-87877 alleviated inhibition of agrin-dependent AChR cluster formation by MuSK-Abs. Dispersal of agrin-dependent/independent AChR clusters was attenuated, and following dispersal by MuSK abs, recovery of AChR clusters was enhanced. Conclusions Modulation of MuSK tyrosine phosphorylation alleviates the in vitro effects of MuSK-MG antibodies.

Objective To report a case of NMDAR encephalitis, possibly related to B Cell lymphoma despite being immunosuppressed post renal transplant. Results A 54-year-old woman presented with a three month history of a sub-acute brainstem syndrome with altered personality and auditory hallucinations. She was on long-term immunosuppression with mycophenolate/prednisone following renal transplantation. MRI showed brainstem lesions, and CSF had lymphocytic pleocytosis without cancer cells. CT of the chest, abdomen, and pelvis was also normal. Despite empirical corticosteroid treatment the patient’s conscious level deteriorated and she developed orofacial dyskinesia with autonomic fluctuation. An autoimmune encephalitis was strongly suspected. Indeed both serum and CSF NMDAR antibodies were positive. Intravenous immunoglobulin and cyclophosphamide were commenced but treatment was complicated by peritonitis secondary to caecal perforation. Shortly thereafter the patient died of sepsis. Surpisingly histology from the resected colonic segment demonstrated high grade non-Hodgkin B-cell lymphoma. Discussion Neoplasia due to reduced immune vigilance is a known complication. However development of autoimmune disorders is unexpected as immunosuppression is the treatment for many autoimmune disorders including encephalitis. To have both complications together was exceptional. Possible mechanisms and implications will be discussed. Sometimes Ockham’s razor simply doesn’t cut.

A middle-aged man of South Asian decent presented with a 4-month history of bilateral sensory disturbance affecting the median nerve distribution and dorsum of both feet. Neurological examination was otherwise normal. A patchy absence of sensory responses was noted on nerve conduction studies and electromyogram (NCS/EMG). Over the next 3 months sensory symptoms progressed to involve median, radial, ulnar, sural and peroneal nerves bilaterally. Repeat NCS/EMG confirmed a mononeuritis multiplex predominantly involving the sensory fascicles. Areas of hypopigmentation, a right-lower motor facial weakness and ophthalmic branch trigeminal nerve involvement were noted on examination. Punch skin biopsy as well as sural nerve biopsy demonstrated chronic granulomatous inflammation without evidence of Mycobacterium. A slit skin smear test demonstrated Mycobacterium leprae consistent with a diagnosis of primary neuritic leprosy. In the appropriate clinical context, leprosy should be included in the differential diagnosis of mononeuritis multiplex.

A 58-year-old lady with waxing and waning of non-specific symptoms including fatigue, dizziness, hearing loss and unsteady gait for 15 months, became acutely confused 12 h prior to presentation. On admission to a district hospital she was feverish and unresponsive. Her travel history consisted of visits to Argentina, Chile and the Outer Hebrides. CT of the brain was normal. Lumbar puncture demonstrated a lymphocytic pleocytosis of 500 cells, protein of 1 g/l, a low glucose ratio with negative cytology and viral PCR (including herpes simplex 1 and 2). MRI revealed multiple abnormal areas of high signal on T2 fluid attenuated inversion recovery sequencing within the cerebellum, temporal lobes and periventricular areas. Western blotting of serum and cerebrospinal fluid for Borrelia burgdoferi were both positive. She was treated with cefuroxime and aciclovir and within 24 h she was alert and responsive. She received 4 weeks of cefuroxime in total and made a good recovery.