We report two children who presented with seizures prior to Multiple Sclerosis (MS) diagnosis. A 12-year-old female presented in status epilepticus with periventricular white matter lesions on MRI. Eleven months later, she had a severe clinical relapse fulfilling MS diagnostic criteria. A 14-year-old male, was found on neuroimaging for cholesteatoma to have multiple cortical and subcortical T2 lesions, with a focal-onset seizure 1-year later. Serial neuroimaging showed new lesions. Oligoclonal bands were positive for both patients. Epileptic seizures can be the first presentation in pediatric MS patients prior to typical demyelination symptoms, with potential for inclusion in future diagnostic criteria

Abdel-Mannan, Omar

Be-Sira, Liat

Hacohen, Yael

Mankad, Kishitij

Meirson, Hadas

Uliel-Sibony, Shimrit

English

UCL Discovery

Neuroimmunology Reports 2 (2022) 100086 Contents lists available at ScienceDirect Neuroimmunology Reports journal homepage: www.elsevier.com/locate/nerep Should epileptic seizures as a first presentation be considered part of diagnostic criteria for relapsing remitting multiple sclerosis? Omar Abdel-Mannan a , b , ∗ , Kshitij Mankad c , Liat Ben-Sira d , Shimrit Uliel-Sibony e , Yael Hacohen a , b , ∗ , Hadas Meirson e a Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom b Department of Neurology, Great Ormond Street Hospital, London, United Kingdom c Department of Neuroradiology, Great Ormond Street Hospital, London, United Kingdom d Department of Neuroradiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel e Department of Neurology, Dana-Dwek Children’s Hospital, Tel Aviv, Israel a r t i c l e i n f o Keywords: Pediatric multiple sclerosis Demyelination seizures 2017 McDonald diagnostic criteria radiologically isolated syndrome (RIS) a b s t r a c t We report two children who presented with seizures prior to Multiple Sclerosis (MS) diagnosis. A 12-year-old female presented in status epilepticus with periventricular white matter lesions on MRI. Eleven months later, she had a severe clinical relapse fulfilling MS diagnostic criteria. A 14-year-old male, was found on neuroimaging for cholesteatoma to have multiple cortical and subcortical T2 lesions, with a focal-onset seizure 1-year later. Serial neuroimaging showed new lesions. Oligoclonal bands were positive for both patients. Epileptic seizures can be the first presentation in pediatric MS patients prior to typical demyelination symptoms, with potential for inclusion in future diagnostic criteria. AMSRCOMAEAM  I a  e  a  t  fi  s  r  i  n  v  g  t  s  f  p  p  d  a  sCP l  w  a  hR2(bbreviations S multiple sclerosis PMS secondary progressive multiple sclerosis IS radiologically isolated syndrome SF cerebrospinal fluid CBs oligoclonal bands OG myelin oligodendrocyte glycoprotein QP4 Aquaporin-4 EG electroencephalogram DEM acute disseminated encephalomyelitis OGAD Myelin oligodendrocyte glycoprotein antibody associated dis-ease ntroduction Previous studies have shown an increased prevalence of epilepsy indult patients with Multiple Sclerosis (MS) (2–4%) compared to the gen-ral population (0.6%) ( Burman and Zelano, 2017 ). Although seizuresre rarely described as the first presentation of MS, the majority of pa-ients are at secondary progressive stages (SPMS) at the time of theirrst epileptic seizure. A number of small studies have also reportedeizure occurrence in pediatric MS patients, who are almost exclusively∗ Corresponding authors. E-mail addresses: o.abdel-mannan@ucl.ac.uk (O. Abdel-Mannan), y.hacohen@ucl.a  ttps://doi.org/10.1016/j.nerep.2022.100086 eceived 12 November 2021; Received in revised form 25 February 2022; Accepted 667-257X/© 2022 The Author(s). Published by Elsevier B.V. This is an open access  http://creativecommons.org/licenses/by-nc-nd/4.0/ ) elapsing remitting in phenotype, and these tend to be more commonn polysymptomatic presentations ( Waldman et al., 2016 ). Advances ineuroimaging techniques now reproducibly demonstrate gray matter in-olvement, cortical lesions and cortical atrophy in MS patients. This sug-ests that epileptogenicity may arise directly from cortical and gray mat-er involvement. Nevertheless, the underlying pathobiology of epilepticeizures in MS has yet to be elucidated. Here we describe two patientsrom two tertiary pediatric neurology centers (Great Ormond Street Hos-ital, London UK and Dana-Dwek Children’s Hospital, Tel Aviv, Israel)resenting prior to the age of 18 years with seizures before a confirmedemyelinating event with radiological evidence of dissemination in timend space. Written informed consent for the publication of both case de-criptions and the figure were obtained. ase series atient 1 A twelve-year-old post-pubertal female, with type 1 diabetes mel-itus (managed with an insulin pump) presented to her local hospitalith an initially unwitnessed tonic-clonic seizure at home lasting overn hour, requiring multiple rescue antiseizure medications, intubationnd admission to intensive care for status epilepticus. Her blood glu-ac.uk (Y. Hacohen). 13 March 2022 article under the CC BY-NC-ND license O. Abdel-Mannan, K. Mankad, L. Ben-Sira et al. Neuroimmunology Reports 2 (2022) 100086 Fig. 1. a) Volume axial Fluid-attenuated inversion recovery (FLAIR) MRI Sequences for patient 1 (left) and patient 2 (right) showing T2 hyperintense lesions at baseline and serially on follow up imaging. New lesions on follow-up imaging are encircled. b) Interictal awake and sleep EEG for patient 2 demonstrated normal alert background activity with anterior- posterior gradient. Generalized and fragmentary regular spike and wave activity, maximal over the bifrontal regions, was seen during alertness, drowsiness and hyperventilation which was not accompanied by clinical symptoms. c  d  y  a  c  e  f  c  (  p  d  v  w  i  (  l  i  t  l  p  t  o  n  o  c  rose level was 2.8 mmol/L during her prolonged seizure, with no evi-ence of infection on neuroimaging and cerebrospinal fluid (CSF) anal-sis, and no focal neurological signs. This episode was presumed to ben acute symptomatic seizure due to hypoglycemia and she was dis-harged without antiseizure medication. She remained seizure free foright months, with some memory and cognitive impairment reported byamily members, before re-presenting following an unprovoked tonic-linic seizure lasting 1 min, after which she was started on levetiracetam30 mg/kg/day). An interictal awake electroencephalogram (EEG) waserformed demonstrating age-appropriate background activity withoutefinite epileptiform discharges. Repeat brain and spine MRI and re-iew of her previous neuroimaging showed multiple T2 hyperintensehite matter lesions ( Fig. 1 a). CSF Oligoclonal bands (OCBs) were pos-2 tive and she had negative serum myelin oligodendrocyte glycoproteinMOG) and Aquaporin-4 (AQP4) antibodies. Serial imaging two monthsater showed evidence of new intracranial and cervical cord lesions, sat-sfying 2017 revised McDonald diagnostic criteria for dissemination inime (DIT) and space (DIS) ( Fig. 1 a). She subsequently presented witheft sided weakness and paresthesia and was ataxic on examination (Ex-anded Disability Severity Score at nadir was 6.0) with further supraten-orial and spinal lesions on repeat neuroimaging confirming a diagnosisf RRMS. She was admitted for treatment with intravenous methylpred-isolone (IVMP) 30 mg/kg for five days followed by a weaning coursef oral prednisolone, and responded well with resolution of her clini-al symptoms. She is currently treated with ocrelizumab for relapsingemitting MS. O. Abdel-Mannan, K. Mankad, L. Ben-Sira et al. Neuroimmunology Reports 2 (2022) 100086 P o  h  (  t  C  a  t  s  s  s  r  b  a  a  m  n  (D p  s  a  t  t  c  a  i  (  m  2  c  w  n  T  t  a t  g  g  r  i  s  n  t  a  e i  m  s  b  d  i  M  t  g  o  o  e  w d  s  s  t  p  (  a  s  (  i  r b  fD o  r  t  HF cS tRA   B   B  B  C  C  F   G   H   K  M  R   T  W  atient 2 A fourteen-year-old male with a history of short stature and chronictitis media complicated by a cholesteatoma was found on MRI brain toave multiple cortical and subcortical T2 lesions without enhancement Fig. 1 b). Spinal imaging was normal. He had no significant family his-ory, with no neurological symptoms nor focal signs on examination.SF OCBs were positive and he had negative serum MOG and AQP4ntibodies. Optical coherence tomography and visually evoked poten-ials were normal. He was given a diagnosis of radiologically isolatedyndrome (RIS). Twelve months later, he presented with a focal onseteizure, describing an episode lasting ten minutes with acute onset leftided visual loss and confusion. Neurological examination was again un-emarkable. Interictal awake and sleep EEG demonstrated normal alertackground with generalized and fragmentary regular spike and wavectivity ( Fig. 1 b). He was not commended on antiseizure medicationnd did not have any further clinical events. Serial neuroimaging at 6onths, 1 year and 2 years follow-up showed evidence of new intracra-ial lesions fulfilling revised 2017 McDonald criteria for DIT and DIS Fig. 1 a). iscussion This case series demonstrates that epileptic seizures can be the firstresentation in pediatric MS patients prior to typical demyelinationymptoms manifesting. In the most recent 2017 revised McDonald di-gnostic criteria for MS, cortical lesions can be used to fulfill MRI cri-eria for DIS ( Thompson et al., 2018 ). Given our understanding nowhat MS not only affects white matter but also gray matter of the brain,ortical lesions in addition to surrounding cytotoxic edema may playn epileptogenic role, with higher numbers of these lesions reportedn MS patients with comorbid epilepsy as compared to those without Koch et al., 2008 ). Cortical or juxtacortical lesions are also more com-only seen on serial MRI in children with MS (93.6%) ( Hacohen et al.,020 ) compared to adult patients (72%) ( Filippi et al., 2018 ). A recentase series reported four young adult patients (age range 19–31 years)ho presented solely with seizures and found to have neuroimaging ab-ormalities fulfilling diagnostic criteria for MS ( Al Hussona et al., 2019 ).his, alongside our case series, raises the possibility of whether epilep-ic seizures, resulting from cortical pathology, should be considered as clinical presentation of demyelination. The International League Against Epilepsy recognizes acute symp-omatic seizures resulting from MS relapses ( Beghi et al., 2010 ). Botheneralized seizures and focal onset seizures (with or without secondaryeneralization) can occur in MS patients, with the latter more commonlyeported. This would support the notion that MS localizing lesions andnflammation could result in an epileptogenic focus triggering clinicaleizures. Patient 1 had an unwitnessed seizure onset and therefore it isot clear if it was focal onset with secondary generalization or a spon-aneous generalized tonic-clonic seizure from the outset. Patient 2 had focal onset seizure, although his EEG showed generalized interictalpileptic activity. Interestingly, in the first randomized controlled trial of disease mod-fying therapies in pediatric MS (PARADIGMS), seven patients on treat-ent were reported to have seizures ( Chitnis et al., 2018 ); specificallyix patients receiving fingolimod and one patient receiving interferoneta-1. Although there have been early reports in adult patients of MSrugs (including baclofen and interferon beta-1) increasing seizure risk,t is not clear in the PARADIGMS study if the seizures were part of theS phenotype of these patients, an incidental finding or even sugges-ive of other antibody-driven MS mimics e.g., Myelin oligodendrocytelycoprotein antibody associated disease (MOGAD). In fact, in a studyf 74 children with acute disseminated encephalomyelitis (ADEM), 50f which were MOG-Ab positive, there was a greater risk of post-ADEM3 pilepsy in children with MOGAD, possibly indicating a chronic diseaseith immune-mediated seizures in these children ( Rossor et al., 2020 ). The extent to which seizures and epilepsy in MS patients influenceisease course and prognosis has not been sufficiently studied; sometudies have shown patients with MS and seizures have worse disabilitycores than those without epileptic seizures ( Grothe et al., 2021 ). Fur-hermore, some studies suggest a high seizure recurrence risk in RRMSatients after a first seizure ( Catenoix et al., 2011 ), whilst others do not Mahamud et al., 2018 ). Furthermore, the association between epilepsynd both disease duration and progressive stages (SPMS) raises the pos-ibility that mechanisms additional to gray matter/cortical lesion loade.g., long-term neuroinflammation) could influence the risk of epilepsy,n line with the emerging body of evidence supporting the role of neu-oinflammation in epileptogenesis ( Barker-Haliski et al., 2017 ). In conclusion, this case series highlights epileptic seizures may rarelye the first clinical manifestation of pediatric MS and there is potentialor including them in future diagnostic criteria. eclaration of Competing Interest Omar Abdel-Mannan is funded by an Association of British Neurol-gists, MS Society and The Berkeley Foundation’s A. W. Pidgley Memo-ial Clinical Research Training Fellowship. Yael Hacohen is funded byhe MS Society . Kshitij Mankad, Liat Ben-Sira, Shimrit Uliel-Sibony andadas Meirson report no disclosures. unding This research did not receive any specific grant from funding agen-ies in the public, commercial, or not-for-profit sectors. upplementary materials Supplementary material associated with this article can be found, inhe online version, at doi:10.1016/j.nerep.2022.100086 . eferences l Hussona, M. , Kearney, H. , Fisher, A. , Lynch, J. , Looby, S. , Delanty, N , 2019. New onsetseizures as a sole clinical presentation of multiple sclerosis. 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Should epileptic seizures as a first presentation be considered part of diagnostic criteria for relapsing remitting multiple sclerosis?

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Should epileptic seizures as a first presentation be considered part of diagnostic criteria for relapsing remitting multiple sclerosis?

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