Published Ahead of Print on August 14, 2020 as 10.1212/WNL.0000000000010655 TE D Neurology Publish Ahead of Print DOI: 10.1212/WNL.0000000000010655 Clinical Reasoning: An 11-year-old girl with focal seizures, fevers, and unilateral, enhancing cortical lesions C EP Jeffrey B. Russ, MD, PhD1; Clare M. Timbie, MD, PhD1; Yi Li, MD2; Ernesto GonzalezGiraldo, MD3* Affiliations: Child Neurology Residency Program, Department of Neurology, University of California San Francisco, San Francisco, California 2 Neuroradiology, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California 3 Division of Epilepsy, Department of Neurology, University of California San Francisco, San Francisco, California 1 C Search Terms: myelin oligodendrocyte glycoprotein, MOG, FLAMES, unilateral, autoimmune encephalitis Publication History: None A Submission Type: Neurology Resident and Fellow Section, Clinical Reasoning Title Character Count: 81 Number of Tables: 1 Number of Figures: 2 References: 15 Word Count: 1614 Neurology® Published Ahead of Print articles have been peer reviewed and accepted for publication. This manuscript will be published in its final form after copyediting, page composition, and review of proofs. Errors that could affect the content may be corrected during these processes. 1 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Corresponding Author Ernesto Gonzalez-Giraldo ernesto.gonzalez-giraldo@ucsf.edu Study funding: No targeted funding reported. A C C EP TE D Disclosures: J. Russ is a member of the Neurology Resident & Fellow Section Editorial Team. C. Timbie, Y. Li, and E. Gonzalez-Giraldo report no disclosures relevant to the manuscript. 2 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Section 1: An 11-year-old Asian American girl with no past medical history experienced acuteonset confusion and speech arrest without loss of consciousness, eye deviation, tonic stiffening, or convulsion. At an outside Emergency Department, her exam included TE D expressive aphasia, right lower facial droop, and right-sided hemiparesis. Non-contrast head CT was negative for acute intracranial pathology, CT angiogram showed patent vasculature, and CT perfusion showed no areas of perfusion mismatch. The patient was transferred to our institution for further management. C EP On arrival, she was afebrile without meningismus, and her neurologic exam had improved substantially with mild expressive aphasia, slight right nasolabial fold flattening, and distal right upper extremity weakness. Over the next day, she had recurrent paroxysmal episodes of confusion, aphasia, right arm tonic stiffening and C subsequent right hemiparesis. Questions for Consideration: A 1. What is the differential for pediatric patients with acute-onset aphasia and hemiparesis? 2. If the episodes were seizures, what lateralization/localization would you suspect for their onset based on semiology? Go to Section 2 3 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Section 2: MRI/MRA brain demonstrated left parietal and perirolandic cortical edema with some reduced diffusion but no abnormal enhancement, overt ischemia, or structural abnormalities (Figure 1). MR spectroscopy over the involved area was normal. An EEG TE D showed left posterior quadrant slowing with occasional left posterior temporal sharp waves, and multiple electrographic seizures originating from the left posterior quadrant (Figure 1), consistent with her aphasic seizures and post-ictal Todd’s paralysis.1 The focal tonic features were thought to represent spread to the left frontal lobe.1 She was started on levetiracetam (60 mg/kg/day). Since she was initially afebrile without EP meningismus, and since her CSF studies (below) did not suggest bacterial or HSV meningoencephalitis, she was not empirically given antimicrobials. A C C On the fifth day of admission, she became intermittently febrile with temperatures up to 39.4°C. At this time, the differential for her acute-onset focal seizures was broad and included infectious, autoimmune, neoplastic, and metabolic possibilities (Table 1). Serum infectious studies were negative. A serum autoimmune encephalopathy panel was negative. Her ANA was positive with a nucleolar pattern and a titer of 1:320, but her ESR, CRP, dsDNA, RF, and SSA/SSB were unremarkable. Serum metabolic studies, including ammonia, lactate, pyruvate, amino acids, free and total carnitine, and acylcarnitine profile, were normal. Urine organic acids were normal. 4 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Lumbar puncture demonstrated a mixed pleocytosis: 35 white blood cells with 40% neutrophils, 47% lymphocytes, and 13% monocytes. CSF glucose, protein, lactate, pyruvate and IgG index were unremarkable and there were zero oligoclonal bands. A CSF autoimmune encephalopathy panel was negative. CSF HSV, VZV, enterovirus, D West Nile virus, and bacterial culture were negative. Metagenomic next-generation sequencing for organisms was performed and resulted in a subthreshold positive result TE for Candida glabrata, which was felt to be a contaminant, particularly in an immunocompetent host. Repeat CSF metagenomic testing was negative. CSF cytology demonstrated lymphocytosis but no atypical cells. C EP Questions for Consideration: 1. Based on these results, how would you prioritize the differential diagnosis? 2. Would you start any empiric therapies? A C Go to Section 3 5 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Section 3: Based on her elevated ANA, mixed CSF pleocytosis, and unrevealing infectious, metabolic, and neoplastic workup, an inflammatory/autoimmune process was favored. She was started on empiric high-dose methylprednisolone (30 mg/kg/day) and D discharged on a prednisone taper with a plan to continue management as an outpatient. TE In the interval, she had no further fevers or seizures. She had near-complete return to baseline with only subtle acalculia and dysgraphia. When an outpatient surveillance MRI demonstrated new enhancing lesions in the left frontal and insular subcortical white C EP matter (Figure 2), she was readmitted for expedited evaluation. While inpatient, she was again febrile with temperatures as high as 39.5°C and had two seizures with acute confusion and aphasia. EEG again demonstrated a left posterior C quadrant origin. Lacosamide (5 mg/kg/day) prevented further seizures. In consultation with our Infectious Disease and Rheumatology colleagues, additional A studies were sent to further consider infectious, autoimmune, endocrine, and neoplastic etiologies (Table 1). Autoinflammatory diseases, genetic disorders of the innate immune system with heterogeneous CNS manifestations,2 were considered, but the time course and absence of typically associated non-neurologic inflammatory symptoms suggested an acquired autoimmune disorder. 6 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Repeat lumbar puncture demonstrated a mixed pleocytosis (41 white blood cells with 55% lymphocytes, 28% neutrophils, 16% monocytes, and 1% eosinophils) with an unremarkable glucose and protein. CSF IgG index was 0.7 and there were zero oligoclonal bands. Ophthalmologic exam was normal. Interval imaging demonstrated D new areas of left-sided linear intraparenchymal enhancement, cortical and subcortical FLAIR hyperintensity, and leptomeningeal enhancement, in addition to evolution of the Questions for Consideration: TE prior findings (Figure 2). MRI spine was normal. 1. Does the differential diagnosis change with these findings? A C Go to Section 4 C EP 2. Is there targeted testing you would send to confirm a diagnosis? 7 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Section 4: At this time, anti-myelin oligodendrocyte glycoprotein (MOG) IgG, tested at Mayo Laboratories via a cell-based assay employing full-length MOG antigen,3 returned positive with a titer of 1:1000. Her presentation was consistent with a newly described D MOG-antibody-associated phenotype called FLAIR-hyperintense Lesions in Anti-MOGassociated Encephalitis with Seizures (FLAMES).4 She was restarted on 5 days of TE methylprednisolone (30 mg/kg/day) followed by an 8-week prednisone taper, and she received a single dose of rituximab (750 mg/m2). Given that her symptoms were not highly debilitating, we opted for steroids over IVIG or plasmapheresis, following an C EP accepted approach to pediatric anti-MOG-associated disease.5 Unfortunately, after discontinuing prednisone, she returned with left optic neuritis. MRI brain demonstrated no other new lesions (not shown). Lymphocyte subsets demonstrated persistent B-cell depletion after rituximab. The patient repeated five days C of pulse-dose steroids with visual improvement and was discharged on a prolonged A course of prednisone (60mg daily) and a plan to follow up in Neuroimmunology Clinic. Discussion: Since its detection in children with autoimmune neuroinflammatory disorders,6 anti-MOG antibody has identified a phenotypically diverse subpopulation of patients with autoimmune CNS disorders. Pediatric anti-MOG-associated disease is prevalent; a recent prospective study found that 22% of pediatric patients diagnosed with encephalitis or acquired demyelinating disease were positive for anti-MOG antibody.7 8 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Various case series have described the presentations of pediatric versus adult antiMOG-associated disorders, revealing some general themes: patients with anti-MOG antibodies tend to be younger than patients with neuromyelitis optica (NMO) or multiple sclerosis (MS); they rarely meet MS diagnostic criteria; they often present with optic D neuritis, myelitis, or acute disseminated encephalomyelitis (ADEM); they often have radiographic involvement of supratentorial white matter, brainstem, or spinal cord; and TE they are rarely simultaneously positive for anti-NMO antibodies.4,8-10 To avoid “overdiagnosis,” an international panel published a consensus guideline for testing and diagnosis, suggesting that criteria for anti-MOG-encephalomyelitis include: 1) monophasic or recurrent optic neuritis, myelitis, encephalitis, or a combination thereof; C EP 2) radiographic or electrophysiologic evidence of demyelination; and 3) MOG-IgG seropositivity via a cell-based assay that uses full-length human MOG antigen.11 Nevertheless, uncommon, heterogeneous features of anti-MOG-associated disease have been described, including patients with seizures,4,9-12 or patients with cortical or C leptomeningeal findings on imaging,4,10,12 suggestive of a novel anti-MOG-associated syndrome. First described in adults by Ogawa et al.,13 this syndrome has been named A FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES).4 Patients with FLAMES often present with focal or generalized seizures as an early symptom.4,13 In a case review of 20 patients with FLAMES, 85% had seizures, 70% had headache, 65% had fevers, and 55% had a focal deficit that corresponded to the unilateral area of cortex involved on imaging.4 The presence of fever is noteworthy, as this can make it harder to rule out infectious causes and delay immunosuppression. 9 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Typical features of autoimmune demyelinating diseases, such as optic neuritis or myelitis, can still precede, co-occur with, or succeed the FLAMES symptoms,4,13 and thus patients may meet diagnostic criteria only over an extended time.11 D On imaging, patients with FLAMES characteristically present with unilateral cortical T2hyperintensity,4,13 and may not initially meet the second diagnostic criterion requiring TE radiologic evidence of demyelination.11 Subcortical involvement, sometimes with enhancement, can evolve later, as seen in our patient.4,13 Findings can be bihemispheric, but are commonly unilateral.4,13 Six out of twenty patients described in C EP Budhram et al.4 also demonstrated leptomeningeal enhancement. Our patient responded to high-dose steroids, which was successful in all 24 previously reported FLAMES cases,4,13 and is a mainstay of acute therapy for anti-MOGassociated disease.5 While there is no standard approach to maintenance therapy for MOG-associated illness, the prominent suspected role of antibody production in the C pathophysiology of this disorder makes rituximab, which depletes B-cell precursors, a common choice.5 Though minimal specific data exists on the risk of relapse in FLAMES, A a study of MOG-antibody-positive children suggests that relapse occurs in roughly onethird of patients, and that older school-aged children (median age of 10 years) with higher initial antibody titers (>1:1280) are most at risk by 24 months.14 Finally, the exact pathogenic mechanism of anti-MOG antibodies in human disease is unclear.8 Our patient had zero CSF oligoclonal bands, which has been observed in 10 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited FLAMES and other MOG-associated disorders, suggesting that anti-MOG disease may have a different neuroinflammatory mechanism than other demyelinating disorders.4,15 Anti-MOG antibodies may bind to myelin, activate complement, and directly precipitate oligodendrocyte death.8 Alternatively, they may act more indirectly via antigen- D presenting-cell uptake leading to T-cell activation and cerebral inflammation.8 A third possibility is that anti-MOG antibodies are an epiphenomenon of a parallel TE neuroinflammatory process and are merely a convenient biomarker.4,8 Human pathology specimens from anti-MOG-positive patients demonstrate antibody and complement deposition, demyelination, and loss of MOG expression by oligodendrocytes,8,15 supporting at least some directly pathogenic role in anti-MOG- C EP associated disease. Outstanding questions about FLAMES are why gray matter rather than white matter is initially involved, and why neuroimaging findings are unilaterally restricted. As FLAMES becomes more widely recognized, our understanding of the unique risk factors, clinical C trajectory, radiographic profile, pathophysiology, and therapeutic options for this unusual A condition will be clarified. 11 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Appendix 1: Authors Name Yi Li, MD Designed and conceptualized study, participated in patient care, analyzed data, drafted and revised the manuscript Designed and conceptualized study, participated in patient care, analyzed data, drafted and revised the manuscript University of California San Francisco, California Designed and conceptualized study, participated in patient care, analyzed data, compiled imaging, drafted and revised the manuscript Designed and conceptualized study, participated in patient care, analyzed data, compiled EEG results, drafted and revised the manuscript EP Ernesto GonzalezGiraldo, MD University of California San Francisco, California University of California San Francisco, California University of California San Francisco, California D Clare Timbie, MD, PhD Contribution TE Jeffrey Russ, MD, PhD Location Data Availability: De-identified patient information from this case will be made available to other clinicians and researchers upon written request to the Corresponding Author. A C C Acknowledgements: The authors would like to thank Kendall Nash, MD; Sharon Wietstock, MD; Carla Francisco, MD; William Soulsby, MD; Susan Kim, MD, MMSc; Greta Peng, MD; and Manjiree Vikas Karandikar, MD for their assistance with clinical management of this patient. The authors would also like to thank Daniel Lachance from the Mayo Clinic for providing information on the anti-MOG-antibody assay. 12 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited A C C EP TE D Figure 1: The patient’s MRI and EEG findings at initial presentation. Patient’s initial MRI brain (A,B) at the onset of symptoms, demonstrating reduced diffusion in in the left supramarginal gyrus (A; arrow), as well as cortical edema in the left perirolandic cortex (B; arrowhead). Patient’s EEG (C,D), shown in a longitudinal bipolar montage, which demonstrates marked interhemispheric asymmetry with focal slowing maximal in the left posterior quadrant (C), and the onset of an electrographic seizure with emergence of rhythmic left posterior spikes with evolution in frequency and morphology 13 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited A C C EP TE D Figure 2: The patient’s repeat MRI findings. Patient’s subsequent MRI during her second admission, which demonstrates multiple foci of subcortical FLAIR hyperintensity with associated punctate and linear enhancement (arrowheads A-F), cortical thickening and FLAIR hyperintensity (arrow, B), and leptomeningeal enhancement (dashed arrow, C). Of note, the pontine lesion (F) surrounds a linear area of enhancement (E), which may reflect an engorged vessel. 14 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Table 1. Comprehensive summary of the serum, CSF, and urine studies obtained as part of the patient’s evaluation. AUTOIMMUNE/INFLAMMATORY METABOLIC INFECTIOUS Serum ESR 35 mm/hr Serum EBV PCR Negative <0.02 West Nile Virus IgG Negative ANA 1:320 West Nile Virus IgM Negative dsDNA <10 Quantiferon Negative Rheumatoid factor <40 Histoplasma SSA/SSB <5 C. Psittacosis anti-Smith 16.2 anti-RNP <10.0 CSF <10 HSV PCR ACE 46 VZV PCR Ribosomal antibody <1 Lysozyme 4.6 anti-TPO 1:200 TSI 101 Thyroglobulin <2 mcg/mL IU/mL umol/L Acylcarnitine profile WNL Enterovirus Negative Lactate 1.4 mmol/L EBV PCR Negative Pyruvate 1.7 mg/dL West Nile Virus IgM Negative West Nile Virus IgG Negative Beta-d-glucan Cryptococcal antigen <60 Negative Negative C Bacterial culture C 1:1000 48 ug/L Urine 498 mg/dL Histoplasma A WNL CSF Autoimmune Encephalopathy Panel Negative CSF Negative Negative Lymphocyte subsets 0.3 Negative anti-NMO/AQP4 6 WNL umol/L Negative Functional NK cells Amino acids 44.7 Fungal culture 970 mg/dL 58.2 Negative Soluable IL-2 mmol/L 1.1 Total carnitine Acyl/free carnitine ratio Negative Fibrinogen 1.3 Pyruvate Free carnitine Autoimmune encephalopathy panel Ferritin Lactate Negative Anti-phospholipid antibody panel anti-MOG umol/L Negative EP pANCA/cANCA 17 TE CRP Ammonia D Serum Urine pg/mL Organic acids WNL ENDOCRINE Serum TSH Negative 0.39 mIU/L Free T4 14 pmol/L T3 2.8 pg/mL LU30 NEOPLASTIC CSF Cytology Negative Table 1. A summary of the serum, CSF, and urine studies that were sent to evaluate for autoimmune/inflammatory, infectious, metabolic, endocrine, and neoplastic etiologies. Abnormal values are in bold font. WNL = within normal limits. 15 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited References: 1. Tufenkjian K and Lüders HO. Seizure Semiology: Its Value and Limitations in Localizing the Epileptogenic Zone. J Clin Neurol 2012; 8:243-250. Uccelli A and Gattorno M. D 2. 2018; 36 Suppl 110(1):61-67. 3. TE Neurological manifestations in autoinflammatory diseases. Clin Exp Rheumatol Waters PJ, et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology 2019; 4. C EP 92(11):e1250-1255. Budhram A, Mirian A, Le C, Hosseini-Moghaddam SM, Sharma M, and Nicolle MW. Unilateral cortical FLAIRhyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome. J Neurol 2019; 5. C 266:2481-2487. Hacohen Y and Banwell, B. A Treatment approaches for MOG-Ab-Associated demyelination in children. Curr Treat Options Neurol 2019; 21(1):2. 6. O’Connor KC, et al. Self- antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007; 13(2):211-217. 7. Armangue T, et al. Associations of paediatric demyelinating and encephalitic syndromes with myelin 16 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited oligodendrocyte glycoprotein antibodies: a multicenter observational study. Lancet Neurol 2020; 19(3):234-246. 8. Reindl M and Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev D Neurol 2019; 15(2):89-102. 9. Cobo-Calvo A, et al. MOG Neurol 2017; 264:1945-1955. 10. TE antibody-related disorders: common features and uncommon presentations. J Cobo-Calvo A, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the C EP MOGADOR study. Neurology 2018; 90:e1858-e1869. 11. Jarius S, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 2018; 15(1):134. 12. Hamid SHM, et al. Seizures C and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease. JAMA Neurol 2018; 75(1):65-71. A 13. Ogawa R, et al. MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy. Neurol Neuroimmunol Neuroinflamm 2017; 4(2):e322 14. Hennes EM, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 2017; 89(9):900-908. 17 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited 15. Höftberger R, et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol A C C EP TE D 2020; doi.org/10.1007/s00401-020-02132-y. 18 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited Clinical Reasoning: An 11-year-old girl with focal seizures, fevers, and unilateral, enhancing cortical lesions Jeffrey B. Russ, Clare M. Timbie, Yi Li, et al. Neurology published online August 14, 2020 DOI 10.1212/WNL.0000000000010655 This information is current as of August 14, 2020 Updated Information & Services including high resolution figures, can be found at: http://n.neurology.org/content/early/2020/08/14/WNL.0000000000010 655.citation.full Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/about/about_the_journal#permissions Reprints Information about ordering reprints can be found online: http://n.neurology.org/subscribers/advertise Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2020 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.