MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome.
Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients.



To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis.



Retrospective case study.



Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up).



Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
Sven
S
Jarius
Department of Neurology, Ruhr University Bochum, Bochum, Germany.
Ingo
I
Kleiter
Department of Neurology, Charité - University Medicine Berlin, Berlin, Germany.
Klemens
K
Ruprecht
Department of Neurology and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Nasrin
N
Asgari
Department of Neurology, Ruhr University Bochum, Bochum, Germany.
Kalliopi
K
Pitarokoili
Department of Neurology, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité University Medicine, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Nadja
N
Borisow
Department of Neurology, Hannover Medical School, Hannover, Germany.
Martin W
MW
Hümmert
Department of Neurology, Hannover Medical School, Hannover, Germany.
Corinna
C
Trebst
Department of Neurology, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité University Medicine, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Florence
F
Pache
Department of Neurology, University of Rostock, Rostock, Germany.
Alexander
A
Winkelmann
Department of Neurology, Albert Ludwigs University, Freiburg, Germany.
Lena-Alexandra
LA
Beume
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
Marius
M
Ringelstein
Department of Neurology, Albert Ludwigs University, Freiburg, Germany.
Oliver
O
Stich
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
Orhan
O
Aktas
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
Mirjam
M
Korporal-Kuhnke
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
Alexander
A
Schwarz
Department of Neuroradiology, Ruhr University Bochum, Bochum, Germany.
Carsten
C
Lukas
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
Jürgen
J
Haas
Institute of Experimental Immunology, affiliated to Euroimmun AG, Lübeck, Germany.
Kai
K
Fechner
Department of Neurology, Julius Maximilians University, Würzburg, Germany.
Mathias
M
Buttmann
Department of Neurology, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité University Medicine, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Judith
J
Bellmann-Strobl
Department of Neurology, Charité - University Medicine Berlin, Berlin, Germany.
Hanna
H
Zimmermann
Department of Neurology, Charité - University Medicine Berlin, Berlin, Germany.
Alexander U
AU
Brandt
IRCCS, C. Mondino National Neurological Institute, Pavia, Italy.
Diego
D
Franciotta
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Kathrin
K
Schanda
Department of Neurology, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité University Medicine, Berlin, Germany.|Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Friedemann
F
Paul
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Markus
M
Reindl
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Otto Meyerhof Center, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
Brigitte
B
Wildemann
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001812:Blood-Brain Barrier / Q000473:pathology; D001933:Brain Stem / Q000000981:diagnostic imaging / Q000503:physiopathology*; D015331:Cohort Studies; D004185:Disability Evaluation; D004660:Encephalitis / Q000097:blood / Q000000981:diagnostic imaging / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D016899:Interferon-beta / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D009187:Myelitis / Q000097:blood / Q000276:immunology / Q000473:pathology; D009471:Neuromyelitis Optica / Q000097:blood* / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000276:immunology; D000069283:Rituximab / Q000627:therapeutic use; D055815:Young Adult
D007074:Immunoglobulin G; D063308:Myelin-Oligodendrocyte Glycoprotein; D000069283:Rituximab; D016899:Interferon-beta
Aquaporin-4 antibodies (AQP4-IgG, NMO-IgG); Ataxia; Brainstem encephalitis; Cerebellitis; Diplopia Internuclear ophthalmoplegia (INO); Facial nerve palsy; Hearing loss; Intractable nausea and vomiting﻿; Longitudinally extensive transverse myelitis (LETM); MOG-IgG; Myelin oligodendrocyte glycoprotein (MOG) antibodies; Myelitis; Neuromyelitis optica spectrum disorders (NMOSD); Optic neuritis; Respiratory insufficiency; Rhombencephalitis