MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome

Abstract

Background: 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.

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

Methods: Retrospective case study.

Results: 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).

Conclusions: 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.

Keywords: 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.

Fig. 1

Examples of the magnetic resonance imaging (MRI) findings in patients with MOG-IgG-positive brainstem encephalitis. a-c Patient 12: T2-hyperintense lesions extending from the pontomedullary junction throughout the cervical cord as far as C5; lesions included the dorsal medulla oblongata (B, arrow). d-h Patient 8: T2-hyperintense lesions in the pons, midbrain, thalamus, and basal ganglia; lesions involved the periependymal surfaces of the third ventricle. j-k Patient 4: T2-hyperintense lesions in the right (j) and left (k) half of the dorsal medulla oblongata including the area postrema (j). l-n Patient 2: T2-hyperintense lesions in the frontal and parietal subcortical white matter, the pontine tegmentum, and the cerebellar peduncles (arrows)

Fig. 2

Serial MRI examination of patient 1. a Sagittal T2 weighted baseline MRI showing no involvement of the brainstem or of the spinal cord. b-e Follow-up MRI 5 month later revealed a new spinal cord lesion extending over 4 vertebral segments with cord swelling on T2-weighted imaging as well as new lesion formation in the pons and medulla oblongata with gadolinium enhancement on T1-weighted imaging. Within the following 5 months clinical symptoms deteriorated further with infratentorial T2 lesion enlargement and new lesion formation in the pons, e.g. adjacent to the middle cerebellar peduncle, accompanied by gadolinium enhancement (f)