Frequency, characteristics, and immunological accompaniments of ataxia in anti-NMDAR antibody-associated encephalitis

Abstract

Introduction: Very rarely, adult NMDAR antibody-associated encephalitis (NMDAR-E) leads to persistent cerebellar atrophy and ataxia. Transient cerebellar ataxia is common in pediatric NMDAR-E. Immune-mediated cerebellar ataxia may be associated with myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP-4), kelch-like family member 11 (KLHL11), and glutamate kainate receptor subunit 2 (GluK2) antibodies, all of which may co-occur in NMDAR-E. Here, we aimed to investigate the frequency, long-term outcome, and immunological concomitants of ataxia in NMDAR-E.

Methods: In this observational study, patients with definite NMDAR-E with a follow-up of >12 months were recruited from the GENERATE registry. Cases with documented ataxia were analyzed in detail.

Results: In 12 of 62 patients (19%), ataxia was documented. Bilateral cerebellar ataxia without additional focal CNS findings was found in four (one child and three adults); one of these was previously reported as a case with persistent cerebellar atrophy and ataxia. Two patients with bilateral cerebellar ataxia had additional focal neurological symptoms, optic neuritis and facial palsy. Two patients developed hemiataxia: one with diplopia suggesting brainstem dysfunction and the other probably resulting from cerebellar diaschisis due to contralateral status epilepticus. In all but the one developing cerebellar atrophy, cerebellar ataxia was transient and not associated with a worse long-term outcome. In all five patients with cerebellar ataxia tested, MOG, AQP-4, GluK2, and KLHL11 antibodies were negative. In two additional patients negative for both MOG and AQP-4 antibodies, ataxia was sensory and explained by cervical myelitis as part of multiple sclerosis (MS) manifesting temporal relation to NMDAR-E. One of the patients with bilateral ataxia with focal neurological deficits was also diagnosed with MS upon follow-up. Finally, in two patients, ataxia was explained by cerebral hypoxic damage following circulatory failure during an ICU stay with severe NMDAR-E.

Discussion: Ataxia of different types is quite common in NMDAR-E. Cerebellar ataxia in NMDAR-E is mostly transient. NMDAR-E followed by persistent ataxia and cerebellar atrophy is very rare. Cerebellar ataxia in NMDAR-E may not be explained by concomitant KLHL11, MOG, AQP-4, or GluK2 autoimmunity. Of note, ataxia in NMDAR-E may result from treatment complications and, most interestingly, from MS manifesting in temporal association with NMDAR-E.

Keywords: MOG antibody; NMDAR-encephalitis; aquaporin-4 antibody; ataxia; cerebellum; multiple sclerosis; outcome.

Figure 1

Study recruitment. AE, autoimmune encephalitis; ab, antibody; CSF, cerebrospinal fluid; NMDAR-E, N-methyl D-aspartate receptor antibody-associated encephalitis.

Figure 2

MRI changes in NMDAR-E patients with cerebellar ataxia are rare. (A) Sagittal 1-weighted MRI of Case 4 at onset (left panel) and after recovery from severe NMDAR- E but with persisting bilateral cerebellar ataxia (month 76; arrows indicate cerebellar atrophy). (B) FLAIR images of Case 8 with reversible left-sided hemiataxia in the acute phase (onset, left panels) show diffuse, mostly cortical left cerebellar T2-hyperintensity (upper left panel, arrowhead) possibly resulting from cerebellar diaschisis following right frontal status epilepticus associated with right frontal cortical hyperintensities (lower panel, arrowhead). T2-hyperintensities were reversible (Month 26, right panels.

Figure 3

MRI in patients NMDAR-E with ataxia and concomitant or later diagnosis of multiple sclerosis. (A) Initial FLAIR cerebral MRI of Case 9 show juxtacortical (left panel, arrowhead) as well as periventricular lesions (middle panel, arrowhead) suggestive of demyelination. T2-weighted MRI of the cervical spinal cord also shows multiple demyelinating lesion (arrowhead). (B) Cerebral FLAIR MRI of Case 10 shows extensive periventricular T2-hyperintense lesions with Dawson finger-like orientation, highly suggestive of MS-like demyelination (left panel, arrowhead) as well as infratentorial lesions (right, arrowhead). (C) Initial cerebral FLAIR MRI of Case 6 (left panels) shows small unspecific subcortical white matter lesions but one periventricular lesion (arrowhead). Upon follow-up (Month 64, right panels) a juxtacortical T2-hyperintense lesion (upper right panel, lower arrowhead) as well as a new periventricular lesion (lower right panel, right arrowhead) in addition to multiple subcortical lesions (other arrowhead), some with radial orientation (lower right panel, left two arrowheads).

Figure 4

Symptomatic non-cerebellar and cerebellar ataxia due to ischemic hypoxic lesion acquired during circulatory failures in severe NMDAR-E. (A) Cerebral FLAIR MRI of Case 11 at onset did not show any cerebellar abnormalities (upper panels). After resuscitated 6 months after disease onset (lower panel, Month 6), repeat cerebral MRI showed bilateral subacute cerebellar infarctions (lower panels, arrowheads). (B) Bilateral hemodynamic ischemic lesions in the parietooccipital region (arrowheads) with hemorrhagic transformation (left upper panel: coronal FLAIR, right upper panel: transverse T1-weighted image, left lower panel: transversal T2-weighted image, right lower panel: Transverse susceptibility-weighted images (white arrows) in Case 12 after cardiopulmonary arrest and successful cardiopulmonary resuscitation.