Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders

Abstract

Antibodies directed against glutamic acid decarboxylase (GAD) have been described in patients with progressive cerebellar ataxia [1] and in a few patients affected by primarily oculomotor disorders [2]. The abnormal eye movements described with anti-GAD antibodies, so far, range from nystagmus (up/down-beat, periodic alternating nystagmus) [2, 3] to opsoclonus [4], but ocular flutter has never been reported. A 69-year-old woman was admitted to our hospital for a 10-month progressive oscillopsia, blurred vision and gait imbalance with significant impairment of daily activities (such as reading a book, watching television and leaving home alone). Neurological examination showed ocular flutter, characterized by intermittent bursts of horizontal conjugate saccades without an intersaccadic interval. The eye oscillations were independent of eye position and occurred during fixation (voluntary and guided changes in gaze position), regardless of gaze direction, with eyes open or closed. The patient had full range of eye motion and did not report diplopia. Unsteadiness with severe retropropulsion was also evident. The remaining neurologic examination was normal. Analysis of ocular movements using video-oculography revealed bursts of rapid horizontal, symmetric movements without intersaccadic interval (Fig. 1a). Results of electrophysiological examinations, such as somatosensory and visual evoked potentials, nerve conduction study and electroencephalography, were normal. Routine blood cell counts and biochemistry were normal. Serological tests, cultures, and polymerase chain reactions performed on blood and cerebrospinal fluid (CSF) samples were negative for viral, bacterial, and fungal infections. Brain magnetic resonance imaging showed no abnormality. Results of screening examinations for neoplasms, including abdominal ultrasonography, computed tomography of the abdomen and chest, as well as whole-body positron emission tomography, were all unremarkable. CSF examination revealed normal protein concentration and no cells, isoelectric focusing showed two oligoclonal bands and the immunoglobulin G index was within the normal range. The patient tested negative for anti-gliadin, paraneoplastic antibodies (anti-Ri, anti-Hu, anti-Yo, antiMa2, anti-CV2 and anti-amphiphysin), anti-LGI1, antiCaspr2, antiganglioside Q1b and anti-NMDA receptor in the serum and CSF. Antibodies against GAD65 were measured by radioimmunoassay. GAD65 antibody titre was increased in serum (2,378 IU/mL, normal value \1 IU/mL) and in CSF (55.7 IU/mL, normal value \1 IU/mL), with an intrathecal synthesis index of 10.64 (normal range 0.7–1.3). An intravenous immunoglobulin (IVIg) treatment (400 mg/kg/day for 5 days) in six cycles once a month was started. The symptoms gradually resolved and continued to improve after the last administration of IVIg and at the same time serum GAD65 antibody titre decreased significantly (Fig. 1c). To avoid clinical relapses, azathioprine 200 mg orally daily was added to the last cycle of IVIg (Fig. 1c). R. Dubbioso F. Manganelli R. Iodice M. Esposito L. Santoro (&) Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples ‘‘Federico II’’, Via Sergio Pansini, 5, 80131 Naples, Italy e-mail: lusantor@unina.it