Elsevier

Journal of Neuroimmunology

Volume 317, 15 April 2018, Pages 5-7
Journal of Neuroimmunology

Short Communication
Vertical nystagmus associated with glutamic acid decarboxylase antibodies responding to cyclophosphamide

https://doi.org/10.1016/j.jneuroim.2018.01.013Get rights and content

Highlights

  • Several neurological disorders may present in patients with GAD-antibodies.

  • Nystagmus and oculomotor dysfunction are under recognized in patients with GAD-antibodies.

  • These ocular abnormalities may be related to central GABAergic dysfunction.

  • Cyclophosphamide is a suitable therapy for nystagmus associated with GAD-antibodies.

Abstract

Several neurological disorders have been described in patients with autoimmunity associated with GAD antibodies. Among these disorders, nystagmus and oculomotor dysfunction are increasingly recognized, although they have been rarely reported isolated or as the main manifestation of anti-GAD autoimmunity. Moreover, therapeutic approaches for such patients are unclear. Here we present a 44-year-old man with disabling oscillopsia secondary to downbeat nystagmus, abnormal saccades, ocular pursuit and optokinetic nystagmus, as well as mild gait ataxia and cerebellar atrophy associated with high serum GAD antibodies with intrathecal secretion of such antibodies. The patient did not have clinical benefit with plasma exchange, but had a robust symptomatic improvement with cyclophosphamide. We discuss the possible pathogenic role of GAD antibodies in nystagmus and the role of immunotherapy in these patients.

Introduction

A number of neurological disorders have been described in patients with autoimmunity related to antibodies directed against the 65 kDa isoform of the enzyme glutamic acid decarboxylase (GAD), the rate-limiting step for the production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Although stiff-person syndrome (SPS) and cerebellar ataxia are the most commonly recognized and studied of these syndromes (Baizabal-Carvallo and Alonso-Juarez, 2017), other neurological manifestations are increasingly recognized. Here we report a patient with vertical nystagmus and oculomotor dysfunction as the main presentation of GAD-related autoimmunity. The patient provided written informed authorization for video and photograph presentation in a scientific journal.

A 44-year-old, right handed, Hispanic male, presented with a 3-month history of disabling oscillopsia, not allowing him to work as a mechanic. The clinical examination showed third degree vertical downbeat nystagmus (Video 1) that increased with lateral gaze. The patient did not have other complains, but there was also mild gait ataxia demonstrated only with tandem gait, but there were no other signs suggestive of cerebellar dysfunction, such as dysmetria, dysdiadochokinesia, or Holmes´ sign. The patient had no symptoms related to his gait ataxia. Visual acuity was 20/40 in both eyes, and other cranial nerves were not clinically affected. There was no evidence of increased rigidity, muscle spasms, spasticity, limb paresis, Babinski sign or abnormal reflexes; and sensation was preserved. No history of epileptic seizures was recorded. The patient has a 20-year history of type 1 diabetes mellitus (DM1), systemic hypertension and a 7-year history of vitiligo (Fig. 1A).

The MRI did not show abnormal hyperintensities in the brainstem or cerebellum, but there was mild cerebellar atrophy (Fig. 1B). Videonystagmography confirmed the presence of spontaneous vertical nystagmus with central fixation, with 5 different vertical ocular positions and with Dix-Hallpike maneuver (Fig. 1C); there were also hypermetric saccades (Fig. 1D) but saccades had normal latency, velocity and accuracy, ocular pursuit was ataxic, optokinetic nystagmus was also ataxic, caloric testing did not show unilateral vestibular pathology. These findings were consistent with nystagmus of central origin. Serum GAD antibodies were assessed by ELISA and showed levels 50 times higher than the reference value: 250 U/ml (negative: <5 U/ml); levels in patients with DM1 are usually < 100 U/ml. CSF showed mildly increased proteins: 83.6 mg/dl (normal range: 12–60 mg/dl), positive oligoclonal bands and GAD antibodies of 6 U/ml, anti-GAD specific index of 1.2 suggesting intrathecal secretion of such antibodies (Baizabal-Carvallo and Alonso-Juarez, 2017); glucose and leucocytes were normal in the CSF. An antibody panel for paraneoplastic disorders (anti-Hu, anti-Ri, anti-Yo antibodies), HIV serology, VDRL, hepatitis virus B and C serology were all negative.

The patient declined treatment with steroids due to risk of uncontrolled hyperglycemia. His initial treatment consisted in five rounds of plasmapheresis (1 plasma volume per exchange), from which mild symptomatic improvement in the oscillopsia was perceived by the patient, but without any improvement in his vertical nystagmus and gait ataxia. Serum GAD antibodies decreased to 176 U/L. This was followed with treatment with monthly IV pulses of cyclophosphamide 700 mg/m2, from which there was remarkable symptomatic improvement in his oscillopsia with improvement in his vertical nystagmus that permitted him to return to work, following a single pulse of cyclophosphamide (Video 2); no improvement was noted in his mild gait ataxia. The patient has received three pulses of cyclophosphamide with sustained benefit and no side effects.

Section snippets

Discussion

Nystagmus and oculomotor dysfunction are under recognized presentations in patients with autoimmunity related to GAD antibodies, these abnormalities may present in patients with SPS and cerebellar syndrome (Table 1); however, there are few reports of these syndromes presenting isolated or as the patient's main complain (Baizabal-Carvallo and Alonso-Juarez, 2017; Antonini et al., 2003).

Downbeat nystagmus is a form of central nystagmus that has been attributed to dysfunction of GABAergic

Acknowledgment

None.

References (14)

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  • The neurological syndromes associated with glutamic acid decarboxylase antibodies

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    Downbeat nystagmus is perhaps the most frequent eye-movement abnormality in patients with GAD-Abs; it has been reported more frequently in patients with CA or with overlapping syndromes (i.e. SPS + CA) [84–87]. Downbeat nystagmus may result from a functional denervation of vestibular nuclei with increased drive to motor neurons of elevator muscles resulting in an upward slow phase followed by a quick compensatory downward phase [85,88,89]. Other forms of central nystagmus [90], fixed or alternating ocular misalignment can be observed in these patients [91,92].

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