Alternating Skew Deviation in Association with Anti-Glutamic Acid Decarboxylase Antibodies

ABSTRACT

The presence of an elevated anti-glutamic acid decarboxylase (GAD) antibody level has been associated with a number of eye movement abnormalities as well as other findings, including cerebellar ataxia and insulin-dependent diabetes mellitus. Skew deviation in association with anti-GAD antibodies has not been previously reported. Here the authors report a case of alternating skew deviation along with cerebellar-brainstem signs in a patient with an elevated anti-GAD antibody titre. Follow-up neurologic evaluation after treatment with intravenous immunoglobulin revealed improvement in cerebellar-brainstem signs, whereas ophthalmic evaluation was stable.

CASE HISTORY

A 58-year-old African American female was referred to the Neuro-ophthalmology Service for worsening diplopia. Eleven months earlier, the patient first began to notice vertical binocular diplopia only on extreme left gaze. An evaluation at that time noted a small left hypertropia in left gaze only. Three months prior to evaluation, she began to have vertical diplopia on right gaze along with slight worsening of vertical diplopia on left gaze. Review of systems was remarkable for gait and balance disturbance that preceded the diplopia.

Past medical history included right orbital trauma, for which she had undergone surgical repair 36 years prior and which was not associated with diplopia. She had had surgical repair of a left medial meniscal tear shortly prior to the onset of gait difficulties. B₁₂ deficiency had been diagnosed on work up for gait disturbance and she had no improvement in her gait after oral or intravenous supplementation with normalisation of serum levels prior to onset of diplopia.

Prior neurologic examination was significant for a wide-based unsteady gait with truncal titubations and mild left dysmetria on finger-to-nose test. Sensation was intact to all modalities, including distal vibratory senses, and knee and ankle reflexes were normal.

On examination, she had visual acuities of 20/20 OU with mild myopic astigmatic correction. Pupils were symmetric and equally reactive to light without a relative afferent pupillary defect. Ishihara colour plates were full in both eyes and intraocular pressures were normal. Versions and ductions were full. Maddox rod testing revealed a 2 prism dioptre (PD) left hyperdeviation in primary gaze, 3 PD right hyperdeviation in right gaze, and 5 PD left hyperdeviation in left gaze. There was a concomitant 6–8 PD exodeviation. Anterior and posterior segment examinations were unremarkable.

Prior blood tests, including folate levels and thyroid function, were normal, and her B₁₂ level was 538 pg/mL prior to the onset of her visual symptoms. Further work-up for continued gait instability included a lumbar puncture that revealed 6 white blood cells/µL, with a lymphocytic predominance, normal protein, elevated glucose, and positivity for oligoclonal bands. Magnetic resonance imaging (MRI) of the brain with and without contrast 13 months prior to evaluation showed non-specific non-enhancing subcortical white matter lesions (Figure 1). Repeat brain MRI 2 and 4 months prior to evaluation were unchanged. MRI of the cervical spine showed degenerative disc disease without spinal stenosis or cord lesions. Electroencephalography was normal. Other laboratory tests, including angiotensin-converting enzyme (ACE), serum copper, and acetylcholine receptor binding and modulating antibodies, were normal.

FIGURE 1.

Axial T2 FLAIR MRI images from the patient demonstrating a lack of brainstem lesions (left) and presence of scattered subcortical white matter lesions (right).

Paraneoplastic evaluation demonstrated elevation of serum anti-glutamic acid decarboxylase (GAD) 65 antibodies: 1755 nmol/L (reference range <0.02 nmol/L). The remainder of the paraneoplastic panel, including collapsin response mediator protein-5 (CRMP-5) immunoglobulin G (IgG), was negative. Imaging of the chest and abdomen showed a small left adrenal adenoma. She received intravenous steroids 2 months prior to our evaluation, with improvement in her gait instability and subjective improvement in diplopia. She is now being managed with intravenous immunoglobulin (IVIG). Follow-up ophthalmologic examination was stable. Follow-up neurologic examinations showed improvements in her truncal ataxia and left-sided finger-to-nose dysmetria following each IVIG administration.

DISCUSSION

We contribute a report of alternating hypertropia consistent with an alternating skew deviation and gait instability associated with anti-GAD antibodies. The presence of an alternating skew deviation localises to the cerebellum or cerebellum-brainstem, and the presence of anti-GAD antibodies has been strongly associated with cerebellar-brainstem features in the literature.1 Although other ocular movement disorders have been reported in association with anti-GAD, this is the first report to our knowledge of an alternating skew deviation in the presence of this antibody. We feel that it is unlikely that a remote history of orbital trauma would present with diplopia decades later with progression to an alternating skew deviation. It is possible that the knee surgery may have contributed to her gait instability, although it is unlikely that this would be steroid responsive. B₁₂ deficiency may have contributed to her symptoms, although her sensory examination was normal, there was no radiographic evidence of myelopathy, and there was no improvement in her gait after her B₁₂ levels were replenished. Demyelinating disease can also cause skew deviation; however, the subcortical white matter lesions in the frontal lobe were not in a pattern consistent with multiple sclerosis and there were no white matter lesions in the cerebellum or brainstem. Additionally, repeat MRI of the brain was unchanged in the setting of progressive symptoms.

GAD is an enzyme that catalyses the rate-limiting step in γ-aminobutyric acid (GABA) synthesis. The presence of anti-GAD antibodies has classically been described in association with stiff person syndrome (SPS). This is a rare disorder of the central nervous system characterised by progressive muscular rigidity and spasms. Although most patients with SPS have anti-GAD antibodies, the pathogenesis of SPS is not well understood; it follows that the presence of these antibodies is not included in the diagnostic criteria. There is also an association between insulin-dependent diabetes mellitus (IDDM) and SPS. Our patient had non-insulin-dependent diabetes mellitus (NIDDM) and did not meet diagnostic criteria for SPS at the time of presentation. Despite in vitro and in vivo investigations, the pathogenic mechanism of anti-GAD antibodies has not yet been clearly demonstrated.2

A number of other findings have been reported in association with anti-GAD antibodies.3–10 Saiz et al. reported a series of 47 patients with anti-GAD antibodies and described several associations, including cerebellar ataxia, autoimmune endocrinopathies (including IDDM), myasthenia gravis, and epilepsy. In addition, one patient was found to have a downbeat nystagmus, two patients had idiopathic limbic encephalitis, and four patients had paraneoplastic neurologic syndromes.3 Cerebrospinal fluid pleocytosis, similar to that seen in our patient, was also seen in some patients. Rakocevic et al. reported a subset of patients with SPS (5 of 38) who had concomitant cerebellar findings and oculomotor dysfunction consisting of nystagmus and hypometric saccades.4 The authors felt that this subset had a more severe clinical course primarily due to disabling cerebellar ataxia. Three of these patients developed IDDM, one of whom also developed gastroparesis and pernicious anaemia. Our patient may also have had pernicious anaemia given her B₁₂ deficiency poorly responsive to oral supplementation. Dalakas described patients with SPS and anti-GAD antibodies, some of whom also had cerebellar ataxia.5 Honnorat et al. reported a series of patients with cerebellar ataxia and anti-GAD in the absence of SPS.6 Thirteen of 14 patients were women, 11 developed IDDM, and 10 had cerebrospinal fluid pleocytosis, similar to our patient.

Although eye movement abnormalities have been reported in association with anti-GAD antibodies, to our knowledge there have been no reported cases of alternating skew deviation. The series reported by Rakocevic et al. described patients with slow, hypometric saccades along with lateral gaze-evoked nystagmus.4 Tilikete et al. described two cases of subacute cerebellar ataxia with anti-GAD. One patient had a periodic alternating nystagmus, whereas the other had a downbeat nystagmus with slow vertical saccades.11^,12 Opsoclonus-myoclonus-ataxia and ocular flutter have also been reported in association with anti-GAD.13–16

Cases of alternating skew deviation were reviewed by Moster et al.1 They found that most patients had a concomitant downbeat nystagmus and ataxia, and a majority was also found to have a cerebellar or cervicomedullary junction lesion. Our patient had three brain MRI scans, which did not reveal a mass lesion in this area.

The findings in our patient of alternating skew deviation, gait instability, and anti-GAD antibodies have not been previously reported together. We feel that these findings, due to their time course, progressive nature, and common anatomic localisation to the cerebellum-brainstem and the improvement in neurologic signs with immunosuppressive therapy, suggest an association. It is therefore our conclusion that our patient’s alternating skew deviation can most likely be attributed to cerebellar-brainstem findings associated with anti-GAD antibodies. Our hope is that this case allows for consideration of anti-GAD antibody testing in other patients with findings similar to what we have discussed here.

Acknowledgment

This work was supported by the National Institutes of Health (K12EY021475 and K23 EY 024345 (H.M.) and an unrestricted grant to the Department of Ophthalmology and Visual Sciences at the University of Illinois from Research to Prevent Blindness Inc. (A.F., K.S., H.M.).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.