Square-Wave Ocular Oscillation and Ataxia in an Anti-GAD-Positive Individual With Hypothyroidism

Antiphospholipid antibody syndrome (APS) has been reported to cause elevated intracranial pressure, but usually this is due to cerebral venous sinus thrombosis (CVST). We present a 36-year old man with APS with elevated intracranial pressure with neuro-ophthalmic, renal and hematological involvement without identifiable CVST.

Clinical Observation Square-Wave Ocular Oscillation and Ataxia in an Anti-GAD-Positive Individual With Hypothyroidism Chrysoula Brokalaki, MD, Evangelia Kararizou, MD, Antonis Dimitrakopoulos, MD, Ioannis Evdokimidis, MD, Evangelos Anagnostou, MD Abstract: Cerebellar ataxia is an uncommon manifestation of hypothyroidism with unknown pathomechanism. The few descriptions of the clinical phenotype range from limb, gait, and trunk ataxia to various ocular motor abnormalities. We evaluated a 62-year-old woman with previously undetected severe hypothyroidism who presented with prominent saccadic intrusions and gait ataxia. She had high titers of antithyroid autoantibodies and anti-glutamic acid decarboxylase (anti-GAD) antibodies. Horizontal eye movement recordings revealed a series of nearly continuous pseudoharmonic square wave jerks (SWJs) constituting a square wave oscillation. Amplitudes reached maximum values of about 4, and wave frequency approached 100 cycles per minute. Thyroxine substitution and corticosteroid administration had little effect on SWJ parameters. The square wave oscillation nearly completely resolved after a single treatment session with intravenous immunoglobulin suggesting a causal link between an autoimmune process and the cerebellar dysfunction. Current concepts of the genesis of saccadic intrusions favor a role for anti-GAD antibodies in the etiology of SWJs. Journal of Neuro-Ophthalmology 2015;35:390-395 doi: 10.1097/WNO.0000000000000275 © 2015 by North American Neuro-Ophthalmology Society T he cardinal symptoms of hypothyroidism are fatigue, bradycardia, hoarseness, weight gain, and cold tolerance. Neurological symptoms also are common, including slowing of physical or mental activity, delayed relaxation phase of deep tendon reflexes, poor memory, somnolence, and rarely dementia or anxiety. Hypothyroidism is either rarely or not included at all as a possible cause of cerebellar ataxia (1,2). We report a 62-year-old woman who Department of Neurology, Eginition Hospital, University of Athens, Athens, Greece. The authors report no conflicts of interest. Address correspondence to Evangelos Anagnostou, MD, Department of Neurology, Eginition Hospital, University of Athens, Vas. Sophias Avenue 74, Athens 11528, Greece; E-mail: [e-mail] 390 developed marked gait unsteadiness and exhibited an uncommon pattern of saccadic intrusions termed square wave oscillation. She was found to have severe hypothyroidism, and further laboratory testing revealed an increased anti-GAD autoantibody titer, prompting us to initiate immunomodulatory treatment in addition to thyroxine replacement. The square wave oscillation along with the gait ataxia subsided only after immunoglobulin administration suggesting a pathophysiological link between anti-GAD antibodies and square wave oscillation and ataxia. CASE REPORT A 64-year-old woman, with a medical history of hypertension and hypercholesterolemia, was referred to our clinic for severe gait unsteadiness. Her symptoms began 6 months previously with mild balance difficulties and fatigue. She gradually became more unstable and developed oscillopsia, vertigo with nausea and vomiting, and a slightly detectable speech disturbance, which progressed to dysarthria and dysphagia. She had no history of alcohol abuse or family history of neurologic disease. On examination, the patient showed bradypsychia and mild sleepiness, but neuropsychological testing yielded intact cognitive functions. Her skin was dry and coarse, and she had suffered from hair loss. She instantly fell backwards and to the left when trying to stand or walk and was unable to sit without support. Her speech was slow and dysarthric. No muscle weakness or sensory disturbance was detected. Deep tendon reflexes were normal although they were more brisk in the lower limbs. Plantar responses were flexor. Heel-to-shin testing was dysmetric and mild dysdiadochokinesia was present. Examination of ocular motility revealed frequent square wave jerks (SWJs) and a left beating horizontal nystagmus on left gaze. Smooth pursuit was grossly normal although difficult to interpret due to superimposed SWJs. Saccades showed no abnormalities Brokalaki et al: J Neuro-Ophthalmol 2015; 35: 390-395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation apart from the impression of slight hypermetria at large angles. A fluctuating finding was a mild downbeat nystagmus, which was not always present on repeated examinations. Ataxia assessment using the Scale for the Assessment and Rating of Ataxia (SARA (3)) yielded a score of 19.5. The SARA has 8 items with total scores ranging from 0 (no ataxia) to 40 (most severe ataxia). Scores for the 8 items range as follows: no ataxia, 1: gait (0-8 points), 2: stance (0-6 points), 3: sitting (0-4 points), 4: speech disturbance (0-6 points), 5: finger chase (0-4 points), 6: nose-finger test (0-4 points), 7: fast alternating hand movement (0-4 points), 8: heel-shin slide (0-4 points). For motor activities of the four extremities (items 5-8), assessments were performed bilaterally and the mean values were used to obtain the total score. Hematologic tests showed elevated low-density lipoproteins of 229 mg/dL (normal: 60-130 mg/dL), glucose of 141 mg/dL (normal: 74-109 mg/dL), and an erythrocytic sedimentation rate of 40 mm/h. Additional tests revealed severe hypothyroidism with thyroid-stimulating hormone (TSH) of .150 mIU (normal: 0.3-5.6 mIU/mL) (TSH .150 mIU/mL) and practically undetectable levels of T3 and T4 with raised antithyroid antibodies (anti-TG, 389 IU/mL; anti-TPO, 1,875 IU/mL; normal range ,70 IU/mL). The cerebrospinal fluid (CSF) examination showed mild pleocytosis of 10 white blood cells (WBC) per cubic millimeter (normal ,8 WBC/mm3) elevated protein of 88 mg/dL (normal: 15-60 mg/dL), raised albumin of 63 mg/dL (normal: 35-52 mg/dL), and albumin index of 14.3 (normal ,10). Antibodies to glutamic acid decarboxylase (anti-GAD) were markedly elevated at 595,000 IU/mL (normal range ,10 IU/mL). Antinuclear and paraneoplastic antineuronal antibodies (Yo, Hu, Ri, Ma2/Ta, CV2, amphiphysin) were absent in the serum, and chest and abdominal computed tomography showed no underlying malignancy. Brain magnetic resonance imaging demonstrated only a few microischemic lesions in the subcortical white matter of the cerebral hemispheres. The cerebellum showed no evidence of atrophy, structural lesions, or volume loss. Autoimmune (Hashimoto) thyroiditis and anti-GAD antibody-related diabetes mellitus and cerebellar ataxia were diagnosed, and the patient received replacement therapy with L-thyroxine and immunotherapy with corticosteroids. The patient required insulin for diabetic control. Horizontal eye movements were recorded with an infrared corneal reflection device (IRIS, Skalar, Delft), with the patient seated in a dimly illuminated room with her head immobilized by a head-chin rest. Voltages were A/D converted at 500 Hz with a National Instruments external card with 14 bit resolution. Data were digitally low-pass filtered at 70 Hz and smoothed with a Savitzky-Golay filter. Targets consisted of an array of 3 LEDs (straight ahead, 15° to the left and 15° to the right) that were continuously present throughout the measurement. Baseline (pretreatment) measurements (Fig. 1 upper panel) demonstrated continuous SWJs with maximal amplitude of 4° appearing FIG. 1. Horizontal eye position record (right eye) while looking straight ahead, 15° to the right and 15° to the left. Upper panel: Recording before treatment, middle panel: 2 weeks after intravenous mehtylprednisolone treatment, lower panel: 2 weeks after intravenous immunoglobulin (IVIg) treatment. Each record consists of 3 fixation epochs: straight ahead, 15° left and 15° right. Insets depict characteristic traces from each epoch on an extended time scale (vertical range of inset box: 10°, horizontal range: 2,000 ms). Horizontal bars above or below insets indicate the segments that correspond to the insets. Pretreatment, continuous SWJs with maximal amplitude of w4° appear at a high frequency (w100/min) during straightahead fixation and on right gaze. On left fixation, gaze-evoked nystagmus emerges with an approximate frequency of 2 Hz and 3° maximal amplitude. After corticosteroid treatment, SWJs tend to occur more sparsely, but they remain in the same amplitude range. Notably, gaze-evoked nystagmus on left gaze is no more evident. After IVIg treatment, marked SWJ reduction appears on all 3 fixation angles. The frequency is now w45/min and the maximal amplitude is 1 degrees. SWJs, square ware jerks. Brokalaki et al: J Neuro-Ophthalmol 2015; 35: 390-395 391 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation at a high frequency (w100/min) during straight-ahead fixation and on right gaze. The range of intersaccadic interval duration was 260-350 ms. On left fixation, gaze-evoked nystagmus emerged with a frequency of 2 Hz and 3° maximal amplitude. Vertical SWJs were not visible. After a 5-day course of intravenous corticosteroids (1,000 mg methylprednisolone per day) and 1-month oral maintenance dose, SWJs occurred less frequently but were unchanged in amplitude (Fig. 1 middle panel). Gazeevoked nystagmus on left gaze was no longer present. This was accompanied by a moderate improvement on SARA (score = 14.5). One month later, corticosteroids were discontinued because of persistent symptoms of esophagitis. Two months after that, the patient was euthyroid but without a clear improvement in her cerebellar syndrome. Although eye movement recordings were not obtained, the clinical impression was that of worsening of SWJ frequency. Immunomodulatory therapy with intravenous immunoglobulin (IVIg) was begun (0.4 g$kg21$d21 for 5 days), and one month later, there was marked SWJ reduction on all 3 fixation angles (Fig. 1 lower panel). In addition, a marked score reduction in SARA (score = 8) reflected a dramatic improvement in stance and gait. Oscillopsia had virtually disappeared, and anti-GAD titers had decreased to 115,000 IU/mL. DISCUSSION Ocular motor abnormalities, such as downbeat nystagmus and periodic alternating nystagmus (4), ocular flutter (5), and opsoclonus (6) have been reported in anti-GAD-positive patients without thyroid dysfunction. Reports of thyroid ataxia (7-18) primarily focus on appendicular cerebellar symptoms and gait and trunk ataxia, whereas ocular motility abnormalities rarely have been described. The first article published in an English-based medical journal reported a 54-year-old hypothyroid woman with a prominent gait ataxia who "had a fine nystagmus to the left" (7). These publications fail to provide an explanation as to why patients with hypothyroidism present with cerebellar findings. Anti-GAD antibody titers have been measured infrequently in patients with thyroid ataxia. In the first description of cases with autoimmune thyroiditis and elevated anti-GAD titers, information on ocular motor function was not provided (19). Subsequently, a few publications linked autoimmune thyroiditis, anti-GAD antibodies, and cerebellar symptoms (12,14,17,20). For example, in patients with hypothyroidism, Selim and Drachman (12) documented gaze-evoked nystagmus and downbeat nystagmus and Fernandez et al (17) described gaze-evoked nystagmus. SWJs have been described in various neurological conditions involving the cerebellum. These include Friedreich ataxia (21-23), X-linked ataxia (24), spinocerebellar ataxia 3 (25), spinocerebellar ataxia 6 (26), and oculomotor 392 apraxia type 2 (27). Frequent SWJs also have been noted in structural cerebellar disorders such as in Arnold-Chiari malformation (28), Langerhans cell histiocytosis (29), and multiple sclerosis (30). Extremely large numbers of SWJs may exhibit the periodicity of a pseudoharmonic oscillation as seen in our patient. Such continuous saccadic intrusions have been termed "square wave oscillation" (31). The genesis of SWJs is still uncertain. One model proposed by Otero-Millan et al (32) assumes a disturbance in the brainstem ocular motor network comprising the excitatory (EBN) and inhibitory (IBN) burst neurons, the omnipause neurons (OPNs) and their connections with the superior colliculus (SC). Central to this model is the concept of enhanced random fluctuations of neural activity within the SC that leads to increased input to burst neurons and decreased input to OPNs. When the inhibition exerted by the IBNs on the OPNs overcomes the inhibition of the OPNs on the IBNs, a short burst of activity emerges in the EBNs released a small saccade. This, in turn, produces a small retinal error that is detected in the SC network resulting in a second saccade in the opposite direction, completing the SWJ. Given the fact that the SC receives input from the basal ganglia, this model provides an elegant explanation for the increased SWJ and microsaccade occurrence in Parkinsonian syndromes (33). However, the frequent occurrence of SWJs in pure cerebellar syndromes without Parkinsonian features is not fully explained by this model. The main link between the vestibulocerebellum and the brainstem structures of the above model is the ocular motor region of the fastigial nucleus. The largest fastigial output, as judged by synaptic terminal density (34) and neural responses to electrical stimulation (35), is to contralateral IBNs. Modifying IBN discharge could change the saccade size. The IBNs on one side of the brain discharge vigorously for ipsiversive saccades. This is the neurons' on-direction. IBNs discharge minimally or not at all for contraversive saccades (the off-direction). The axons of EBNs cross the midline to terminate on and inhibit contralateral EBNs and ocular motor neurons (36,37). It has been demonstrated, both histologically and electrophysiologically, that the main cerebellar targets of anti-GAD antibodies are the presynaptic terminals of GABAergic interneurons (basket cells) (38,39). These antibodies selectively suppress the GABA-mediated transmission from basket cells to Purkinje cells, which ultimately results in a disinhibition of EBNs and motoneurons (Fig. 2). This may be a candidate mechanism for generation of SWJs in anti-GAD-related cerebellar dynfunction. The dramatic improvement of the saccadic intrusions after IVIg in our patient is consistent with an autoimmune basis, although involvement of other, as yet unidentified, autoantibodies cannot be excluded. The early description of patients with hypothyroid ataxia who responded to treatment with thyroid replacement (7,9) suggests that cerebellar malfunction also can be caused by hormone deficiency. It is not known, Brokalaki et al: J Neuro-Ophthalmol 2015; 35: 390-395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 2. Cerebellar-brainstem connectivity that could explain saccadic intrusions in anti-GAD-mediated cerebellar damage. Under physiological conditions, basket cells (BC) inhibit Purkinje neurons (PC) in the cerebellar vermis, which in turn send inhibitory axons to the fastigial nucleus. Fastigial neurons (FN) cross the midline and enter the brainstem reticular formation where they form excitatory synapses with the inhibitory burst neurons (IBN). IBN axons cross back over the midline and inhibit excitatory burst neurons (EBN) and ocular motoneurons (MN) of the abducens nucleus. Anti-GAD antibodies disrupt selectively the GABAergic inhibitory transmission at the basket-to-Purkinje cell synapse, which ultimately results in a disinhibition of EBNs and MNs. Superior colliculus and omnipause neurons were omitted for simplicity. however, whether these cases also exhibited abnormal fixational eye movements. The difference between sporadic SWJs and square wave oscillation remains unclear. Abel et al (31) favor a "SWJcontinuum" hypothesis, according to which the same mechanism accounts for both SWJs and square wave oscillation with the oscillation representing a more pronounced functional deficit. Our findings are compatible with this hypothesis given the fact that the pretreatment eye movement recordings reflect strong presynaptic Purkinje-cell disinhibition (very high anti-GAD antibody titer) causing square wave oscillation. The eye movement disorder transformed into sporadic SWJs as the anti-GAD antibody levels fell during immunomodulatory treatment. Some of our patient's findings such as dysarthria and nausea could have been caused by brainstem dysfunction. In that case, SWJ occurrence could be sufficiently explained by the model of Otero-Millan et al (32). Nevertheless, we favor the cerebellar over the brainstem hypothesis for 2 reasons. First, most of the clinical abnormalities in our patient can be the result of cerebellar dysfunction without the need of hypothesizing additional brainstem involvement. Second, there is no known anti-GAD epitope in the brainstem. The CSF finding of elevated protein and mild pleocytosis deserves comment. Increased protein is a known feature of hypothyroid cerebellar syndrome and has been attributed to myxedematous increase of capillary permeability (9). Case Brokalaki et al: J Neuro-Ophthalmol 2015; 35: 390-395 reports of anti-GAD ataxia (with normal or nonreported thyroid function) usually are associated with normal CSF composition, but there are also instances of inflammatory CSF findings with elevated protein and/or lymphocyte counts (17,40,41). Patients with ataxia and autoimmune thyroiditis should be tested for elevated anti-GAD antibody titers. Immunomodulatory treatment, such as IVIg, should be started promptly in addition to hormone replacement to control symptoms that arise from the action of anti-GAD antibodies on the cerebellar cortex. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. Brokalaki, E. Kararizou, A. Dimitrakopoulos, I. Evdokimidis, and E. Anagnostou; b. Acquisition of data: C. Brokalaki and E. Anagnostou; c. Analysis and interpretation of data: C. Brokalaki and E. Anagnostou. Category 2: a. Drafting of manuscript: C. Brokalaki and E. Anagnostou; b. Revising it for intellectual content: C. Brokalaki, E. Kararizou, A. Dimitrakopoulos, I. Evdokimidis, and E. Anagnostou. Category 3: a. Final approval of the completed manuscript: C. Brokalaki, E. Kararizou, A. Dimitrakopoulos, I. Evdokimidis, and E. Anagnostou. ACKNOWLEDGMENTS The authors would like to thank E. 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