Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti-Glutamic Acid Decarboxylase Antibodies

An immune attack by anti-glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid-mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission.

Original Contribution Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti-Glutamic Acid Decarboxylase Antibodies Ana I. Martins, MD, João N. Carvalho, MD, Ana M. Amorim, MD, Argemiro Geraldo, MD, Eric Eggenberger, DO, MSEpi, João Lemos, MD Abstract: An immune attack by anti-glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid-mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission. Journal of Neuro-Ophthalmology 2018;38:32-35 doi: 10.1097/WNO.0000000000000547 © 2017 by North American Neuro-Ophthalmology Society Departments of Neurology (AIM, JNC, AG, JL) and Otorhinolaryngology (AMA), Coimbra University Hospital Centre, Coimbra, Portugal; and Department of Neurology and Ophthalmology (EE), Michigan State University, East Lansing, Michigan. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). A. I. Martins and J. Lemos contributed equally to this article. Address correspondence to João Lemos, MD, Department of Neurology, Coimbra University Hospital Centre, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal; E-mail: [e-mail] 32 T he presence of anti-glutamic acid decarboxylase (GAD) antibodies (Ab) has been associated with several types of spontaneous nystagmus, including downbeat (DBN) (1), upbeat (UBN) (2), and periodic alternating nystagmus (PAN) (3). Most of these are believed to be caused by an anti-GAD Ab-mediated autoimmune attack on the cerebellum and/or brainstem, causing a selective deficiency in gamma-aminobutyric acid (GABA) neurotransmission (4). Particularly in the cerebellum, flocculus/paraflocculus dysfunction has been associated with DBN, whereas nodulus/uvula dysfunction seems to account for the presence of PAN. The loss of cerebellar inhibitory output over the central vestibular pathways carrying anterior semicircular canal (SCC) signals and over the central velocitystorage mechanism seems to promote DBN and PAN, respectively (1,3-6). To the best of our knowledge, central paroxysmal positioning nystagmus (CPPN) and vertigo have not been reported in anti-GAD Ab-associated neurological disorders. CPPN is triggered by changes in head position and has been associated with focal lesions in the posterior fossa (e.g., nodulus/uvula) (7,8). It has been postulated that some forms of CPPN, including the DBN type, may be due to an exaggerated/disinhibited rebound response of the irregular afferent signals originating in the SCCs during head acceleration along with a deficient adjustment by the velocity-storage mechanism (8). In the past, the occurrence of central paroxysmal positioning UBN has been explained by a general disinhibition of the vestibular nuclei during head positioning due to nodular/uvular dysfunction (9). Our patient had severe central positioning UBN associated with high titers of anti-GAD Ab and showed a remarkable improvement with intravenous immunoglobulin (IVIg). We believe that this association is related to the loss of cerebellar nodulus/uvula inhibitory input to the vestibular nuclei. Martins et al: J Neuro-Ophthalmol 2018; 38: 32-35 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution CASE REPORT A 68-year-old woman with insulin-dependent diabetes and posttraumatic paraplegia reported a 2-year history of daily disabling vertigo and nausea exclusively when lying supine. These episodes resolved spontaneously after 1 minute and recurred every time the patient moved from seated to supine position. She also reported intermittent vertical binocular diplopia in lateral gaze for 1 year. On examination, the patient was paraplegic and had a complete sensory loss below T8 level with bilateral extensor responses. There was mild upper limb ataxia. Visual acuity was 20/20 in each eye, with normal pupillary reactions and funduscopy. In the upright position, eye movements revealed continuous square wave jerks (oscillations), spontaneous DBN, gaze-evoked nystagmus, preserved smooth pursuit apart from the superimposition of DBN on downward vertical pursuit, hypermetric horizontal saccades, and hyperactive vestibulo-ocular reflex (VOR) responses on the bilateral horizontal head impulse test (HIT) (i.e., the presence of corrective saccades in the direction of head rotations). There was a 4-prism diopter hypertropia of the abducting eye in lateral gaze, consistent with alternating skew deviation. When moved to the supine position, the patient developed UBN lasting w15-30 seconds, which was consistently triggered at 30°, 60°, 90°, and 135° angles. This was accompanied by vertigo and nausea. Once UBN resolved, DBN returned in the primary position. When moving the patient back to the upright position, UBN could no longer be triggered. No other head starting position apart from head straight in the upright position could elicit positioning UBN when moving the patient to the supine position. Still in supine position, with either ear down, an asymptomatic and transient (w5-10 seconds) geotropic nystagmus (quick phases of the nystagmus beating toward the ground) was noted. Positioning nystagmus and vertigo could not be abated with repeated canalith repositioning maneuvers designed for benign paroxysmal position vertigo. Infrared binocular video-oculography (Interacoustics VO425; Assen, Denmark; 105 Hz), performed in dark, replicated the above findings (Fig. 1A and see Supplemental Digital Content, Video, http://links.lww.com/WNO/A242 [initial segment]). Quantitative analysis of the VOR during high-acceleration head rotations using monocular videooculography (EyeSeeCam; EyeSeeTec GmbH, Munich, Germany; 250 Hz) showed abnormally high VOR gains for the horizontal and anterior SCC function along with compensatory reversed saccades in the direction of head movement (Fig. 2). Horizontal VOR function during low-acceleration stimuli (i.e., caloric responses, sinusoidal, and step rotatory chair testing) revealed normal VOR gains and time constants (data not shown). Brain MRI was unremarkable. Laboratory testing revealed high titers of anti-GAD65 Ab (239.07 U/mL; Martins et al: J Neuro-Ophthalmol 2018; 38: 32-35 FIG. 1. Vertical eye position (degrees) over time (seconds) from monocular recordings of the right eye. Nystagmus progression can be seen before (A) and after treatment with oral baclofen (B) and intravenous immunoglobulin (C). Before any treatment (A), downbeat nystagmus (DBN) was present in light and dark in the upright position, and a strong upbeat nystagmus (UBN) was consistently elicited in dark in the supine position. After treatment with oral baclofen (B), UBN in dark in the supine position subsided, whereas DBN persisted in light and dark. After treatment with intravenous immunoglobulin (C), only DBN in light in the upright position remained. Eye movements up are represented by an upward deflection of the tracing, whereas down are represented by a downward deflection. On the left side of each recording, the patient's position (upright vs supine) and light conditions (light vs dark) are indicated. On the right side of each recording, the mean velocity (degrees per second) of the slow phases of the nystagmus is shown. (Recordings in light during the supine position are not shown, but results were similar to analysis in dark.) normal range: ,1.0 U/mL in serum). An extensive workup for occult malignancy was negative. Before antiGAD Ab result availability, treatment with baclofen 2.5 mg 3 times daily was started. This abated positioning UBN, while leaving spontaneous DBN in light and dark (Fig. 1B and see Supplemental Digital Content, Video, http://links.lww.com/WNO/A242 [middle segment]) and high-acceleration VOR responses unchanged. However, this effect only lasted 1-2 weeks, and the dosage could not be increased because of gastric intolerance. With detection of anti-GAD Ab, the patient was given IVIg, 33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Video head impulse test (vHIT) of the 6 semicircular canals (SCCs), before any treatment. To evaluate each SCC vestibulo-ocular reflex (VOR), the patient's head is briskly moved in the maximally excitatory direction for each SCC plane (e.g., rightward rotation, for the right horizontal SCC) while the patient keeps fixating a visual target at 1.5-m distance. In a normal individual, the eyes will move in the opposite direction at equal velocity, giving rise to a gain of eye velocity/head velocity of approximately 1. Note the abnormally high VOR gains (.1.2) for all the anterior and horizontal SCCs (the peak of black curves-eye velocity-markedly surpasses the peak of gray curves-head velocity-at w60 milliseconds). (Peak waves at the end of the impulse correspond to beats of spontaneous downbeat nystagmus, small black arrowheads.) In the center, a detailed view of the vHIT of the right horizontal SCC is provided (eye and head velocity curves here are not superimposed). Note that the velocity of the eye movement (black curve) greatly exceeds that of the head movement (gray curve). To compensate for such enhanced gain (w1.6), the eyes drift back at the end of the head impulse (reversed saccade, large black arrowhead). 30 g/day over 5 days. Positioning UBN and spontaneous DBN (the latter only in dark) had disappeared (Fig. 1C and see Supplemental Digital Content, Video, http://links.lww.com/WNO/A242 [final segment]) and VOR responses moderately decreased. Skew deviation, square wave jerks, saccade hypermetria, and upper limb ataxia remained unchanged. The patient was kept on a monthly IVIg regimen. Six months later, antiGAD65 Ab levels had fallen to 40.88 U/mL, and UBN and DBN were still not present. DISCUSSION Our patient had disabling central paroxysmal positioning UBN and vertigo associated with high titers of anti-GAD Ab, in whom a remarkable clinical improvement occurred after treatment with IVIg. Previous reports of nystagmus associated with the presence of anti-GAD Ab have only described forms of spontaneous nystagmus (i.e., DBN and less often, PAN and UBN), occurring without an obvious trigger (1-3,10). In our patient, quantitative analysis of the HIT responses showed abnormally high VOR gains (w1.5) during anterior SCC 34 stimulation relative to normal values during posterior SCC stimulation (w0.8) (Fig. 2), while vertical smooth pursuit was relatively preserved. Thus, VOR asymmetry between the anterior and posterior SCCs may have accounted for spontaneous DBN in our patient. This is believed to reflect the effect of anti-GAD Ab on cerebellar flocculus/paraflocculus GABAergic neurons, lessening their inhibitory influence over the central vestibular pathways carrying anterior SCC signals, and leading to vestibular asymmetry (1,5,11-14). In contrast to spontaneous nystagmus, to elicit positioning nystagmus there must be a change of head position in space relative to gravity (10). Our patient showed transient positioning symptomatic UBN when moving backward to a supine position and asymptomatic geotropic horizontal nystagmus in the supine position with either ear down. UBN and geotropic nystagmus constitute a rare form of CPPN, contrasting with the more frequent types of DBN in the supine position and ageotropic form in the ear-down position (8). For the latter CPPN types, Choi et al (8) proposed that lesions of the cerebellar nodulus/uvula may greatly enhance the rebound response of neuronal discharge occurring immediately after head acceleration, thus inducing a prominent inhibition of the SCC previously being Martins et al: J Neuro-Ophthalmol 2018; 38: 32-35 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution stimulated (e.g., posterior SCCs' prominent inhibition during head movement from upright to the supine position, causing positioning DBN). Although highly speculative, an alternative mechanism may account for the UBN and geotropic forms of CPPN, as seen in our patient. If lesions of the cerebellar nodulus/uvula selectively (or preferentially) promote the enhancement of the rebound response of neuronal discharge immediately after head deceleration, then a prominent activation of the SCC being stimulated will occur (15). In case of the posterior SCCs, when moving the head backward, UBN will be elicited at the end of the movement. Although brain imaging was unremarkable in our patient, that does not exclude a functional impairment of the nodulus/uvula (13). Because lesions of the nodulus/uvula are also believed to promote disinhibition of the velocity-storage mechanism, the demonstration of an abnormal prolongation of vestibular responses during or immediately after sustained vertical head rotations would be supportive of nodulus/uvula dysfunction in our patient (3,16). Although we were unable to perform vertical head rotations, the transient improvement of positioning UBN seen after baclofen trial points to the presence of disinhibition of the velocity-storage mechanism because baclofen is a GABA agonist known to shorten the VOR time constant (17). HIT responses were elevated, specifically for horizontal and anterior SCC function. Elevated VOR gains on HIT anecdotally have been described in patients with cerebellitis and cerebellar degeneration and may reflect the loss of inhibitory input from flocculus/paraflocculus and/or nodulus/uvula to vestibular nuclei (18,19). Treatment with IVIg possibly restored nodulus/uvula and flocculus/paraflocculus GABAergic inhibitory output over the vestibular nuclei, resolving CPPN (Fig. 1C) and DBN and improving VOR responses (20). The absence of IVIg response for the remaining signs in our patient might either reflect permanent neuronal loss and/or the existence of a non-GABAergic neural circuitry for the control of limb movements, ocular fixation and alignment, and saccade accuracy (3). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. I. Martins, E. Eggenberger, and J. Lemos; b. Acquisition of data: A. I. Martins, J. N. Carvalho, A. M. Amorim, A. Geraldo, E. Eggenberger, and J. Lemos; c. Analysis and interpretation of data: A. I. Martins, J. N. Carvalho, A. M. Amorim, A. Geraldo, E. Eggenberger, and J. Lemos. Category 2: a. Drafting the manuscript: A. I. Martins and J. Lemos; b. Revising it for intellectual content: A. I. Martins, J. N. Carvalho, A. M. Amorim, A. Geraldo, E. Eggenberger, and J. 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