Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder

A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G(IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range ,0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cer- ebellar workup should be considered.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65Associated Stiff Person Syndrome Spectrum Disorder Nicholas E. F. Hac, MD, Olwen C. Murphy, MBBCh, Ankur A. Butala, MD, Scott D. Newsome, DO, Daniel R. Gold, DO Abstract: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild–moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a widebased stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and realtime quaking-induced conversion (RT-QuIC). However, her antiglutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0–5 IU/mL) and in CSF to 18.1 nmol/L (reference range ,0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered. Journal of Neuro-Ophthalmology 2023;43:273–276 doi: 10.1097/WNO.0000000000001774 © 2023 by North American Neuro-Ophthalmology Society Drs. Hac, Murphy, and Gold: A 68-year-old woman with a history of hypertension, hypothyroidism, and polio at age 2 (with residual left leg Department of Neurology (NEFH), Northwestern University, Chicago, Illinois; and Department of Neurology (OCM, AAB, SDN, DRG), The Johns Hopkins University School of Medicine, Baltimore, Maryland. The authors report no conflicts of interest. Address correspondence to Nicholas E. F. Hac, MD, Department of Neurology, Northwestern University, 251 E Huron Street, Chicago, IL 60611; E-mail: [e-mail] Hac et al: J Neuro-Ophthalmol 2023; 43: 273-276 weakness) began experiencing dizziness primarily when lying with her right ear down. She also described unsteadiness while walking. After these symptoms progressed over 2 months, she presented to the emergency department, where magnetic resonance imaging (MRI) of the brain with and without contrast was unremarkable. She received a diagnosis of vestibular neuritis and was prescribed a short course of oral corticosteroids and 2 months of physical therapy. Neither intervention helped, and she required a cane by the conclusion of physical therapy. Three months after symptom onset, she saw an otolaryngologist who diagnosed probable benign paroxysmal positional vertigo (BPPV). Videonystagmography (VNG) was reported to show positional left-beating nystagmus and a 16% left-sided weakness on caloric testing (where ,20% is considered within normal limits). Diazepam was prescribed for 3 months, but symptoms again worsened. Fourteen months after onset she was seen through telemedicine in vestibular clinic, describing dizziness as a continuous circular motion that worsened during all position changes. She experienced vertical oscillopsia when focusing on objects and feeling “drunk” when standing or walking, resulting in falls. She also endorsed asymmetric right . left hearing loss, and previous audiogram demonstrated high-frequency sensorineural hearing loss. She could only sleep supine with head in a neutral position due to positional dizziness, and she required a walker to ambulate. She underwent vestibular and ocular motor testing including video head impulse test (vHIT), which demonstrated normal gains and no corrective saccades. Video-oculography (VOG) was notable for mild spontaneous downbeat nystagmus (DBN) and horizontal and vertical gaze-evoked nystagmus (GEN). When returning from lateral to primary gaze, there was rebound nystagmus (e.g., GEN—right-beating nystagmus [RBN] in right gaze; rebound—left-beating nystagmus [LBN] when returning to primary position), but when the eyes were held in lateral gaze for 5–10+ seconds, the GEN transitioned to centripetal nystagmus (1,2). She was symptomatic with right and left supine roll and Dix–Hallpike testing and had positional apogeotropic nystagmus (e.g., RBN with the left ear down and LBN with the right ear down). DBN increased in a prone position. Smooth pursuit and vestibulo-ocular reflex suppression (VORS) horizontally 273 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study and vertically seemed moderately saccadic, and saccades were mildly slow with inconsistent dysmetria (occasional hypometria or hypermetria). There were poor fast phases with an optokinetic stimulus horizontally and vertically. The VOG findings were consistent with a cerebellar disorder, specifically the combination of DBN, GEN with rebound, centripetal nystagmus, saccadic smooth pursuits and VORS, and dysmetric saccades (3). Apogeotropic nystagmus can be seen in lateral canal BPPV; however, it is also common with lesions of the cerebellar nodulus (4). Our patient had already undergone weeks of physical therapy and repositioning maneuvers for lateral canal BPPV, without resolution. Therefore, a central positional nystagmus seemed more likely. Centripetal nystagmus is a rare finding but has been reported in cerebellar disease (5) and Creutzfeldt–Jakob disease (CJD) (6). Slow saccades (and poor optokinetic nystagmus fast phases) in all planes suggested additional dysfunction of the brainstem burst neurons. Given her subacute to chronic progression over more than 1 year, this patient’s differential diagnosis for posterior fossa disease included toxic, metabolic, demyelinating, autoimmune, paraneoplastic, prion-related, genetic, neurodegenerative, vitamin deficiency, or structural etiologies. Contrastenhanced MRI was normal, and blood work was ordered to look for reversible causes of cerebellar ataxia. 4-Aminopyridine (4-AP), a medication that has demonstrated efficacy in several randomized controlled trials in select patients by reducing DBN slow-phase velocity and improving visual acuity (7,8), was prescribed. She was also referred for movement disorder consultation given progressive cerebellar disease. Dr. Butala (Movement Disorders and Ataxia Neurology): She was evaluated for a late-onset sporadic cerebellar ataxia. She denied prodromal Parkinsonian symptoms (hyposmia, dream enactment, and dysuria) and dysautonomia (urinary retention, constipation, and symptomatic orthostasis). Examination was notable for right . left decrementing bradykinesia and rigidity (clinical “parkinsonism”), slightly masked facies with diminished blink rate, left arm and leg weakness with atrophy (attributed to remote polio), dysdiadochokinesia and past-pointing, and appendicular plus truncal ataxia. Examination of gait and stance demonstrated an upright posture (not stooped and no anterocollis to suggest multiple system atrophy [MSA]), and there was a wide-based, lurching gait with arms partially flexed, with some resemblance to progressive supranuclear palsy (PSP). Additional serology and imaging were requested with a short follow-up visit scheduled. In follow-up 2 months later, an atypical extrapyramidal (perhaps PSP-like) phenotype seemed more clear with bilateral decrementing bradykinesia, spasticity, slight restriction with voluntary upgaze and downgaze, worsened postural instability, and retropulsion. Such a rapid evolution over 2 months strongly 274 argued against a late-onset neurodegenerative disorder, which would evolve over years. Drs. Hac, Murphy, and Gold: Metabolic laboratory results including investigation for relevant vitamin deficiencies (e.g., vitamin B1, B12, and E) were normal. Blood count was only notable for slight anemia. Rheumatologic studies demonstrated an ANA elevated to 1:320 in a speckled/cytoplastic pattern, with otherwise negative studies. Endocrine study findings were normal, and serum protein electrophoresis with immunofixation was normal. Heavy metal studies, celiac panel, and infectious studies such as testing for HIV, syphilis, and Lyme disease were also negative. Serum paraneoplastic autoantibody panel was notable for a mildly elevated neuronal AChR ganglionic (alpha-3) antibody to 0.03 (reference range ,0.03 nmol/L) and markedly elevated serum GAD65 IgG antibody at 426,202 IU/mL (reference range 0–5 IU/mL). Repeat contrast-enhanced brain MRI with attention to the brainstem and vestibulocerebellum (flocculus/paraflocculus, nodulus/uvula) was again unremarkable. Lumbar puncture showed normal cell counts, slightly elevated protein to 58, negative 14-3-3 and RT-QuIC (markers of prion disease), 1 oligoclonal band, normal IgG index, and pan-negative infectious studies such as VDRL, bacterial cultures, HSV, and VZV testing. CSF paraneoplastic autoantibody panel (Mayo Clinic Laboratory) was notable for an elevated GAD65 IgG to 18.1 nmol/L (reference range ,0.03 nmol/L). Given the anti-GAD65 antibody findings, she was referred to neuroimmunology for further evaluation. Dr. Newsome (Neuroimmunology): In neuroimmunology clinic, further history-taking elucidated the presence of torso stiffness with superimposed intermittent painful spasms in her chest and lower back as well as intermittent mild dyspnea. In addition to her previously noted ocular motor and gait dysfunction, she was noted to have significant axial rigidity and paraspinal muscle stiffness/spasms. Her progression of symptoms, regions of neuroaxis and musculoskeletal involvement along with her aforementioned work-up seemed most consistent with an immune-mediated condition. Given this patient’s level of disability and final diagnosis, it was recommended for her to start an immune-based treatment along with continuing her symptomatic interventions. Final Diagnosis Anti-GAD65-associated stiff person syndrome (SPS)-plus (musculoskeletal plus cerebellar and/or brainstem involvement). DISCUSSION Given the clinical diagnosis of anti-GAD65-associated neurologic disorder and specifically SPS-plus, it was recommended for her to initiate IVIg 2g/kg/month spread over 3–5 days for at least 6 consecutive months. A whole-body fluorodeoxyglucose-positron emission tomography (FDGHac et al: J Neuro-Ophthalmol 2023; 43: 273-276 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study PET) with computerized tomography (CT) scan and mammogram were obtained to evaluate for an underlying paraneoplastic etiology which proved to be normal. Because the patient is older (68 years old) than the average age of symptom onset for SPS (middle age), repeat malignancy screening was recommended over the ensuing few years along with routine, age-appropriate cancer screening. After 6 months of IVIg treatment, she noted marked improvement in her symptoms and overall function. Before treatment she needed to use a walker, but after several months of IVIg treatment, she only occasionally required a cane for support. Moreover, her balance and mobility have improved without further falls. She still experiences imbalance when bending forward, but no longer complains of “circular dizziness.” Her oscillopsia has also improved, presumably in part due to immunotherapy and/or 4-aminopyridine. Dr. Newsome (Neuroimmunology): Stiff person syndrome spectrum disorders (SPSDs) are a heterogenous group of rare disorders which are often misdiagnosed due to a lack of clinician awareness for these conditions and lack of gold standard diagnostic criteria. The original description (9) of the most common phenotype, classic SPS, dates back to 1956 and consists of muscle rigidity, painful spasms, and hyperlordosis. Over time, there has been identification of other phenotypes (10) including what our patient was ultimately diagnosed with (SPS-plus; classic features plus brainstem and/or cerebellar involvement). Other phenotypes include partial SPS (exclusively limb or torso involvement), PERM (progressive encephalomyelitis, rigidity, and myoclonus), and overlapping syndromes (e.g., classic SPS with limbic encephalitis). Certain experts consider a pure cerebellar ataxia syndrome under the umbrella of SPSD because some of these patients will eventually develop musculoskeletal involvement resulting in the phenotype, SPS-plus. Nonetheless, the clinical spectrum of these disorders is broad and most often associated with high-titer anti-GAD65 antibodies (up to 80%). It is not clear whether these autoantibodies are truly pathogenic or just a marker of immune dysregulation. Although, it is suspected that they play some role in disrupting GABAergic pathways resulting in the clinical manifestations seen among the different SPSD phenotypes. Other autoantibodies affecting the GABAergic pathways in SPSD that are commercially available for testing include amphiphysin (11) and glycine receptor antibodies. Amphiphysin antibodies are almost exclusively associated with a paraneoplastic SPSD (usually breast cancer) as compared to anti-GAD65-associated SPSD (,5% of cases are paraneoplastic) (12,13). Glycine receptor antibodies occur with PERM more often than the other SPS phenotypes and seem to be pathogenic (14). SPSD often coexists with other autoimmune diseases and most commonly thyroid disease, diabetes, and pernicious anemia. Monitoring for the development of these conditions over time is important. It is unknown if their coexistence portends a worse outcome over time. However, Hac et al: J Neuro-Ophthalmol 2023; 43: 273-276 other factors intrinsic to SPSD have recently been identified as risk factors for poor outcomes including initial clinical features of brainstem/cerebellar involvement, higher level of disability at onset, and/or high-titer antiGAD65 antibody (15,16). Our patient seemed to have all of these factors which became relevant when discussing treatment options. Currently, there are no consensus guidelines for the treatment of SPSD. Most individuals will require a combination of pharmacological and nonpharmacological therapies. GABAergic agonist medications are used as first-line to help treat musculoskeletal and myelopathic symptoms. Many patients will need immunotherapy despite aggressive symptomatic intervention (10). Our patient was ultimately started on immunotherapy given her significant disability, localization of dysfunction, and pace at which her disease was progressing. Her current functional status is overall improved from her nadir dysfunction with maintenance IVIg, and hence, this immune therapy will be continued in conjunction with her symptomatic interventions. In fact, a recent study demonstrated that maintenance IVIg can be a durable treatment for patients with SPS (17). Dr. Butala (Movement Disorders and Ataxia Neurology): The primary presentation of autoimmune causes of movement disorders are, in descending prevalence, ataxia, hyperkinetic, and then hypokinetic (18). Cerebellar ataxia secondary to GAD65 antibodies was first described in 1997 (19), comorbid with lateonset insulin-dependent diabetes mellitus. Excluding paraneoplastic processes, gluten-mediated ataxias are the most common acquired autoimmune ataxia—these antibodies were lacking in our case. Parkinsonism, namely, a combination of asymmetrically slowed movement, rigidity, and tremor, is an uncommon manifestation of an autoimmune condition but has been associated with anti-GAD65 antibodies. However, MSA- and PSPlook-alike disorders have been reported with GAD65, GAD67, glycine receptor, among other autoantibodies (20–22). Cerebellar ataxia is known to occur with SPSD, and given the multiple cerebellar ocular motor, truncal, and appendicular signs that were present in our patient, these can be explained by the patient having SPS-plus. Drs. Hac, Murphy, and Gold: Many ocular motor abnormalities have been described in association with anti-GAD65-associated neurological disorders (23). Dizziness and diplopia are common presenting complaints. Although patients often experience imbalance from cerebellar ataxia, vestibular loss may be another contributing factor in some. Slow saccadic velocities have been reported in antiGAD65 syndromes and suggest brainstem burst neuron dysfunction (paramedian pontine reticular formation for horizontal and rostral interstitial medial longitudinal fasciculus for vertical) (23). DBN commonly accompanies cerebellar ataxia, causing blurriness or oscillopsia (i.e., head movement independent), 275 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study often with associated dizziness/vertigo. Oscillopsia can be debilitating, affecting visual function, and aggravating imbalance. Central positional nystagmus is often downbeat or apogeotropic, and patient can be variably symptomatic. Binocular diplopia (which our patient did not have) in the setting of cerebellar ataxia is commonly due to divergence insufficiency when horizontal and at distance, or an alternating skew deviation (e.g., right hypertropia in right gaze and left hypertropia in left gaze) when vertical/oblique and in lateral gaze. DBN usually localizes to the cerebellar flocculus/paraflocculus, which is associated with gaze-evoked and rebound nystagmus as well as saccadic pursuit and VOR suppression, all of which our patient had. Saccadic dysmetria is often due to involvement of the fastigial oculomotor region (when hypermetric) or ocular motor vermis (when hypometric), although our patient’s dysmetria was somewhat inconsistent. Central positional apogeotropic nystagmus typically localizes to the nodulus; therefore, cerebellar involvement in this patient was quite diffuse. When slow saccades are seen in combination with cerebellar ocular motor signs, an anti-GAD65 syndrome should always be on the differential. If parkinsonism is also present, disorders such as PSP and MSA should be strongly considered but evaluate for antiGAD65 and related autoimmune disorders in patients with a more rapid than expected progression (weeks to months instead of years). When GEN is present, it is also important to observe the nystagmus in sustained lateral gaze for a period (w10+ seconds) to look for a transition to centripetal nystagmus. Although centripetal nystagmus (rare) and rebound nystagmus (common) probably both represent adaptive processes at work (a shifting of the null point for eye position), for unknown reasons, centripetal nystagmus is uncommon in the clinic and is sparsely mentioned in the literature, although notably it has been reported in the setting of CJD (6,24). 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