Annals of Indian Academy of Neurology
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Year : 2021  |  Volume : 24  |  Issue : 3  |  Page : 441-443

Upbeat nystagmus in late onset cerebellar ataxia: Think of anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Submission18-May-2020
Date of Acceptance31-May-2020
Date of Web Publication10-Feb-2021

Correspondence Address:
Dr. Rohan R Mahale
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_470_20

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How to cite this article:
Mahale RR, Dutta D, Kovoor J, Mailankody P, Padmanabha H, Mathuranath P S. Upbeat nystagmus in late onset cerebellar ataxia: Think of anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia. Ann Indian Acad Neurol 2021;24:441-3

How to cite this URL:
Mahale RR, Dutta D, Kovoor J, Mailankody P, Padmanabha H, Mathuranath P S. Upbeat nystagmus in late onset cerebellar ataxia: Think of anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Aug 3];24:441-3. Available from:

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Glutamate decarboxylase (GAD) is an intracytoplasmic enzyme involved in the conversion of excitatory neurotransmitter glutamate to inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Antibodies against 65-kDa isoform of GAD (GAD 65) are known to cause immune-mediated cerebellar ataxia.[1] GAD 65 associated cerebellar ataxia (CA) is second common neurologic manifestation of GAD 65 antibodies associated neurological syndromes. It is seen commonly in women in about 80–90% of cases usually in sixth decade. Most of the patients present with chronic ataxia with one-third of the patients having subacute presentation.[2] Patients with GAD 65 associated CA can have other autoimmune diseases such as insulin-dependent diabetes mellitus, Addison's disease, hemolytic anaemia, or thyroiditis.[3] The neuro-ophthalmological manifestation in GAD 65 associated CA is downbeat nystagmus, periodic alternating nystagmus (PAN), ocular flutter, opsoclonus and impaired smooth pursuits.[4],[5] The occurrence of upbeat nystagmus in GAD 65 associated CA is uncommon. Hereby, we describe a 52-year-old lady with seropositive GAD65 antibodies who presented with slowly progressive ataxia with dysarthria and gravity independent upbeat nystagmus.

A 52-year-old lady presented with history of gait unsteadiness since 1 year. Gait unsteadiness was insidious in onset and slowly progressive with no diurnal variation. She was able to ambulate on her own with occasional need of support at the time of presentation. She had tremulousness of both upper limbs on target oriented activities like holding glass of water, placement of morsel of food into the mouth, etc., slurring of speech in the form of scanning speech and vertiginous sensation while walking since 6 months. There was no headache, seizures, myoclonus, cognitive, or behavioral disturbance. There was no family history of similar complaints. She did not have any medical comorbidity. Systemic examination was unremarkable. Cognitive assessment was normal. She had scanning dysarthria. Fundus examination was normal. Saccades and pursuit were normal. Upbeat nystagmus was noted on asking her to look up with fast phase up both in supine and upright position [Videos 1 and 2; consent taken]. There was ill-sustained horizontal gaze-evoked nystagmus. Motor and sensory examination was normal. She had bilateral finger–nose incoordination, dysdiadochokinesia, knee–heel incoordination and gait ataxia. Plantar responses were flexor. Routine blood examination including thyroid function test was within normal limits. Glycosylated hemoglobin was normal. Brain magnetic resonance imaging showed mild cerebellar atrophy [Figure 1]. Serum anti-GAD 65 antibodies were strongly positive (qualitative assay). Cerebrospinal fluid analysis was normal. Computed tomography of thorax and abdomen was normal. She was treated with intravenous methylprednisolone (1 g for 5 days) with no improvement followed by large volume plasmapheresis (5 cycles on alternate days) with mild improvement in gait.
Figure 1: Brain MRI T2 sagittal image (a) and (b) axial image shows cerebellar atrophy (red arrow)

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Upbeat nystagmus is seen in patients with brainstem infarctions, hemorrhages, tumors, multiple sclerosis, Wernicke encephalopathy, epilepsy, brainstem encephalitis, Creutzfeldt-Jakob disease, Behcet syndrome, meningitis, Chiari malformation, and cerebellar degeneration. It occurs in pontomesencephalic, pontomedullary, and anterior vermis of cerebellum lesions.[6] The cause of spontaneous nystagmus in GAD65 associated CA is due to deficiency of GABAergic neurotransmission in cerebellum with or without brainstem involvement. Downbeat nystagmus is due to the dysfunction in flocculus/paraflocculus. PAN is due to the dysfunction of nodulus/uvula of cerebellum. The cerebellar flocculus inhibits anterior canal vestibular pathways though not the posterior canal pathways. As a result, GAD65 antibodies mediated reduced GABAergic inhibitory control of floccular Purkinje cells cause downbeat nystagmus.[4]

The occurrence of upbeat nystagmus in GAD 65 associated CA is uncommon but has been reported. Martins et al., reported a 68-year-old lady with seropositive GAD65 antibodies who had paraoxysmal central positioning upbeat nystagmus in supine position. On upright position, there was asymptomatic downbeat nystagmus with alternating skew deviation.[7] Feldman et al., reported a 72-year-old woman with progressive cerebellar ataxia, dysarthria of 1 year duration, and upbeat nystagmus which was gravity independent.[8] The involvement of afferents from the vestibular nuclei projecting to the flocculus through caudal medulla, and involvement of cerebellar feedback loop cause upbeat nystagmus which is gravity dependent.[9] The dysfunction of neural integrator for vertical gaze holding also causes upbeat nystagmus which is gravity independent.[10]

We report a middle-aged lady with progressive pan-cerebellar syndrome with gravity independent upbeat nystagmus and seropositive for GAD65 antibodies. The occurrence of upbeat nystagmus in GAD 65 associated CA widens the aetiology of upbeat nystagmus and provides a clue for the etiological diagnosis in patients presenting with late-onset cerebellar ataxia.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, Andres C, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: Study of 14 patients. Arch Neurol 2001;58:225-30.  Back to cited text no. 1
Nanri K, Niwa H, Mitoma H, Takei A, Ikeda J, Harada T, et al. Low-titer anti-GAD-antibody-positive cerebellar ataxia. Cerebellum 2013;12:171-5.  Back to cited text no. 2
Fernandes M, Munhoz RP, Carrilho PE, Arruda WO, Lorenzoni PJ, Scola RH, et al. Neurological disorders associated with glutamic acid decarboxylase antibodies: A Brazilian series. Arq Neuropsiquiatr 2012;70:657-61.  Back to cited text no. 3
Vale TC, Pedroso JL, Alquéres RA, Dutra LA, Barsottini OG. Spontaneous downbeat nystagmus as a clue for the diagnosis of ataxia associated with anti-GAD antibodies. J Neurol Sci 2015;359:21-3.  Back to cited text no. 4
Tilikete C, Vighetto A, Trouillas P, Honnorat J. Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol 2005;62:1300-3.  Back to cited text no. 5
Kim JS, Yoon B, Choi K-D, Oh S-Y, Park S-H, Kim B-K. Upbeat nystagmus: Clinicoanatomical correlations in 15 patients. J Clin Neurol 2006;2:58-65.  Back to cited text no. 6
Martins AI, Carvalho JN, Amorim AM, Geraldo A, Eggenberger E, Lemos J. Disabling central paroxysmal positioning upbeat nystagmus and vertigo associated with the presence of anti-glutamic acid decarboxylase antibodies. J Neuroophthalmol 2018;38:32-5.  Back to cited text no. 7
Feldman D, Otero-Millan J, Shaikh AG. Gravity independent upbeat nystagmus in syndrome of anti-GAD antibodies. Cerebellum 2019;18:287-90.  Back to cited text no. 8
Fisher A, Gresty M, Chambers B, Rudge P. Primary position upbeating nystagmus. A variety of central positional nystagmus. Brain 1983;106:949-64.  Back to cited text no. 9
Shin BS, Oh SY, Kim JS, Lee H, Kim EJ, Hwang SB. Upbeat nystagmus changes to downbeat nystagmus with upward gaze in a patient with Wernicke's encephalopathy. J Neurol Sci 2010;298:145-7.  Back to cited text no. 10


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