The Cerebellum

, Volume 18, Issue 2, pp 287–290 | Cite as

Gravity-Independent Upbeat Nystagmus in Syndrome of Anti-GAD Antibodies

  • Daniel Feldman
  • Jorge Otero-Millan
  • Aasef G. ShaikhEmail author
Short Report


An autoimmune disorder of the central nervous system, stiff person syndrome, frequently presents with increased titers of 65KD anti-glutamic acid decarboxylase (anti-GAD) antibodies. The clinical phenomenology of this syndrome includes stiffness, ataxia, vertigo due to horizontal gaze-evoked and downbeat vertical nystagmus, and dysmetria of saccades and reaching movements. Here, we describe a novel phenomenology of syndrome of anti-GAD antibody, non-position-dependent upbeat nystagmus and superimposed horizontal gaze-evoked nystagmus. Lack of gravity dependence of primary position upbeat nystagmus, intense nystagmus on up-gaze, relatively stable gaze on downward orientation, and the exponentially decaying waveform suggests neural integrator dysfunction. The titer of anti-GAD in our patient (30 U/ml) was consistent with a variant called “low-titer anti-GAD syndrome”. In addition of presenting as an unusual manifestation of a rare neurological syndrome, this case presents a neurochemical correlate of upbeat nystagmus in GABA-mediated control system involving horizontal and vertical neural integrators. Furthermore, the variant of “low-titer anti-GAD syndrome” suggests that GABAergic system may be affected at lower level or antibodies, and/or the epitopes of antibody in those with full-blown clinical syndrome, but low titers of anti-GAD may be different.


Cerebellum Brainstem Stiff person syndrome Anti-GAD Anti-gliadin 



AS is supported by career development award from the American Academy of Neurology, George C. Cotzias Memorial Fellowship from the American Parkinson’s Disease Association, and Dystonia Medical Research Foundation neural network in dystonia grant.

Funding Information

JO-M is covered by NIH K99 EY027846.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12311_2018_972_MOESM1_ESM.mp4 (14.3 mb)
ESM 1 (MP4 14,680 kb)


  1. 1.
    Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med. 1990;322(22):1555–60.CrossRefGoogle Scholar
  2. 2.
    Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med. 1988;318(16):1012–20.CrossRefGoogle Scholar
  3. 3.
    Fouka P, Alexopoulos H, Akrivou S, Trohatou O, Politis PK, Dalakas MC. GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders. J Neuroimmunol. 2015;281:73–7.CrossRefGoogle Scholar
  4. 4.
    Ances BM, Dalmau JO, Tsai J, Hasbani MJ, Galetta SL. Downbeating nystagmus and muscle spasms in a patient with glutamic-acid decarboxylase antibodies. Am J Ophthalmol. 2005;140(1):142–4.CrossRefGoogle Scholar
  5. 5.
    Tilikete C, Vighetto A, Trouillas P, Honnorat J. Potential role of anti-GAD antibodies in abnormal eye movements. Ann N Y Acad Sci. 2005;1039:446–54.CrossRefGoogle Scholar
  6. 6.
    Tilikete C, Vighetto A, Trouillas P, Honnorat J. Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol. 2005;62(8):1300–3.CrossRefGoogle Scholar
  7. 7.
    Economides JR, Horton JC. Eye movement abnormalities in stiff person syndrome. Neurology. 2005;65(9):1462–4.CrossRefGoogle Scholar
  8. 8.
    Markakis I, Alexiou E, Xifaras M, Gekas G, Rombos A. Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase. Clin Neurol Neurosurg. 2008;110(6):619–21.CrossRefGoogle Scholar
  9. 9.
    Shaikh AG, Wilmot G. Opsoclonus in a patient with increased titers of anti-GAD antibody provides proof for the conductance-based model of saccadic oscillations. J Neurol Sci. 2016;362:169–73.CrossRefGoogle Scholar
  10. 10.
    Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Straumann D, et al. Gaze fixation deficits and their implication in ataxia-telangiectasia. J Neurol Neurosurg Psychiatry. 2009;80(8):858–64.CrossRefGoogle Scholar
  11. 11.
    Zivotofsky AZ, Siman-Tov T, Gadoth N, Gordon CR. A rare saccade velocity profile in stiff-person syndrome with cerebellar degeneration. Brain Res. 2006;1093(1):135–40.CrossRefGoogle Scholar
  12. 12.
    Ramat S, Leigh RJ, Zee DS, Shaikh AG, Optican LM. Applying saccade models to account for oscillations. Prog Brain Res. 2008;171:123–30.CrossRefGoogle Scholar
  13. 13.
    Shaikh AG, Miura K, Optican LM, Ramat S, Leigh RJ, Zee DS. A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders. Brain. 2007;130(Pt 11):3020–31.CrossRefGoogle Scholar
  14. 14.
    Shaikh AG, Ramat S, Optican LM, Miura K, Leigh RJ, Zee DS. Saccadic burst cell membrane dysfunction is responsible for saccadic oscillations. J Neuroophthalmol. 2008;28(4):329–36.CrossRefGoogle Scholar
  15. 15.
    Jen JC, Lopez I, Baloh RW. Opsoclonus: clinical and immunological features. J Neurol Sci. 2012;320(1–2):61–5.CrossRefGoogle Scholar
  16. 16.
    Wong AM, Musallam S, Tomlinson RD, Shannon P, Sharpe JA. Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci. 2001;189(1–2):71–81.CrossRefGoogle Scholar
  17. 17.
    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(1):32–5.CrossRefGoogle Scholar
  18. 18.
    Pierrot-Deseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain. 2005;128(Pt 6):1237–46.CrossRefGoogle Scholar
  19. 19.
    Pierrot-Deseilligny C, Milea D, Sirmai J, Papeix C, Rivaud-Pechoux S. Upbeat nystagmus due to a small pontine lesion: evidence for the existence of a crossing ventral tegmental tract. Eur Neurol. 2005;54(4):186–90.CrossRefGoogle Scholar
  20. 20.
    Fisher A, Gresty M, Chambers B, Rudge P. Primary position upbeating nystagmus. A variety of central positional nystagmus. Brain. 1983;106(Pt 4):949–64.CrossRefGoogle Scholar
  21. 21.
    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(1–2):145–7.CrossRefGoogle Scholar
  22. 22.
    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(2):171–5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Daniel Feldman
    • 1
  • Jorge Otero-Millan
    • 2
  • Aasef G. Shaikh
    • 1
    Email author
  1. 1.Department of Neurology, Cleveland VA Medical CenterUniversity HospitalsClevelandUSA
  2. 2.Department of NeurologyJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations