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
This is a preview of subscription content, log in to check access.
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.
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.
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
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
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
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
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
Tilikete C, Vighetto A, Trouillas P, Honnorat J. Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol. 2005;62(8):1300–3.CrossRefGoogle Scholar
Economides JR, Horton JC. Eye movement abnormalities in stiff person syndrome. Neurology. 2005;65(9):1462–4.CrossRefGoogle Scholar
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
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
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
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
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
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
Jen JC, Lopez I, Baloh RW. Opsoclonus: clinical and immunological features. J Neurol Sci. 2012;320(1–2):61–5.CrossRefGoogle Scholar
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
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
Pierrot-Deseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain. 2005;128(Pt 6):1237–46.CrossRefGoogle Scholar
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
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
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