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BRIEF COMMUNICATIONS: Goran Rakocevic, Raghavan Raju, Cristina Semino-Mora, and Marinos C. Dalakas Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies Neurology 2006; 67: 1068-1070 [Abstract] [Full text] [PDF]

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Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies

Carlos R. Gordon, Ari Z Zivotofsky, Tali Siman-Tov, Natan Gadoth   (4 December 2006)

Reply from the Authors

Marinos C. Dalakas   (4 December 2006)

Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies 4 December 2006
Carlos R. Gordon, Department of Neurology, Tel Aviv University, Israel Meir Medical Center, Kfar Saba 44281, Israel, Ari Z Zivotofsky, Tali Siman-Tov, Natan Gadoth Send Correspondence to journal: Re: Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies cgordon{at}post.tau.ac.il Carlos R. Gordon, et al.	Rakocevic et al [1] report five out of 38 consecutively studied patients with stiff person syndrome (SPS) and high-titer anti-GAD antibodies who also developed cerebellar disease. We would like to highlight the issue of eye movement abnormalities in those patients, and commend them on including that information. The authors reported that in Patient 1 "hypometric saccades were prominent"; Patient 2 had "square-wave nystagmus", Patient 4 had "nystagmus and hypometric saccades" and Patient 5 had "impaired eye movements". They did not mention ocular motor abnormalities in Patient 3. They again introduced ocular motor abnormalities in the Discussion, stating that: "Gait or focal limb ataxia, dysarthria, and visual disturbances were prominent in all patients. Slow and hypometric saccades and sustained lateral gaze-evoked nystagmus were common." Unfortunately, the documentation and discussion of eye movement disturbances in SPS and in cerebellar ataxia with GAD antibodies is rare and is usually based on vague, non-quantitative, clinical descriptions. [2] Economides and Horton [3] were the first to objectively report the presence of gaze-holding nystagmus, limited abduction, ocular misalignment, deficient smooth pursuit, and impaired saccadic initiation in a patient with SPS. They attributed these findings to a dysfunction of GABAergic pathways. Using the magnetic search coil technique, we recently reported a detailed quantitative documentation of a rare saccade velocity profile, downbeat nystagmus and loss of downward smooth pursuit in a patient with SPS and cerebellar ataxia. [4] Additional studies using precise measurement of eye movements in SPS patients with and without cerebellar signs could be useful in clarifying the link between GAD antibodies and cerebellar dysfunction. The possibility of using quantitative eye measures as a biomarker of neurodegeneration has been discussed [5] regarding the assessment of eye movements in presymptomatic and symptomatic individuals with Huntington disease. We would like to encourage the authors and the neurological community to quantitatively study eye movements in SPS patients with and without cerebellar signs and in cerebellar ataxia with GAD antibodies. References 1. Rakocevic G, Raju R, Semino-Mora C, Dalakas MC. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 2006;67:1068-1070. 2. Honnorat J, Saiz A, Giometto B, et al. Cerebellar ataxia with anti- glutamic acid decarboxylase antibodies. Arch Neurol 2001; 58: 225-230. 3. Economides JR, Horton JC. Eye movement abnormalities in stiff person syndrome. Neurology 2005;65:1462-1464. 4. Zivotofsky AZ, Siman-Tov T, Gadoth N, Gordon CR. A rare saccade velocity profile in stiff-person syndrome with cerebellar degeneration. Brain Res 2006;1093:135-140. 5. Biglan KM, Halmagyi M. The eyes as a window into disease prevention. Neurology 2006;67:376-377. Disclosure: The authors report no conflict of interest.
Reply from the Authors 4 December 2006
Marinos C. Dalakas, Chief, Neuromuscular Diseases Section, NIH Bldg 10, Room 4N 248, Bethesda, MD Send Correspondence to journal: Re: Reply from the Authors dalakasm{at}ninds.nih.gov Marinos C. Dalakas	Gordon et al emphasize that abnormal eye movements can occur in patients with SPS and cerebellar ataxia. We agree. We have observed such abnormalities not only in patients with SPS and cerebellar ataxia reported in our present series [1], but also in some SPS patients without ataxia. The association is highlighted even further by another patient we have recently seen who presented only with nystagmus and saccadic eye movement abnormalities and positive GAD antibodies, but without signs of SPS. These observations indicate that GABAergic pathways are involved in abnormal eye movements. We also agree with Gordon et al that the eye movements need to be studied quantitatively and serially in SPS patients, but do not believe that GAD antibodies provide an etiologic link with this phenomenon. As we have repeatedly discussed, GAD is a cytosolic antigen and antibodies directed against intracellular antigens are not pathogenic. [6,7,8] In SPS, anti- GAD antibodies are only disease markers suggesting GABAergic dysfunction. [6,7] There is a need to search for other autoantigens, possibly a surface antigen, responsible for these patients’ symptomatology. Towards this goal, we have recently identified the GABAA-receptor Associated Protein (GABARAP) as one such autoantigen because up to 70% of SPS patients, including those with ataxia and abnormal eye movements, have circulating anti-GABARAP antibodies. [9] Because these patients’ IgG inhibited the surface expression of GABAA-receptor in vitro, we have proposed that anti-GABARAP antibodies may play a role in the patients’ symptomatology. [9] The GABAergic system is therefore a target for an autoimmune attack resulting in various manifestations including SPS, cerebellar ataxia, and abnormal eye movements. Because such disorders are amenable to immunotherapy, clinical vigilance to identify them early in the disease course is strongly suggested. References 6. Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55:1531-1535. 7. Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff-Person Syndrome: Quantification, Specificity and Intrathecal Synthesis of GAD65 Antibodies. Neurology 2001;57:780-785. 8. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immunoglobulin for Stiff-Person Syndrome. N Engl J of Med 2001;345:1870-1876. 9. Raju R, Rakocevic G, Chen Z, Hoehn G, Semino-Mora C, Shi W, Olsen R, and Dalakas MC. Autoimmunity to GABARAP in Stiff-Person Syndrome. Brain 2006 Sep 19; [Epub ahead of print] Disclosure: The author reports no conflicts of interest.