The Cerebellum

, Volume 15, Issue 4, pp 491–497 | Cite as

Strabismus and Micro-Opsoclonus in Machado-Joseph Disease

  • Fatema F. Ghasia
  • George Wilmot
  • Anwar Ahmed
  • Aasef G. ShaikhEmail author
Original Paper


We describe novel deficits of gaze holding and ocular alignment in patients with spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD). Twelve MJD patients were studied. Clinical assessments and quantitative ocular alignment measures were performed. Eye movements were quantitatively assessed with corneal curvature tracker and video-oculography. Strabismus was seen in ten MJD patients. Four patients had mild to moderate intermittent exotropia, three had esotropia, one had skew deviation, one had hypotropia, and one patient had moderate exophoria. Three strabismic patients had V-pattern. Near point of convergence was normal in two out of three patients with exotropia. Gaze holding deficits were also common. Eight patients had gaze-evoked nystagmus, and five had micro-opsoclonus. Other ocular motor deficits included saccadic dysmetria in eight patients, whereas all had saccadic interruption of smooth pursuit. Strabismus and micro-opsoclonus are common in MJD. Coexisting ophthalmoplegia or vergence abnormalities in our patients with exotropia that comprised 50 % of the cohort could not explain the type of strabismus in our patients. Therefore, it is possible that involvement of the brainstem, the deep cerebellar nuclei, and the superior cerebellar peduncle are the physiological basis for exotropia in these patients. Micro-opsoclonus was also common in MJD. Brainstem and deep cerebellar nuclei lesion also explains micro-opsoclonus, whereas brainstem deficits can describe slow saccades seen in our patients with MJD.


Cerebellum Brainstem Burst neurons Vergence Saccade 



This work was supported by Dystonia Medical Research Foundation Clinical Fellowship grant (AS), Knights Templar Eye Foundation grant (FG), Research to Prevent Blindness grant (FG), and Blind Children’s Center grant (FG). Authors thank Dr. John Leigh for collegial support and help with technical equipment. Dr. Leigh was supported by NIH EY06717. Patients recruited from Emory University also participated in studies supported by the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA). The consortium was funded through the Rare Disease Clinical Research Network (RDCRN) (RC1NS068897).

Conflict of Interests



  1. 1.
    Taroni F, DiDonato S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci. 2004;5:641–55. doi: 10.1038/nrn1474.CrossRefPubMedGoogle Scholar
  2. 2.
    Matilla T, McCall A, Subramony SH, Zoghbi HY. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol. 1995;38:68–72. doi: 10.1002/ana.410380113.CrossRefPubMedGoogle Scholar
  3. 3.
    Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol. 2009;29:227–37. doi: 10.1097/WNO0b013e3181b416de.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Riess O, Rub U, Pastore A, Bauer P, Schols L. SCA3: neurological features, pathogenesis and animal models. Cerebellum. 2008;7:125–37. doi: 10.1007/s12311-008-0013-4.CrossRefPubMedGoogle Scholar
  5. 5.
    Coutinho P, Sequeiros J. Clinical, genetic and pathological aspects of Machado-Joseph disease. J Genet Hum. 1981;29:203–9.PubMedGoogle Scholar
  6. 6.
    Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet. 1993;4:300–4. doi: 10.1038/ng0793-300.CrossRefPubMedGoogle Scholar
  7. 7.
    Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol. 1997;42:924–32. doi: 10.1002/ana.410420615.CrossRefPubMedGoogle Scholar
  8. 8.
    Maruyama H, Kawakami H, Kohriyama T, Sakai T, Doyu M, Sobue G, et al. CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification. J Neurol Sci. 1997;152:166–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Rabiah PK, Bateman JB, Demer JL, Perlman S. Ophthalmologic findings in patients with ataxia. Am J Ophthalmol. 1997;123:108–17.CrossRefPubMedGoogle Scholar
  10. 10.
    Versino M, Hurko O, Zee DS. Disorders of binocular control of eye movements in patients with cerebellar dysfunction. Brain. 1996;119(Pt 6):1933–50.CrossRefPubMedGoogle Scholar
  11. 11.
    Durig JS, Jen JC, Demer JL. Ocular motility in genetically defined autosomal dominant cerebellar ataxia. Am J Ophthalmol. 2002;133:718–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Ohyagi Y, Yamada T, Okayama A, Sakae N, Yamasaki T, Ohshima T, et al. Vergence disorders in patients with spinocerebellar ataxia 3/Machado-Joseph disease: a synoptophore study. J Neurol Sci. 2000;173:120–3.CrossRefPubMedGoogle Scholar
  13. 13.
    Parks MM, Kelly CJ, Mitchell PR. Alignment. Lipincott Williams and Wilkins; 2006.Google Scholar
  14. 14.
    Tokumaru AM, Kamakura K, Maki T, Murayama S, Sakata I, Kaji T, et al. Magnetic resonance imaging findings of Machado-Joseph disease: histopathologic correlation. J Comput Assist Tomogr. 2003;27:241–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Rub U, Brunt ER, Deller T. New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol. 2008;21:111–6. doi: 10.1097/WCO.0b013e3282f7673d.CrossRefPubMedGoogle Scholar
  16. 16.
    Iwabuchi K, Tsuchiya K, Uchihara T, Yagishita S. Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations. Rev Neurol (Paris). 1999;155:255–70.Google Scholar
  17. 17.
    Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, et al. An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol. 1998;8:669–79.CrossRefPubMedGoogle Scholar
  18. 18.
    Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum. 2005;4:62–73. doi: 10.1080/14734220510007950.CrossRefPubMedGoogle Scholar
  19. 19.
    Murata Y, Yamaguchi S, Kawakami H, Imon Y, Maruyama H, Sakai T, et al. Characteristic magnetic resonance imaging findings in Machado-Joseph disease. Arch Neurol. 1998;55:33–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Guimaraes RP, D’Abreu A, Yasuda CL, Franca Jr MC, Silva BH, Cappabianco FA. A multimodal evaluation of microstructural white matter damage in spinocerebellar ataxia type 3. Mov Disord. 2013;28:1125–32. doi: 10.1002/mds.25451.CrossRefPubMedGoogle Scholar
  21. 21.
    Keane JR. Alternating skew deviation: 47 patients. Neurology. 1985;35:725–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Hamed LM, Maria BL, Quisling RG, Mickle JP. Alternating skew on lateral gaze. Neuroanatomic pathway and relationship to superior oblique overaction. Ophthalmology. 1993;100:281–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Goldstein JE, Cogan DG. Lateralizing value of ocular motor dysmetria and skew deviation. Arch Ophthalmol. 1961;66:517–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Williams AS, Hoyt CS. Acute comitant esotropia in children with brain tumors. Arch Ophthalmol. 1989;107:376–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Hoyt CS, Good WV. Acute onset concomitant esotropia: when is it a sign of serious neurological disease? Br J Ophthalmol. 1995;79:498–501.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Das VE. Responses of cells in the midbrain near-response area in monkeys with strabismus. Invest Ophthalmol Vis Sci. 2012;53:3858–64. doi: 10.1167/iovs.11-9145.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Joshi AC, Das VE. Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus. J Neurophysiol. 2013;110:1882–91. doi: 10.1152/jn.00233.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Keller EL. Participation of medial pontine reticular formation in eye movement generation in monkey. J Neurophysiol. 1974;37:316–32.PubMedGoogle Scholar
  29. 29.
    Scudder CA, Fuchs AF, Langer TP. Characteristics and functional identification of saccadic inhibitory burst neurons in the alert monkey. J Neurophysiol. 1988;59:1430–54.PubMedGoogle Scholar
  30. 30.
    Hikosaka O, Igusa Y, Nakao S, Shimazu H. Direct inhibitory synaptic linkage of pontomedullary reticular burst neurons with abducens motoneurons in the cat. Exp Brain Res. 1978;33:337–52.CrossRefPubMedGoogle Scholar
  31. 31.
    Buttner-Ennever JA, Buttner U. Neuroanatomy of the oculomotor system. The reticular formation. Rev Oculomot Res. 1988;2:119–76.PubMedGoogle Scholar
  32. 32.
    Van Gisbergen JA, Robinson DA, Gielen S. A quantitative analysis of generation of saccadic eye movements by burst neurons. J Neurophysiol. 1981;45:417–42.PubMedGoogle Scholar
  33. 33.
    Ramat S, Leigh RJ, Zee DS, Optican LM. Ocular oscillations generated by coupling of brainstem excitatory and inhibitory saccadic burst neurons. Exp Brain Res. 2005;160:89–106. doi: 10.1007/s00221-004-1989-8.CrossRefPubMedGoogle Scholar
  34. 34.
    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;130:3020–31. doi: 10.1093/brain/awm240.CrossRefPubMedGoogle Scholar
  35. 35.
    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;28:329–36. doi: 10.1097/WNO.0b013e31818eb3a5.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Cohen B, Henn V. Unit activity in the pontine reticular formation associated with eye movements. Brain Res. 1972;46:403–10.CrossRefPubMedGoogle Scholar
  37. 37.
    Luschei ES, Fuchs AF. Activity of brain stem neurons during eye movements of alert monkeys. J Neurophysiol. 1972;35:445–61.PubMedGoogle Scholar
  38. 38.
    Enderle JD, Engelken EJ. Simulation of oculomotor post-inhibitory rebound burst firing using a Hodgkin-Huxley model of a neuron. Biomed Sci Instrum. 1995;31:53–8.PubMedGoogle Scholar
  39. 39.
    Miura K, Optican LM. Membrane channel properties of premotor excitatory burst neurons may underlie saccade slowing after lesions of omnipause neurons. J Comput Neurosci. 2006;20:25–41. doi: 10.1007/s10827-006-4258-y.CrossRefPubMedGoogle Scholar
  40. 40.
    Shaikh AG, Wong AL, Optican LM, Miura K, Solomon D, Zee DS. Sustained eye closure slows saccades. Vis Res. 2010;50:1665–75. doi: 10.1016/j.visres.2010.05.019.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kaneko CR. Effect of ibotenic acid lesions of the omnipause neurons on saccadic eye movements in rhesus macaques. J Neurophysiol. 1996;75:2229–42.PubMedGoogle Scholar
  42. 42.
    Soetedjo R, Kaneko CR, Fuchs AF. Evidence that the superior colliculus participates in the feedback control of saccadic eye movements. J Neurophysiol. 2002;87:679–95.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Fatema F. Ghasia
    • 1
  • George Wilmot
    • 2
  • Anwar Ahmed
    • 3
  • Aasef G. Shaikh
    • 4
    • 5
    Email author
  1. 1.Cleveland ClinicCole Eye InstituteClevelandUSA
  2. 2.Department of NeurologyEmory UniversityAtlantaUSA
  3. 3.Center for Neurological Restoration, Cleveland ClinicClevelandUSA
  4. 4.Department of NeurologyCase Western Reserve UniversityClevelandUSA
  5. 5.Neurology Service, Louis Stokes Cleveland VA Medical CenterClevelandUSA

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