The Cerebellum

, Volume 10, Issue 4, pp 812–819

Torpedoes in the Cerebellar Vermis in Essential Tremor Cases vs. Controls

  • Elan D. Louis
  • Phyllis L. Faust
  • Karen J. Ma
  • Mia Yu
  • Etty Cortes
  • Jean-Paul G. Vonsattel
Article

Abstract

The study of the postmortem changes in essential tremor (ET) is in its infancy, although recent evidence points to a central role of the cerebellum, where Purkinje cell axonal swellings (“torpedoes”) are significantly more common in ET than control brains. Yet, all existing studies have been confined to the cerebellar hemispheres, and whether there is a more widely distributed cerebellar problem is presently unknown. Our aims were to address whether: (1) ET cases have greater numbers of torpedoes in the vermis than controls, (2) there a correlation between the extent of vermal torpedo pathology and hemispheric torpedo pathology, and (3) vermal torpedo pathology is correlated with clinical features of the disease. A parasagittal neocerebellar block and a vermal block were harvested from 24 ET and 10 control brains. Paraffin sections (7 μm) were stained with Luxol fast blue/hematoxylin and eosin, and torpedoes were quantified. All torpedo counts were corrected for Purkinje cell layer length. Vermal corrected torpedo count (VermTc) was higher in ET cases than controls (7.1 ± 6.8 [median, 4.3] vs. 2.6 ± 2.5 [median, 2]), p = 0.002). The VermTc and the hemispheric corrected torpedo count (HemTc) were correlated with one another (Spearman’s r = 0.54, p = 0.002). ET cases with neck, voice, and jaw tremors had the highest VermTc (p = 0.046). The abundance of torpedoes in the ET brain is not confined to the ponto- or neocerebellum but is more broadly distributed, also involving the spino- or paleocerebellum. These data further confirm the central role of the cerebellum in the underlying pathophysiology of this common neurological disorder.

Keywords

Essential tremor Pathology Postmortem Purkinje cell Torpedoes Neurodegenerative 

References

  1. 1.
    Louis ED, Thawani SP, Andrews HF. Prevalence of essential tremor in a multiethnic, community-based study in northern Manhattan, New York, N.Y. Neuroepidemiology. 2009;32:208–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Zesiewicz TA, Chari A, Jahan I, Miller AM, Sullivan KL. Overview of essential tremor. Neuropsychiatr Dis Treat. 2010;6:401–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Louis ED, Dure LS, Pullman S. Essential tremor in childhood: a series of nineteen cases. Mov Disord. 2001;16:921–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Dogu O, Sevim S, Camdeviren H, Sasmaz T, Bugdayci R, Aral M, et al. Prevalence of essential tremor: door-to-door neurologic exams in Mersin province, Turkey. Neurology. 2003;61:1804–6.PubMedGoogle Scholar
  6. 6.
    Benito-Leon J, Bermejo-Pareja F, Morales JM, Vega S, Molina JA. Prevalence of essential tremor in three elderly populations of central Spain. Mov Disord. 2003;18:389–94.PubMedCrossRefGoogle Scholar
  7. 7.
    Benito-Leon J, Bermejo-Pareja F, Louis ED. Incidence of essential tremor in three elderly populations of central Spain. Neurology. 2005;64:1721–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 2009;66:1202–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Benito-Leon J. Essential tremor: one of the most common neurodegenerative diseases? Neuroepidemiology. 2011;36:77–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Louis ED, Vonsattel JP. The emerging neuropathology of essential tremor. Mov Disord. 2007;23:174–82.CrossRefGoogle Scholar
  11. 11.
    Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol. 2010;9:613–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain. 2007;130:3297–307.PubMedCrossRefGoogle Scholar
  13. 13.
    Singer C, Sanchez-Ramos J, Weiner WJ. Gait abnormality in essential tremor. Mov Disord. 1994;9:193–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Louis ED, Rios E, Rao AK. Tandem gait performance in essential tremor: clinical correlates and association with midline tremors. Mov Disord. 2010;25:1633–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Louis ED, Ford B, Frucht S. Factors associated with increased risk of head tremor in essential tremor: a community-based study in northern Manhattan. Mov Disord. 2003;18:432–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Louis ED, Rios E, Applegate LM, Hernandez NC, Andrews HF. Jaw tremor: prevalence and clinical correlates in three essential tremor case samples. Mov Disord. 2006;21:1872–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Sulica L, Louis ED. Clinical characteristics of essential voice tremor: a study of 34 cases. Laryngoscope. 2010;120:516–28.PubMedCrossRefGoogle Scholar
  18. 18.
    Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R. Neuropathologic findings in essential tremor. Neurology. 2006;66:1756–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Louis ED, Borden S, Moskowitz CB. Essential tremor centralized brain repository: diagnostic validity and clinical characteristics of a highly selected group of essential tremor cases. Mov Disord. 2005;20:1361–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Harasymiw JW, Bean P. Identification of heavy drinkers by using the early detection of alcohol consumption score. Alcohol Clin Exp Res. 2001;25:228–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Louis ED, Zheng W, Applegate L, Shi L, Factor-Litvak P. Blood harmane concentrations and dietary protein consumption in essential tremor. Neurology. 2005;65:391–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Pahwa R, et al. Torpedoes in Parkinson’s disease, Alzheimer’s disease, essential tremor, and control brains. Mov Disord. 2009;24:1600–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging. 1997;18:S85–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Mirra SS. The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging. 1997;18:S91–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.PubMedCrossRefGoogle Scholar
  26. 26.
    Yokota O, Tsuchiya K, Terada S, Oshima K, Ishizu H, Matsushita M, et al. Alcoholic cerebellar degeneration: a clinicopathological study of six Japanese autopsy cases and proposed potential progression pattern in the cerebellar lesion. Neuropathology. 2007;27:99–113.PubMedCrossRefGoogle Scholar
  27. 27.
    Karhunen PJ, Erkinjuntti T, Laippala P. Moderate alcohol consumption and loss of cerebellar Purkinje cells. BMJ. 1994;308:1663–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Torvik A, Torp S. The prevalence of alcoholic cerebellar atrophy. A morphometric and histological study of an autopsy material. J Neurol Sci. 1986;75:43–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Ota S, Tsuchiya K, Anno M, Niizato K, Akiyama H. Distribution of cerebello-olivary degeneration in idiopathic late cortical cerebellar atrophy: clinicopathological study of four autopsy cases. Neuropathology. 2008;28:43–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Louis ED. Clinical practice. Essential tremor. N Engl J Med. 2001;345:887–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Leegwater-Kim J, Louis ED, Pullman SL, Floyd AG, Borden S, Moskowitz CB, et al. Intention tremor of the head in patients with essential tremor. Mov Disord. 2006;21:2001–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Louis ED, Frucht SJ, Rios E. Intention tremor in essential tremor: prevalence and association with disease duration. Mov Disord. 2009;24:626–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain. 2001;124:2278–86.PubMedCrossRefGoogle Scholar
  34. 34.
    Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R, et al. Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction. Brain. 2003;126:1319–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Trillenberg P, Fuhrer J, Sprenger A, Hagenow A, Kompf D, Wenzelburger R, et al. Eye–hand coordination in essential tremor. Mov Disord. 2006;21:373–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Avanzino L, Bove M, Tacchino A, Ruggeri P, Giannini A, Trompetto C, et al. Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor. Eur J Neurosci. 2009;30:1971–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Bares M, Lungu OV, Husarova I, Gescheidt T. Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson’s disease. Cerebellum. 2010;9:124–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Farkas Z, Szirmai I, Kamondi A. Impaired rhythm generation in essential tremor. Mov Disord. 2006;21:1196–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Kronenbuerger M, Gerwig M, Brol B, Block F, Timmann D. Eyeblink conditioning is impaired in subjects with essential tremor. Brain. 2007;130:1538–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Bares M, Lungu OV, Liu T, Waechter T, Gomez CM, Ashe J (2011) The neural substrate of predictive motor timing in spinocerebellar ataxia. Cerebellum (in press).Google Scholar
  41. 41.
    Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, et al. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Arch Neurol. 2005;62:1250–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Bucher SF, Seelos KC, Dodel RC, Reiser M, Oertel WH. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol. 1997;41:32–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Jenkins I, Bain P, Colebatch J, Thompson P, Findley L, Frackowiak S, et al. A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections. Ann Neurol. 1993;34:82–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ. Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomographic study. Ann Neurol. 1994;36:636–42.PubMedCrossRefGoogle Scholar
  45. 45.
    Colebatch JG, Findley LJ, Frackowiak RS, Marsden CD, Brooks DJ. Preliminary report: activation of the cerebellum in essential tremor. Lancet. 1990;336:1028–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Louis ED, Shungu DC, Chan S, Mao X, Jurewicz EC, Watner D. Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study. Neurosci Lett. 2002;333:17–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Pagan FL, Butman JA, Dambrosia JM, Hallett M. Evaluation of essential tremor with multi-voxel magnetic resonance spectroscopy. Neurology. 2003;60:1344–7.PubMedGoogle Scholar
  48. 48.
    Shin DH, Han BS, Kim HS, Lee PH. Diffusion tensor imaging in patients with essential tremor. AJNR Am J Neuroradiol. 2008;29:151–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Klein JC, Lorenz B, Kang JS, Baudrexel S, Seifried C, van de Loo S, et al. Diffusion tensor imaging of white matter involvement in essential tremor. Hum Brain Mapp. 2011;32(6):896–904. doi:10.1002/hbm.21077.PubMedCrossRefGoogle Scholar
  50. 50.
    Nicoletti G, Manners D, Novellino F, Condino F, Malucelli E, Barbiroli B, et al. Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor. Neurology. 2010;74:988–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Benito-Leon J, Alvarez-Linera J, Hernandez-Tamames JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Louis ED. Brain structural changes in essential tremor: voxel-based morphometry at 3-tesla. J Neurol Sci. 2009;287:138–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Quattrone A, Cerasa A, Messina D, Nicoletti G, Hagberg GE, Lemieux L, et al. Essential head tremor is associated with cerebellar vermis atrophy: a volumetric and voxel-based morphometry MR imaging study. Am J Neuroradiol. 2008;29:1692–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Cerasa A, Messina D, Nicoletti G, Novellino F, Lanza P, Condino F, et al. Cerebellar atrophy in essential tremor using an automated segmentation method. Am J Neuroradiol. 2009;30:1240–3.PubMedCrossRefGoogle Scholar
  54. 54.
    Manni E, Petrosini L. A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci. 2004;5:241–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Grodd W, Hulsmann E, Lotze M, Wildgruber D, Erb M. Sensorimotor mapping of the human cerebellum: fMRI evidence of somatotopic organization. Hum Brain Mapp. 2001;13:55–73.PubMedCrossRefGoogle Scholar
  56. 56.
    Louis ED, Faust PL, Vonsattel JP, Erickson-Davis C. Purkinje cell axonal torpedoes are unrelated to advanced aging and likely reflect cerebellar injury. Acta Neuropathol. 2009;117:719–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Elan D. Louis
    • 1
    • 2
    • 3
    • 4
    • 6
  • Phyllis L. Faust
    • 5
  • Karen J. Ma
    • 1
  • Mia Yu
    • 1
  • Etty Cortes
    • 5
  • Jean-Paul G. Vonsattel
    • 3
    • 5
  1. 1.GH Sergievsky Center, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Department of Neurology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  4. 4.Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  5. 5.Department of Pathology and Cell BiologyColumbia University Medical Center and the New York Presbyterian HospitalNew YorkUSA
  6. 6.Unit 198, Neurological InstituteNew YorkUSA

Personalised recommendations