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Drugs and Treatments for Ataxia

Drugs and Treatments for Ataxia. Christopher M. Gomez The University of Chicago. Two types of treatments. Disease-modifying (neuroprotective) Symptomatic. Disease-modifying. Very few options right now. Most will be highly disease specific Some exceptions

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Drugs and Treatments for Ataxia

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  1. Drugs and Treatments for Ataxia Christopher M. Gomez The University of Chicago

  2. Two types of treatments • Disease-modifying (neuroprotective) • Symptomatic

  3. Disease-modifying • Very few options right now. • Most will be highly disease specific • Some exceptions • AVED, or other disorders of vitamin E deficiency • Hypothyroidism • Immune mediated ataxias • Disorders with some promise • Friedreichs ataxia: anti-oxidants, e.g. CoQ10, vitamin E, HDAC inhib. • Immunological disorders, esp MS: immunotherapies • Many promising avenues and drugs under consideration • e.g. anti-oxidants, kinase inhibitors, protease inhibitors, stem cells

  4. Symptomatic treatments • Target to individual symptoms. • Gold standard examples are: • L-dopa for Parkinson’s • Seizure medicines for epilepsy • May not be disease-specific. • Concept of negative vs positive symptoms • All drugs have some side effects

  5. Symptoms • Ataxia (motor incoordination, gait, limbs, speech) • Ataxic episodes • Tremor • Action • Resting • Vertigo • Blurred vision • Spasticity • Rigidity, slowness of movements • Fatigue

  6. Ataxia • Ataxia (motor incoordination, gait, limbs, speech) • Amantadine (Symmetrel) • Buspirone (Buspar) • Ataxic episodes • Acetazolamide (Diamox) • Topiramide (Topamax) • Valproate (Depakote)

  7. Tremor • Resting • L-dopa (Sinemet) • Intention/Action • Propranolol (Inderal) • Primidone (Mysoline) • Clonazepam (Klonopin) • Levitiracetam (Keppra) • Carbemazemine (Tegretol) • Isonoazid (INH)

  8. Vertigo and Blurred vision • Meclizine (Antivert) • Acetazolamide (Diamox) • Topiramate (Topamax) • Gabapentin (Neurontin) • Baclofen (Lioresal) • 3, 4 Diaminopyridine • Ondansetron (Zofran) • Valproate (Depakote)

  9. Non-ataxia motor symptoms • Spasticity • Baclofen (Lioresal) • Tizanidine (Xanaflex) • Dystonia • Baclofen (Lioresal) • Botulinum (Botox) • Rigidity, slowness of movements • Amantadine (Symmetrel) • L-dopa (Sinemet)

  10. Sleep disorders • Restless legs • L-dopa (Sinemet) • Pramipexole (Mirapex) • Sleep apnea • C-PAP • REM behavior disorder • Clonazepam (Klonopin)

  11. Novel Concept: Potential for Deep brain stimulation (DBS) in the treatment of tremor in ataxia

  12. Deep Brain Stimulation

  13. DBS historydifferent targets in brain • Ventral intermediate nucleus (VIM) DBS for ET and medically refractory parkinsonian tremor in 1997 • Globus pallidus interna (GPi) and subthalamic nucleus (STN) DBS for PD in 2002 • GPi and STN DBS for primary dystonia under humanitarian device exemption program in 2003 • Caudal Zona Incerta (cZi) tremors, dystonia in PD and MS

  14. DBS Anatomy zona incerta

  15. Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747

  16. Target Sites for DBS Therapy cZI Vim Thalamus: Essential Tremor Subthalamic Nucleus: Parkinson’s diseaseand Dystonia Globus Pallidus: Parkinson’s diseaseand Dystonia

  17. Zona incerta (cZi) • Very effective in controlling various tremors, PD and dystonia • Better than VIM in controlling various tremors by electrode-by-electrode comparison, including intention tremor and proximal tremor. • Better than STN in controlling PD symptoms in direct comparison. • Very effective in controlling various dystonia as well • Possibly less complications than VIM based on current knowledge

  18. DBS Stereotactic Frame:used for image guided target localization

  19. DBS for MS tremor OFF ON

  20. DBS for MS tremor OFF ON

  21. DBS for MS tremor OFF ON

  22. Novel concept • cZi DBS might be a good target to control various symptoms of SCA, particularly debilitating tremors, with a better efficacy and few complications. • A successful case of cZi DBS on SCA2 was reported in the literature (Freund et al, 2007).

  23. Inclusion criteria with SCA for cZi DBS • SCAx • Severe symptoms affecting daily functions • Failed Propranolol at 320mg/d • Failed Primidone (Mysoline) at 250mg/d. • Optional: Failed either Keppra, Sinemet, or Xyrem (if symptoms respond to alcohol) • No significant depression or dementia • Generally healthy • Realistic expectation • Good family support

  24. Surgery and Measurements • DBS Surgery • We place DBS electrodes along the VIM to cZi area, with upper 2 electrodes in VIM and bottom 2 electrodes in cZi area. • Measurements of cZi vs VIM DBS • Fahn-Tolossa-Marin Tremor Rating Scale will be used for the quantitative comparison of the therapeutic outcomes. • UPDRS, ataxia and dystonia scales • Quality of life and mood scales.

  25. Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747

  26. Deep Brain Stimulation

  27. Zona Incerta Gross Anatomy

  28. Physiologic Target confirmation: Microelectrode Recording Border Sagittal Section Through the Thalamus 10sec 80ms STN 10sec 80ms Border/SN 10sec 80ms

  29. Implantation of Unilateral DBS into the zona incerta, to be connected to a programmable IPG

  30. Demographic and Clinical Characteristics: 4 Case Studies

  31. Tremor Assessment • Activities of Daily Living (ADL) Questionnaire: • Scores 25 activities in terms of severity ranging from 1 to 4; high disability = 100 • 1 = able to do without difficulty • 4 = cannot do without assistance

  32. Tremor Assessment: Global Rating Score • Patient and examiner independently rated the patient’s pre-op vs post-op status • Score ranges from -3 (markedly worse) to +3 (markedly improved) • No change (score = 0)

  33. ADLs pre and post DBS MS

  34. Tremor Global Rating Score Assessor: Patient Physician

  35. SCA • Very debilitating neurodegenerative disease with ataxia, various tremors, dystonia and parkinsonism. • Balance and gait difficulty, dysarthria, clumsy of the hands. • No effective medications so far.

  36. Current targets for DBS are not effective for ataxia. • Current VIM target is not very effective for intention tremor and proximal tremor, commonly seen in SCA • VIM DBS is also associated with tolerance, dysarthria, and disturbance of gait and balance, particularly in bilateral procedures

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