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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 – 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 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 Symptoms • Ataxia (motor incoordination, gait, limbs, speech) • Ataxic episodes • Tremor – Action – Resting • • • • • Vertigo Blurred vision Spasticity Rigidity, slowness of movements Fatigue Ataxia • Ataxia (motor incoordination, gait, limbs, speech) – Amantadine (Symmetrel) – Buspirone (Buspar) • Ataxic episodes – Acetazolamide (Diamox) – Topiramide (Topamax) – Valproate (Depakote) Tremor • Resting – L-dopa (Sinemet) • Intention/Action – – – – – – Propranolol (Inderal) Primidone (Mysoline) Clonazepam (Klonopin) Levitiracetam (Keppra) Carbemazemine (Tegretol) Isonoazid (INH) Vertigo and Blurred vision • • • • • • • • Meclizine (Antivert) Acetazolamide (Diamox) Topiramate (Topamax) Gabapentin (Neurontin) Baclofen (Lioresal) 3, 4 Diaminopyridine Ondansetron (Zofran) Valproate (Depakote) Non-ataxia motor symptoms • Spasticity – Baclofen (Lioresal) – Tizanidine (Xanaflex) • Dystonia – Baclofen (Lioresal) – Botulinum (Botox) • Rigidity, slowness of movements – Amantadine (Symmetrel) – L-dopa (Sinemet) Sleep disorders • Restless legs – L-dopa (Sinemet) – Pramipexole (Mirapex) • Sleep apnea – C-PAP • REM behavior disorder – Clonazepam (Klonopin) Novel Concept: Potential for Deep brain stimulation (DBS) in the treatment of tremor in ataxia Deep Brain Stimulation DBS history different 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 DBS Anatomy zona incerta Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747 Target Sites for DBS Therapy cZI Vim Thalamus: Essential Tremor Subthalamic Nucleus: Parkinson’s disease and Dystonia Globus Pallidus: Parkinson’s disease and Dystonia 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 DBS Stereotactic Frame: used for image guided target localization DBS for MS tremor OFF ON DBS for MS tremor OFF ON DBS for MS tremor OFF ON 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). 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 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. Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747 Deep Brain Stimulation Zona Incerta Gross Anatomy Physiologic Target confirmation: Microelectrode Recording Border 10sec 80ms STN 10sec 80ms Border/SN 10sec 80ms Sagittal Section Through the Thalamus Implantation of Unilateral DBS into the zona incerta, to be connected to a programmable IPG Demographic and Clinical Characteristics: 4 Case Studies Case Age Affected at Preop meds cZI site DBS param No.op areas 1 46 y/o Bilateral baclofen, natalizumab L unilat Amp 4.0V female UE, LE amantadine, memantine, PW 180 µs RH truncal mirtazapine, ine sertral Rate 185Hz ataxia 2 35 y/o Bilateral natalizumab baclofen, L unilat Amp 3.8V female U E scopolamine patch PW 150 µs RH Rate 160Hz 3 44 y/o Bilateral natalizumab, desipramine, Rt unilat Amp 3.4V female UE citalopram, baclofen, PW 240 µs LH gabapentin Rate 100Hz 4 31 y/o Bilateral s/p stem ell tx c L unilat Amp 3.6V maleUE, LE None currently PW 120 µs RH Rate 145Hz 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 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) ADLs pre and post DBS MS #1 #2 100 #3 90 #4 80 70 60 50 40 #4 30 #3 20 #2 10 0 #1 Pre Post Tremor Global Rating Score Patient and Physician Assessment 4 3 2 pt pt pt pt Score 1 0 -1 -2 -3 Assessor: Patient Physician 1 2 3 4 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. • 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