Drugs and Treatments for Ataxia
Christopher M. GomezThe 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 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
DBS Anatomy
zona incerta
Anatomic Location and Connection of cZi
Plaha et al 2006, Brain 129: 1732-1747
Target Sites for DBS Therapy
Vim Thalamus: Essential Tremor
Subthalamic Nucleus: Parkinson’s disease
and Dystonia
Globus Pallidus: Parkinson’s disease
and Dystonia
cZI
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
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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
STN
Border/SN
10sec
10sec
10sec
80ms
80ms
80ms
Sagittal Section Through the Thalamus Border
Implantation of Unilateral DBS into the zona incerta, to be connected to a programmable
IPG
Demographic and Clinical Characteristics: 4 Case Studies
Case No.
Age at op
Affected areas
Preop meds cZI site DBS param
1 46 y/o female RH
Bilateral UE, LE truncal ataxia
baclofen, natalizumab amantadine, memantine, mirtazapine, sertraline
L unilat Amp 4.0V PW 180µs Rate 185Hz
2 35 y/o female RH
Bilateral UE
natalizumab baclofen, scopolamine patch
L unilat Amp 3.8V PW 150µs Rate 160Hz
3 44 y/o female LH
Bilateral UE
natalizumab, desipramine, citalopram, baclofen, gabapentin
Rt unilat Amp 3.4V PW 240µs Rate 100Hz
4 31 y/o male RH
Bilateral UE, LE
s/p stem cell tx None currently
L unilat Amp 3.6V PW 120µs 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
0
10
20
30
40
50
60
70
80
90
100
Pre Post
#1
#2
#3
#4
#1
#2
#3
#4
Tremor Global Rating Score
Patient PhysicianAssessor:
Patient and Physician Assessment
-3
-2
-1
0
1
2
3
4
Score
pt 1
pt 2
pt 3
pt 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