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
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–
–
–
–
–
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
P reop 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, P W
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