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

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

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