Drugs and Treatments for Ataxia

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Drugs and Treatments for Ataxia

• Christopher M. Gomez
• The University of Chicago

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Two types of treatments

• Disease-modifying (neuroprotective)
• Symptomatic

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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

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Symptomatic treatments

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

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Symptoms

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

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Ataxia

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

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Tremor

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

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Vertigo and Blurred vision

• Meclizine (Antivert)
• Acetazolamide (Diamox)
• Topiramate (Topamax)
• Gabapentin (Neurontin)
• Baclofen (Lioresal)
• 3, 4 Diaminopyridine
• Ondansetron (Zofran)
• Valproate (Depakote)

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Non-ataxia motor symptoms

• Spasticity
• Baclofen (Lioresal)
• Tizanidine (Xanaflex)
• Dystonia
• Baclofen (Lioresal)
• Botulinum (Botox)
• Rigidity, slowness of movements
• Amantadine (Symmetrel)
• L-dopa (Sinemet)

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Sleep disorders

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

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Novel Concept Potential for Deep brain
stimulation (DBS) in the treatment of tremor in
ataxia
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Deep Brain Stimulation
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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

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DBS Anatomy
zona incerta
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Anatomic Location and Connection of cZi
Plaha et al 2006, Brain 129 1732-1747
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Target Sites for DBS Therapy
cZI
Vim Thalamus Essential Tremor
Subthalamic Nucleus Parkinsons diseaseand
Dystonia
Globus Pallidus Parkinsons diseaseand Dystonia
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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

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DBS Stereotactic Frameused for image guided
target localization
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DBS for MS tremor
OFF
ON
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DBS for MS tremor
OFF
ON
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DBS for MS tremor
OFF
ON
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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).

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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

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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.

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Anatomic Location and Connection of cZi
Plaha et al 2006, Brain 129 1732-1747
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Deep Brain Stimulation
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Zona Incerta Gross Anatomy
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Physiologic Target confirmation Microelectrode
Recording
Border
Sagittal Section Through the Thalamus
10sec
80ms
STN
10sec
80ms
Border/SN
10sec
80ms
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Implantation of Unilateral DBS into the zona
incerta, to be connected to a programmable IPG
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Demographic and Clinical Characteristics 4 Case
Studies
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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

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Tremor Assessment Global Rating Score

• Patient and examiner independently rated the
  patients pre-op vs post-op status
• Score ranges from -3 (markedly worse) to 3
  (markedly improved)
• No change (score 0)

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ADLs pre and post DBS MS
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Tremor Global Rating Score
Patient
Physician
Assessor
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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.

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• 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