Transcript Essential Tremor Slide Set

Essential Tremor:
Approaches to Treatment
Part 6 of 7
www.wemove.org
Essential Tremor Slide Library Version 1.0 - All Contents Copyright © WE MOVE 2001
ET: Therapeutic Options
• No treatment
• Physical/psychological measures/lifestyle
changes
• Pharmacologic approaches
• Surgical management
www.wemove.org
Rationale for No Treatment
• Side effects may be more severe than
symptoms or disability from tremor
• No agents are known to effect the rate of
disease progression
• Disability may be minimal in some patients
www.wemove.org
Physical and Psychological
Measures/Lifestyle Changes
• Application of weights to affected limbs
with decreases in tremor amplitude
proportional to the weight applied
• Biofeedback and relaxation techniques
www.wemove.org
Drug Therapy for Essential Tremor
• Reasonable option for any patient with
disabling tremor
• Pharmacologic therapy may produce a
significant reduction in tremor
www.wemove.org
Pharmacologic Approaches
• Beta-blockers such as propranolol
(Inderal®)
• Primidone (Mysoline®)
• Combination Primidone/propranolol therapy
• Calcium channel blockers
• Carbonic anhydrase inhibitors
• Botulinum toxin type A (BOTOX®)
• Other medications
www.wemove.org
Beta-blockers
Propranolol (Inderal®) is the most studied
beta-blocker for ET
– Response is highly variable and the tremor is
rarely totally suppressed
– Approximately 50% to 70% of patients obtain
some symptomatic relief
– Amplitude may be decreased but frequency
typically remains constant
www.wemove.org
Other Beta-blockers
•
•
•
•
•
Available and studied for ET...
Metoprolol (Lopressor®)
Timolol (Timoptic®)
Atenolol (Tenormin®)
Nadolol (Corgard®)
www.wemove.org
Propranolol
www.wemove.org
Primidone
®
(Mysoline )
• Demonstrated efficacy in placebo-controlled trials
with reported 66% reduction in tremor severity
• Initiation of therapy with low dose. Mysoline
suspension may be useful (250mg/5ml)
• Slow upward titration
• Dosage of 250 mg/day appears to be an
effective dose
• Maximum dosage is 750 mg/day in three
divided doses
www.wemove.org
Primidone (cont.)
• Primidone as effective or slightly more effective
than propranolol (Koller, 1986; Wastelewski et al.,
1998)
• Long duration of benefit from a single dose
• Occasional acute, transient idiosyncratic toxic
response
• Long-term therapy generally well tolerated
www.wemove.org
Primidone (cont.)
• Experiment with a single evening dose equal to
total daily dose
• CBC before drug initiation
• Recheck CBC every 6 to 12 months for rare
hematologic dyscrasias
• Some patients become tolerant to the effects,
perhaps with disease progression
www.wemove.org
Response to Primidone
• Some patients have a shorter clinical
response to primidone
• More frequent dosing may be required
(Koller W. Neurology 1986;36:121-124)
www.wemove.org
Primidone (cont.)
Primidone has been shown in several
placebo-controlled trials to be...
• Effective for essential tremor
• Resulting in a reported 66% reduction
of tremor
www.wemove.org
Primidone: Adverse Effects
• Adverse effects with chronic therapy
minimal in most patients. Propranolol often
less well tolerated
• Up to 20% or fewer experience an acute
toxic reaction
• Acute reactions are more common with
larger initial doses
www.wemove.org
Primidone: Adverse Effects (cont.)
• Recovery from acute reaction is invariable
• Ongoing therapy after reaction generally tolerated
• Patients advised about the risk of acute reactions
are more likely to continue therapy
• Slow upward titration of primidone or use of
primidone in suspension may reduce the risk
of acute reactions
www.wemove.org
Combination Therapy
Primidone and propranolol may be used in
combination
• Primidone initiated at 12.5 mg to 25 mg
at bedtime
• Propranolol added, usually at 40 mg tid
• Long-acting formulation of propranolol may be
substituted if once-daily administration is desired
www.wemove.org
Other Pharmacologic Approaches
• Calcium channel blockers: nimodipine
(Nimotop®) and nicardipine (Cardene®)
• Carbonic anhydrase inhibitors:
acetazolamide (Diamox®) and
methazolamide (Neptazane®)
• Benzodiazepines: clonazepam (Klonopin®),
diazepam (Valium®) and alprazolam
(Xanax®)
www.wemove.org
Efficacy of Medications in
Essential Tremor Patients*
* Values express percentage of patients reporting greater than 50% tremor reduction.
www.wemove.org
† Not applicable as these data were not collected.
Other Miscellaneous
Pharmacologic Agents
•
•
•
•
•
•
Theophylline
Isoniazid (Nydrazid®): ineffective
Clonidine (Catapres®): ineffective
Gabapentin (Neurontin®): ineffective
Topiramate: under investigation
Clozapine (Clozaril®): effective
in open-label studies
www.wemove.org
Botulinum Toxin Type A (BOTOX®)
• Hand tremor: Reduced tremor amplitude
by 30%. No improvement in functional
ratings. Finger weakness usually
unacceptable to the patient.
• Head tremor: BTX-A produced clear
improvement in clinical rating scales and
subjective patient ratings. Minimal side
effects.
www.wemove.org
Summary: Drug Therapy for ET
• Primidone as initial therapy for patients with
disabling tremor
• Nonselective beta-blocker added to primidone
therapy in patients with residual tremor or
substituted for primidone in nonresponders
• Botulinum toxin type A (BOTOX®) injections
considered for patients with medication-refractory
head tremor
• BTX-A occasionally considered for patients with
severe hand tremor
www.wemove.org
Surgical Management of ET
Procedures with proven efficacy:
• Stereotactic thalamotomy
• Chronic thalamic stimulation (DBS)
Pahwa R, Koller W. Surgical treatment of essential tremor. In: Bain P, Brin M,
Deuschl G, Elble R, Findley L, Jankovic J, Koller W, Pahwah R. Current
issues in essential tremor. A continuing medical education monograph.
Embryon 1999;27.
www.wemove.org
Thalamotomy for ET
• For severe unilateral or asymmetric tremor
• Stereotactic lesioning of the ventralis
intermedius (VIM) nucleus
• Efficacy: approximately 78% to 100% of
patients show contralateral improvement
and tremor remission
• Long-term relief with benefits continuing
in most patients
www.wemove.org
Thalamotomy for ET (cont.)
• Bilateral thalamotomies usually not
performed due to high risk of permanent
dysarthria
• ~70% of patients with voice tremor improve
with unilateral thalamotomy
• Incomplete lesioning may lead to
reemergent tremor within two months
www.wemove.org
Thalamotomies in ET
www.wemove.org
Thalamotomy: Adverse Effects
Risk of major operative complications
less than 2%
• Surgical morbidity is rare but can be catastrophic
• Uncommon but usually transient occurrence of
cerebral hemorrhage, seizure, cerebellar signs,
hemiparesis, cognitive deficits
• Dysarthria may be severe in bilateral
thalamotomies
www.wemove.org
Thalamic Deep Brain Stimulation (DBS)
• Approved for use in patients with ET
in 1998
• No lesioning as in thalamotomy
• Wire electrode placed in the target area
(VIM)
www.wemove.org
Thalamic DBS (cont.)
• Connecting wire tunneled under the scalp to
subclavicular region
• Wire connected to surgically placed
implantable pulse generator (IPG)
• Continuous electrical stimulation delivered
to the target area
• Hand-held magnet turns stimulator on or off
www.wemove.org
Thalamic DBS (cont.)
• Programming of the pulse generator
includes setting…
–
–
–
–
Optimal electrode montage
Pulse width
Voltage
Stimulation frequency
• Contralateral arm tremor reduced by ~80%
www.wemove.org
Pathways Relevant to the
Pathophysiology of Tremor
Vidailhet M, Jedynak C, Pollak P, Agid Y. Pathology of symptomatic tremors.
Mov Disord 1998;13(suppl 3):49-54.
www.wemove.org
High Frequency Thalamic
Stimulation for ET
www.wemove.org
Thalamic DBS: Side Effects
• Double-blind study comparing DBS and
thalamotomy showed them equally effective
but fewer side effects with DBS
• Bleeding may occur
• Limb parasthesias most common side effect
• Hardware failure and infections
www.wemove.org
Thalamic DBS: Advantages
• Reversibility
• Adaptability
• Potential ability to perform bilateral operations
for hand tremor with reduced risk of morbidity
• Late tremor recurrence addressed by adjustments
of pulse generator programming parameters
Pahwa Rajesh, Koller William C. Surgical treatment of essential tremor.
In: Bain Peter, Brin Mitchell, Deuschl Günther, Elble Rodger, Findley
Leslie, Jankovic Joseph, Koller William, Pahwah Rajesh. Current
issues in essential tremor. Embryon 1999;30.
www.wemove.org
Thalamic DBS: Disadvantages
•
•
•
•
Increased expense
Implantation of foreign material
Need to replace batteries/hardware
Effort and time to optimize stimulation
parameters
www.wemove.org
Patient Selection for Surgery
Possible candidates for stereotactic
procedures include ET patients with
disabling medication-resistant tremor
Contraindicated in those with...
• Marked cognitive problems
• Unstable medical diagnosis that may
significantly increase surgical risk
www.wemove.org
ET Treatment Summary
• Therapy plan guided by measures of disability,
handicap, and quality of life
• When disability exists, drug treatment should be
attempted, unless contraindicated
• Nonresponders to oral medications may respond
to botulinum toxin type A injections
• Surgical options may be appropriate for severe
tremor refractory to conservative management
www.wemove.org