Based On NEJM

1. JOURNAL PRESENTATION ON
ESSENTIAL TREMOR
Presented By-
Dr. Ejaj Uddin Ahmed
MD Resident (Phase A)- Critical Care Medicine
BIRDEM
The NEW ENGLAND JOURNAL Of
MEDICINE

3. Introduction
Tremor
Tremor may be defined as involuntary rhythmic oscillatory
movement produced by alternating contractions of
reciprocally innervated muscle.
Classification can be broadly based on whether it occurs during rest
or during action.

4. Tremor Branch Diagram
Tremor
Resting
Better on
action
Parkinsonian
Persists or
worsens on
action
Rubral
Action
Intention
Cerebellar
Postural
Symmetrical
at onset
Physiologic
Asymmetrical
at onset
Essential

5. Essential Tremor
A task force of International Parkinson and Movement Disorder
Society proposed a new formal definition of Essential tremor. It’s as
follows-
A syndrome of isolated tremor of both upper limbs with a duration of
at least 3 years, with or without tremor in other locations, such as
head, larynx (voice tremor) or lower limbs.
Isolated in this context means that, tremor is the only abnormal sign.

6. Another syndrome ‘Essential Tremor Plus’ includes additional
neurologic signs so mild as to be of uncertain clinical significance. (e.g.
impaired tandem gait, questionable dystonic posturing, impaired
memory) that do not suffice for additional or alternative diagnosis.

9. Epidemiology
Prevalence of 415/100,000 persons older than 40 (Haerer et al).
Affect 1% of the population worldwide.
Male: Female ratio 1:1
Bimodal Distribution with age. Peaks in 2nd and 6th decades of life.
Positive family history in more than 50% of the cases.
Autosomal Dominant in pattern with high penetrance.

10. Co relates
• Environmental risk factor includes higher exposure to beta-carboline
alkaloids. These are present in overcooked meats.
• Genetic risk Variants have been described in LING01, SLC1A2, STK32B,
PPARGC1A and CTNNA3
• Worsened by- Emotion, Exercise, fatigue

11. Pathophysiology
Several lines of evidence suggests towards cerebellar dysfunction. In
case of essential tremor--
i. Decreased amount of N-acetylaspartate in the cerebellum,
indicating loss or dysfunction of neurons.
ii. Loss of purkinje’s cell in the cerebellum.
iii. Increased number of torpedoes( swollen axons of purkinje’s cell)
and loss of dendritic arborization.

12. • iv. Increased LING01 level and GABA dysfunction in cerebellum.
• v. Cerebellar metabolism is high at rest, increases with arm extension
and decreases by taking ethanol( ethanol suppresses ET)
• vi. Cellular burst in the cerebellar receiving zone of the
thalamus(Ventral Intermediate Nucleus) correlates with the tremor
itself.
• vii. Pathophysiology of tremor certainly involves cortico-ponto-
cerebello-thalamo-cortical loop. Source of oscillation is unknown
though.

14. Assessment
Full assessment should include history taking, neurological
examinations and laboratory testing.
 History should include particularly duration of illness, age of onset,
family history and drug history.
 Drugs known to potentiate tremor includes- Valproate, SSRI,
Sympathomimetic drugs, Lithium
 Complete neurological examination with visual estimation of tremor
and assessing signs to find other systemic illness is mandatory.

15. Laboratory testing
• Routine lab tests are done to exclude any metabolic or hormonal
illness which may cause enhanced physiological tremor.
• Complete History and examination are often sufficient to make a
diagnosis.
• Early Parkinson’s disease can reliably be distinguished from ET by
single photon-emission computed tomography using tracer 123I-
Ioflupane.
• Surface electromyography and accelerometry can be done to evaluate
muscle activation characteristic and differentiate ET from Enhanced
Physiological Tremor.

16. Treatment
Treatment
Pharmacological
1st line: Propanolol
,Primidone
2nd line:
Gabapentine,Topiramate,
Alprazolam
Neurostimulation
and ablative therapy
Deep Brain
Stimulation
Thalamotomy

17. Pharmacotherapy
• Propanolol and Primidone are the two compounds with highest level
of evidence to treat ET by reducing severity of upper limb symptoms.
• Across randomized controlled trials it has been shown that
propranolol is effective at doses ranging from 120 to 240 mg/day. Can
be given in divided dose or sustained release form.
• It takes several days to weeks to show effect.
• Trials show that tremor amplitude are reduced by 55%

18. • Primidone is also effective in reducing tremor and trials show that it
reduced 60% of upper limb tremors.
• Primidone has been effective in doses ranging from 250 to 750
mg/day.
• A randomized trial of propranolol-primidone combination showed
70% reduction in tremor amplitude versus a placebo.

19. Side effects
Propanolol Primidone
Bradycardia, Hypotension Dizziness
Bronchospasms Fatigue
Erectile Dysfunction Ataxia
Suicidal Tendency Malaise
Occurs in 8% of patient taking propanolol Occurs in 23-32% of people taking
primidone

20. RCT shows NO clinical benefits in case of following drugs
Flunarizine
Acetazolamide
Mirtazapine
Nifedipine
Pindolol
Trazodone
Verapamil
Amiframpidine
Levetiracetam

21. Surgical Approach
Thalamotomy (Unilateral)
Targets thalamic nucleus ventralis intermedius. Used in case of
medically intractable upper limb tremor in ET
Its use is limited to unilateral approach as bilateral thalamotomy
causes high risk of irreversible dysarthria or ataxia,sensory
disturbance.
Randomized trials shows less effectiveness of thalamotomy
compared to deep brain stimulation.

22. Deep Brain Stimulation(DBS)
It causes greater functional improvement and less side effects.
But unfortunately, at a 5 year follow up it was seen that half the
patient receiving DBS having a diminished effect. It has been reported
as a result of disease progression or tolerance to stimulation.
Adverse effects include- ataxia, dysarthria, paresthesias, muscle
contraction and impaired balance.

23. Focused Ultrasound
In 2016, the Food and Drug Administration approved a focused
ultrasound device to treat essential tremor that is refractory to medical
therapy. The approval was based on the results of a randomized,
controlled trial involving 76 participants with essential tremor, in which
unilateral thalamic thermoablation using focused ultrasound with
magnetic resonance imaging guidance resulted in a significantly greater
reduction in hand tremor and better quality of life over a period of 12
months.

24. The most common adverse events with focused ultrasound
thalamotomy were intra-procedural discomfort, as well as
postoperative paresthesia or numbness (in 38% of participants) and
gait disturbance (in 36%). At 12 months after the intervention, the rate
of paresthesia or numbness was 14%, and the rate of gait disturbance
was 9% .

25. Areas of Potentials
Essential tremor requires further study. The extent of degenerative
processes in the cerebellum in affected patients and their relevance to
the broad spectrum of essential tremor remain unclear. More data are
needed from randomized trials to provide information regarding the
effectiveness and risks of treatments for essential tremor. Clinical rating
scales and transducer-based methods to objectively quantify tremor
have been developed for use in clinical trials as well as in routine
practice.However, the clinical meaningfulness of observed changes in
these instruments is uncertain, and data are needed on patient-
reported outcomes and quality of life.

26. Development in Pharmacological Sector
Potential molecular targets for treatment of essential tremor include
the T-type calcium channel and GABA type A receptors. On the
basis of the tremor-suppressing effect of ethanol and its presumed
molecular action on these targets, the long-chain alcohol 1-octanol and
its metabolite octanoic acid have been proposed for treatment of
essential tremor; preliminary data have suggested benefit,although
further study is needed.

27. Development in interventional sector
Although the ventral intermedius nucleus of the thalamus has been the
primary target for surgical treatment of tremor, two regions below
the thalamus — the zona incerta and the white matter tract of
cerebellothalamic fibers (the prelemniscal radiation) — have been
proposed as alternative targets, with uncontrolled
studies suggesting a potentially greater effect than with the
conventional target.However, controlled trials are needed to confirm
efficacy.

28. Gadgets
New developments in stimulation therapies for essential tremor
include closed-loop stimulation using sensors to monitor tremor
activity to trigger and adjust stimulation in real time and
“on demand.” A tremor-cancelling spoon, which uses tremor sensors
that drive micro-motors to counteract the tremor and stabilize the
utensil, has been developed.