Tremor

INDEX

Essential tremor is a common disorder affecting ~1% of the general population and ~5% of the population over 65 years of age.

An approximately symmetric postural or kinetic tremor involving the hands and forearms is mandatory for the diagnosis.

Definition includes the following1:

  1. Isolated tremor syndrome of bilateral upper limb action tremor with or without tremor in other locations (e.g. head, voice, lower limbs)
  2. Duration of more than 3 years
  3. With or without tremor in other locations (e.g., head, voice, or lower limbs)
  4. Absence of other neurological signs (e.g. dystonia, ataxia and Parkinsonism) which could explain the tremor.

Alcohol responsiveness and family history are not sufficiently consistent to aid the definition of ET. Largely, the diagnosis of ET is based on excluding distinctive tremor types rather than asserting what is the tremor of ET2.

There is ongoing uncertainty about the meaning of clinically detectable additional findings in subgroups of ET, such as mild dystonic or ataxic signs. Therefore the new classification proposes to keep these subgroups as a separate entity called ‘Essential tremor plus’ which is defined as tremor with the characteristics of ET and additional neurological signs of uncertain significance such as impaired tandem gait, tremor at rest, questionable dystonic posturing, memory impairment or other mild neurological signs of unknown significance1.

ORIGIN

The pathophysiology of essential tremor has been linked to abnormal, oscillatory activity within the cortico-olivo-cerebello-thalamic circuit3. Oscillations are then transmitted to the spinal motor neuronal pool, and coherence for both proximal and distal muscles between cortex and the motor unit has been demonstrated.

The relatively stable tremor in essential tremor may fit with a single oscillator, that is, the inferior olive or deep cerebellar nuclei, although there is increasing scepticism about the role of the inferior olive in ET4.  Evidence supporting this network hypothesis include lesion analysis (a lesion of the cerebellum or its outflow tracts can abolish the tremor in ET patients almost completely) and the success of VIM DBS for alleviating ET.

CLASSIFICATION

There are very different approaches to understanding ET:

The main phenotypes of ET are:

ET may be considered to be a prototypical syndrome of an isolated action tremor.

Head movements occur in a vertical or horizontal plane (yes/yes and no/no tremor). Postural tremor may occur in the head in about 40% of patients with ET. Typically, the head tremor is a postural tremor which resolves at rest, that is, the tremor abates in the supine position. Head tremor is more often present in patients with disease of long duration, and is six times more common in women than men.

Jaw tremor is present in 10-20% of ET cases with persistent rest tremor and 10% of cases without rest tremor. ET patients with jaw tremor tend to be older, and have a more clinically severe and widespread disorder.  The tremor is predominantly a postural tremor (occurring during voluntary mouth opening) or kinetic tremor (occurring while speaking). A small number of patients may also exhibit mild tremor while their mouth is closed; however, in these it can be difficult to determine whether the jaw is fully relaxed. Overall, jaw tremor is uncommon in patients with ET, and it is important to note that jaw tremor is well recognized in PD and is also seen in dystonia.  (Jaw tremor may also be associated with neuroleptic treatment, and there is also a high frequency isolated jaw tremor of 14-16 Hz.)

Frequently tremor in these regions occurs in association with hand tremor. These midline tremors occur in patients with long-standing ET affecting the upper limbs, with older age and female gender appearing to be risk factors. Many patients with isolated voice tremor do not have ET, but suffer from laryngeal dystonia.

This is an infrequent form of tremor with kinetic leg tremor seen in fewer than 10% of patients.

CLINICAL FEATURES

The tremor of ET is typically a postural and/or kinetic tremor (i.e. tremor during voluntary motion) most commonly affecting the arms and hands. When rest tremor is present, it will increase during movement onset in about half the patients, and stay the same in the remainder, and will not decrease or disappear as in PD5.

Frequency: Typically, tremor has a frequency of from 4 to 12 Hz in the arms without any other neurological signs.  The frequency of tremor is inversely related to age, with older patients generally having the slowest tremor frequencies. Amplitude, and to a lesser extent, frequency can vary, and change with different tasks.

Symmetry: Although ET is classically a symmetrical tremor, the arm tremor of ET may be mildly to moderately asymmetric (30% of cases have asymmetry of more than 50%). 

Regularity: Tremor in early ET may be jerky and intermittent, and some types may be myoclonic and jerky many years still after tremor onset.

Presentation: ET may start with a postural tremor that can still be suppressed during goal- directed movements, resulting in a non-disabling tremor, and as a result, many ET patients are never seen by a neurologist.

Task related difficulties such as with eating and drinking are typical of ET.  Tremor may be suppressed by performing skilled manual tasks, and tremor resolves when the body part relaxes as well as during sleep.

The tremor of ET may improve with alcohol intake (50-75% of patients), but alcohol responsiveness is not specific for ET since other tremors, such as dystonic tremor, may improve as well. Alcohol-responsive patients may also experience a “rebound” period, typically 3 to 4 hours after consumption, during which time there is worsening of the tremor.

A number of subtle abnormalities may also be found in ET, which can be grouped into:

TREMOR TYPES

SPECIFIC EXAMINATION FEATURES

(vv)ExaminationpatientET.mp4(tt)

Examination of patients with Essential Tremor6

(vv)4RapidmovementandRETinPD.mp4(tt)

To assess resting tremor suppression by a voluntary movement (and to test for tremor re-emergence thereafter), wrist extension is often more suitable than the other postures, because this movement can be done rapidly.

WRITING AND DRAWING

With respect to generation of a spiral, ET patients are more likely to demonstrate a single predominant axis as compared to dystonic tremor. The ET tremor often has an intentional component at the moment of initiation of the spiral.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

    In ET, spirals drawn with the right hand typically have a single identifiable tremor orientation axis (i.e., tremor is most severe at 1-2 o'clock), whereas those drawn with the left hand have a single identifiable tremor orientation axis that is 90° to that on the right (i.e., tremor is most severe at 10–12 o'clock) 8.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

    (A) The Archimedes spiral shows a unidirectional tremor axis in the 8–2 o’clock direction, suggesting essential tremor, but it is not clear whether the amplitude and frequency are constant. The line drawn perpendicular to the tremor axis emphasises the amplitude and makes it easier to discern that it is also constant, as is the frequency9.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

   

(B) The handwriting is tremulous and potentially compatible with either essential tremor or dystonic tremor. The spirals show a unidirectional 8–2 o’clock axis on the right, and a 10–4 o’clock axis on the left, symmetrical in size and severity—all features that point towards essential tremor.

However, the regularity of the amplitude and frequency is difficult to determine from the spirals as the severity of the tremor causes the turns to overlap. The straight line drawings demonstrate that the amplitude, frequency and axis are all constant. The left (dominant) handed vertical line has 18 oscillations drawn over 2 s, giving an estimated frequency of 9 Hz9.

 

 

 

 

 

 

  

 

 

 

 

 

 

 

 

 

 

 

 

 

    (C) Spiral drawings from a patient with severe essential tremor showing large tremor oscillations with a unidirectional axis, fairly regular amplitude and frequency, and symmetry between the hands. An enlarged spiral is sometimes seen in severe essential tremor, perhaps reflecting ataxia that may occur as part of the disorder, or to compensate for the size of the penstroke undulations9.

 

 

 

 

 

 

 

 

 

 

One method to clarify tremor variability is to ask the patient to draw a line at a steady rate and in a direction perpendicular to the tremor axis of the spiral (see figure B above). A longer tracing of the tremor makes it easier to see whether the amplitude and frequency are constant (usual in essential tremor) or variable (more suggestive of dystonic or functional tremor).

AGE OF ONSET

Hereditary ET is fully penetrant by 65 years and all forms of ET have a bimodal age of onset with peaks in the 2nd and 6th decade. This suggests the existence of at least two different pathophysiologic entities, potentially with different courses.  There is an undefined boundary between senile tremor and the reported distinct second epidemiological age peak of ET: see Senile Tremor in the section on Differential Diagnosis, below. Many elderly patients retrospectively recall the onset of tremor as young adults, but then a long period of relative stability with mild tremor (i.e., a plateau), followed by a relatively rapidly progressive worsening of tremor in the seventh or eighth decade of life.

PROGNOSIS

The late-onset ET group may be associated with nonmotor symptoms possibly representing the transitional manifestations to developing PD, dementia and postural impairment.  Predictive factors of greater severity include older age, longer disease duration, and the presence of voice tremor.

DISTRIBUTION

Upper limbs >> head >> voice >> face/jaw >> tongue >> trunk >> lower limbs

Lower limb tremor occurs in classic ET but is typically mild and asymptomatic. Rest tremor in the lower limbs is not a feature of ET, even when there is rest tremor in the hands. 

DIAGNOSIS

The core features are bilateral postural tremor of the forearms, with or without additional kinetic tremor. No other neurological signs should be present, apart from Froment's sign. However, note that many patients will show difficulty with tandem gait, and intention tremor that is indistinguishable from cerebellar disease.

DIFFERENTIAL DIAGNOSIS

See Table: Types of Tremor note that misdiagnosis of ET is common, and that, in particular, dystonia is frequently misdiagnosed as ET. 

Isolated focal, position-specific, and task-specific tremors are not likely to be ET and are often associated with subtle dystonia (see section on dystonic tremor).

Features that are not typical of ET are:

  1. Unilateral arm tremor
  2. Isolated head or leg tremor
  3. Re-emergent tremor
  4. Presence of a null point or sensory trick
  5. Tremor directionality
  6. Reduced arm swing

DIAGNOSTIC TESTS

On the whole, no specific tests are required, and ET is, to some extent, a diagnosis of exclusion.

Tests that may be performed include:

  1. Spiral drawing before and after alcohol.
  2. Tandem gait: More than three missteps over 10 metres.

NEUROPHYSIOLOGICAL CRITERIA FOR ET14

1. Rhythmic burst of postural tremor on EMG.

2. Tremor frequency > 4 Hz.

3. Absence of rest tremor, or, if rest tremor is present, frequency 1.5 Hz lower than the postural tremor.

4. Absence of tremor latency from rest to postural position (>2 s).

5. Changes of the dominant frequency peak to less than or equal to 1 Hz after the weight load test. ET is therefore characterized by a tremor frequency which does not change significantly with loading (due to a fixed central oscillating mechanism).

6. No changes in tremor amplitude after mental concentration.

TREATMENT

Medical treatment leads to a reduction of tremor symptoms in 50% of patients but rarely to complete disappearance of tremor symptoms. Medical treatment often has a better effect in patients with low amplitude tremor than for individuals with high amplitude tremor. Intention tremor has a major impact on patients’ disability, but intention tremor responds less well to medication than pure postural tremor.

Surgical treatments include:

1. Deep brain stimulation (DBS)

2.  Radiofrequency (RF) thalamotomy

3. Gamma knife radiosurgical (GKRS) thalamotomy

4. Focused ultrasound (FUS) thalamotomy.

See:

Martino, D., Espay, A., Fasano, A. and Morgante, F. (2016). Disorders of Movement. Berlin, Heidelberg: Springer Berlin Heidelberg. Guidelines from this reference are found below15:

Gironell, A. & Kulisevsky, J. Review: Diagnosis and management of essential tremor and dystonic tremor. Ther. Adv. Neurol. Disord. 2, 215–222 (2009)16.

http://www.nasafordoctors.co.za/pdfs/ETmed2.pdf

 

Comparison of Surgical Outcomes for ET17.

REFERENCES

1.           Bhatia KP, Bain P, Bajaj N, et al. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018;33(1):75-87. doi:10.1002/mds.27121

2.           Espay AJ, Lang AE, Erro R, et al. Essential pitfalls in “essential” tremor. Mov Disord. 2017;32(3):325-331. doi:10.1002/mds.26919

3.           Hopfner F, Helmich RC. The etiology of essential tremor: Genes versus environment. Park Relat Disord. 2018;46:S92-S96. doi:10.1016/j.parkreldis.2017.07.014

4.           Nieuwhof F, Panyakaew P, Van De Warrenburg BP, Gallea C, Helmich RC. The patchy tremor landscape: Recent advances in pathophysiology. Curr Opin Neurol. 2018;31(4):455-461. doi:10.1097/WCO.0000000000000582

5.           Papengut F, Raethjen J, Binder A, Deuschl G. Rest tremor suppression may separate essential from parkinsonian rest tremor. Park Relat Disord. 2013;19(7):693-697. doi:10.1016/j.parkreldis.2013.03.013

6.           Hopfner F, Deuschl G. Is essential tremor a single entity? Eur J Neurol. 2018;25(1):71-82. doi:10.1111/ene.13454

7.           Zach H, Dirkx M, Bloem BR, Helmich RC. The clinical evaluation of Parkinson’s tremor. J Parkinsons Dis. 2015;5(3):471-474. doi:10.3233/JPD-150650

8.           Michalec M, Hernandez N, Clark LN, Louis ED. The spiral axis as a clinical tool to distinguish essential tremor from dystonia cases. Park Relat Disord. 2014;20(5):541-544. doi:10.1016/j.parkreldis.2014.01.021

9.           Alty J, Cosgrove J, Thorpe D, Kempster P. How to use pen and paper tasks to aid tremor diagnosis in the clinic. Pract Neurol. 2017;17(6):456-463. doi:10.1136/practneurol-2017-001719

10.        Chaudhuri KR, Buxton-Thomas M, Dhawan V, Peng R, Meilak C, Brooks DJ. Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. J Neurol Neurosurg Psychiatry. 2005;76(1):115-117. doi:10.1136/jnnp.2004.046292

11.        Bain PG. Essential tremor and senile varieties of action tremor an evolving ART. Mov Disord. 2015;30(10):1301-1303. doi:10.1002/mds.26342

12.        O’Hearn E, Holmes SE, Calvert PC, Ross CA, Margolis RL. SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology. 2001;56(3):299-303. doi:10.1212/WNL.56.3.299

13.        Kalia L V., Rockman-Greenberg C, Borys A, Lang AE. Tremor in Spinocerebellar Ataxia Type 12. Mov Disord Clin Pract. 2014;1(1):76-78. doi:10.1002/mdc3.12015

14.        Gironell A, Kulisevsky J, Pascual-Sedano B, Barbanoj M. Routine Neurophysiologic Tremor Analysis as a Diagnostic Tool for Essential Tremor: A Prospective Study. J Clin Neurophysiol. 2004;21(6):446-450. doi:10.1097/00004691-200411000-00009

15.        Martino D, Espay AJ, Fasano A, Morgante F. Disorders of Movement: A Guide to Diagnosis and Treatment. Berlin-Heidelberg: Springer; 2016.

16.        Gironell A, Kulisevsky J. Review: Diagnosis and management of essential tremor and dystonic tremor. Ther Adv Neurol Disord. 2009;2(4):215-222. doi:10.1177/1756285609104791

17.        Dallapiazza RF, Lee DJ, De vloo P, et al. Outcomes from stereotactic surgery for essential tremor. J Neurol Neurosurg Psychiatry. 2019;90(4):474-482.