Tremor

INDEX

ORIGIN

The aetiology of tremor in PD is poorly understood, but is thought to involve networks of both cortical and subcortical areas.  Rest tremors are modulated predominantly by multiple generators within the corticobasal ganglia and corticocerebellar circuitry.

A pharmacological fMRI study has shown that dopamine reduces Parkinson’s tremor by increasing inhibition in the ventral intermediate nucleus of the thalamus, which receives input from the cerebellum. This indicates that thalamic dopamine depletion may be involved in Parkinson’s resting tremor. Equally, dopamine failed to increase thalamic inhibition in patients with a relatively dopamine-resistant tremor1. Stereotactic interventions either in the basal ganglia or in the cerebellar thalamus (VIM) are highly effective in reducing Parkinson’s disease tremor, supporting the involvement of both circuits in tremor2.

CLASSIFICATION

Tremor types include:

Type I: classic Parkinsonian tremor at rest3

Unilateral (or asymmetric) rest tremor that increases in amplitude under mental stress, is suppressed when a goal directed voluntary movement is initiated and often during the course of a movement.  Note that re-emergent tremor is highly correlated with resting tremor, both in terms of tremor severity and in terms of dopamine response2. Rest tremor is less common  in other parkinsonian conditions such as multisystem atrophy (about 30%)4, corticobasal degeneration, and progressive supranuclear palsy.

Postural tremor, an action tremor, can be divided into re-emergent tremor (80%), with a dopaminergic basis, and pure postural tremor(20%), with a largely non-dopaminergic basis5:

Type II: rest and postural and kinetic tremors of different frequencies

Bilateral (usually asymmetric) action tremor coexisting with type I tremor, but may be of higher frequency (at least 1.5 Hz > rest tremor frequency)6. Some patients with this presentation have their postural tremor long before onset of other features of PD.

It is likely that the majority of PD patients with postural tremor have re-emergent tremor and the minority have a pure postural tremor1. In the majority of cases, the frequency of postural tremor is not different to their rest tremor frequency.

Type III: action tremor of the hands without a resting component

The frequency lies between 4 and 9 Hz. This is less common, and action tremors of this type can be difficult to distinguish from ET.  Pure postural tremor in PD, with a high frequency (8.1 Hz), is characterised by commencing without delay after assuming a posture holding position, and does not respond to levodopa5. Pure postural tremor, with features of minipolymyoclonus, is also found in degenerative conditions other than PD (eg Lewy body dementia, multisystem atrophy, corticobasal syndrome) and in secondary parkinsonism4.  This tremor, also described as ‘rippling’, is often found in the akinetic–rigid variant of PD or other degenerative (e.g. Lewy body dementia, corticobasal syndrome) or secondary parkinsonism.  

Monosymptomatic tremor at rest: A classic PD type I tremor (e.g. involving one limb or the jaw) for more than 2 years with no additional symptoms sufficient to diagnose PD characterizes the so-called monosymptomatic tremor at rest or benign tremulous parkinsonism, a specific variant of PD.

CLINICAL FEATURES

Early in the disease, tremor amplitude fluctuates significantly with mental or physical demands and thus is often described as intermittent.  As with most movement disorders, PD tremor is worsened by stress (which can be useful to bring out tremor during clinical evaluation) and disappears during sleep. Anxiolytics or alcohol can improve symptoms simply by reducing anxiety, which may lead to confusion as other tremulous disorders may also be responsive to alcohol, such as ET and myoclonus dystonia. 

 

(vv)1PDatrest.mp4(tt)

Examination of PD tremor at rest, upper limbs7.

(vv)2PDtremorrelaxedsupine.mp4(tt)

Examination of PD tremor at rest in supine position, upper and lower limbs7.

Tremor may emerge during other components of the examination, such as when the patient is walking, or when performing a movement with another body part, or by distraction manoeuvres such as counting backwards from 20.  Some patients may only have an increase in tremor amplitude during motor co-activation, such as when asked to open and close the contralateral hand, toe tapping or walking5.

(vv)3Activation.mp4(tt)

Activation of PD tremor by various manoeuvres7.

The tremors of PD progress more proximally up the arm as they generalize to both sides. A characteristic feature of PD rest tremor is suppression of tremor at onset of movement.The amplitude of rest tremor almost always diminishes or is abolished, at least transiently, during goal-directed voluntary movements. This suppression of tremor in PD may be best seen when adopting a posture holding position or reaching for a target, in both cases after rest tremor has been noted to be present; this may be replaced by a higher frequency postural tremor, for example, when grasping an object.

 

Examination of patient with PD to check for lessening or disappearance of rest tremor when carrying out an action. When carrying out such a manoeuvre, typically over half of patients have abolition of rest tremor, a third have a reduction of amplitude, and about 10% have no change in tremor severity8.

 

An alternative manoeuvre to assess resting tremor suppression is shown below; 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, that is, a brief ballistic movement7.

(vv)4RapidmovementandRETinPD.mp4(tt)

Video showing patient performing brief ballistic movement, with RET7.

 

http://nasa-courses.co.za/wp-content/uploads/2018/06/Emergent.bmp

 

Figure showing re-emergent tremor appearing with latency of 7 seconds9.

When evaluating RET it is important to appreciate that small voluntary movements may prevent the re-emergent tremor developing. This problem may be lessened by asking patients to make a brief ballistic movement and then to keep their arms outstretched for up to 60 seconds, as shown in the video below7:

(vv)5RETPDwithadaptations.mp4(tt)

Video showing patient with RET, diminished by small voluntary movements, and then re-emerging7.

 

(vv)Jankemergent.mp4(tt)

How to examine for Re-emergent Tremor5

WRITING AND DRAWING

Other than micrographia, decrementing bradykinesia, a gradual reduction in both speed and size of writing, occurs in some patients with Parkinson’s disease.

Figure showing the sequence effect: when an automatic sequence is elicited (in this case by repetitively copying the letter m), an incremental decrement in amplitude is seen12.

AGE OF ONSET

Rest tremor in PD usually starts after the age of 60 and progresses gradually.

DISTRIBUTION

Parkinson’s disease seldom causes head tremor, but is associated with tremor of the tongue, chin, jaw, or mouth, none of which are common features of ET. Tremor in the leg may be seen, and unilateral leg tremor is usually an indication of underlying PD.

NEUROPHYSIOLOGICAL TESTING

PD rest tremor typically shows alternating (less commonly synchronous) contraction of agonist and antagonist muscles at a frequency of less than 6 Hz with relatively sinusoidal displacement on accelerometric tracings.

http://nasa-courses.co.za/wp-content/uploads/2018/06/PD-tremor.bmp

Electromyography (EMG) Profile, Movement Analysis, and Frequency Spectrum of Rest Tremor in a patient with PD.

(A) EMG profile. The first two traces represent surface EMG signal from forearm muscles; ECR, extensor carpi radialis; FCR, flexor carpi radialis. The bottom trace reflect displacement (darker line) derived from accelerometry. Note the relatively sinusoidal tremor displacement in the symptomatic left hand13.

(B) Frequency spectrum of tremor displacement demonstrating a peak between 4 and 6 Hz in the symptomatic left (upper gray line) hand, with a trace peak present in the right (lower black line) hand13.

DIFFERENTIAL DIAGNOSIS

Rest tremor/Pill-rolling tremor is seen uncommonly in:

  1. Dystonic Tremor: see section on dystonic tremor.
  2. ET: may have rest tremor present.
  3. Holmes’ tremor: this has rest component
  4. Parkinsonism:

Postural Tremor:

As noted, higher frequency 5-8 Hz lower amplitude action tremors are not uncommon in PD and can be difficult to distinguish from ET. In the case of postural tremor due to enhanced physiological tremor (a peripherally generated tremor), weighting the limb changes the tremor frequency, which distinguishes it from centrally generated tremor conditions (such as ET and PD).

 

Table: Distinguishing PD from ET 14

 

TREATMENT

Rest tremor

A consistent and excellent response to levodopa is obtained for bradykinesia and rigidity, but not for tremor in PD15.  Rest tremor may be treated with anticholinergics, clozapine, or STN DBS, and some authors suggest levodopa up to 1500 mg for six months.

Clozapine Test: 25-50 mg at night is predictive and can be performed at home;  typical clozapine dose is 75-100 mg daily.  A test dose of 12. 5 mg has also been given in the daytime (for example, in the clinic).  Clozapine requires monitoring of the white cell count for the first 18 weeks of treatment, then monthly.   Clozapine must be discontinued immediately if either the WBC count is less than 3,000/mm3 or the absolute neutrophil count (ANC) is less than 1,500/mm3 at any time during treatment.

DBS, typically of STN, is an effective treatment in many patients.

Type II and III tremors

These tremors may be treated with propranolol, primidone or topiramate. These drugs may be combined.

 

 

REFERENCES

  1. Dirkx MF, Den Ouden HEM, Aarts E, et al. Dopamine controls Parkinson’s tremor by inhibiting the cerebellar thalamus. Brain. 2017;140(3):721-734. doi:10.1093/brain/aww331
  2. 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
  3. Deuschl G, Papengut F, Hellriegel H. The phenomenology of Parkinsonian tremor. Parkinsonism Relat Disord. 2011;18:S87-S89. doi:10.1016/s1353-8020(11)70028-1
  4. Kaindlstorfer C, Granata R, Wenning GK. Tremor in Multiple System Atrophy - a review. Tremor Other Hyperkinet Mov (N Y). 2013;3(0):1-9. doi:10.7916/D8NV9GZ9
  5. Dirkx MF, Zach H, Bloem BR, Hallett M, Helmich RC. The nature of postural tremor in Parkinson disease. Neurology. 2018;90(13):e1095-e1102. doi:10.1212/WNL.0000000000005215
  6. Deuschl G, Bain P, Brin M, et al. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord. 1998;13 Suppl 3(S3):2-23. doi:10.1002/mds.870131303
  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. 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
  9. Mailankody P, Thennarasu K, Nagaraju BC, Yadav R, Pal PK. Re-emergent tremor in Parkinson’s disease: A clinical and electromyographic study. J Neurol Sci. 2016;366:33-36. doi:10.1016/j.jns.2016.04.041
  10. Roze E, Coêlho-Braga MC, Gayraud D, et al. Head tremor in Parkinson’s disease. Mov Disord. 2006;21(8):1245-1248. doi:10.1002/mds.20918
  11. Thomas A, Bonanni L, Antonini A, Barone P, Onofrj M. Dopa-responsive pseudo-orthostatic tremor in Parkinsonism. Mov Disord. 2007;22(11):1652-1656. doi:10.1002/mds.21621
  12. Chatterjee A, Hamilton RH, Amorapanth PX. Art Produced By a Patient with Parkinson’s Disease. Behav Neurol. 2006;17(2):105-108. doi:10.1155/2006/901832
  13. Hess CW, Pullman SL. Tremor: clinical phenomenology and assessment techniques. Tremor Other Hyperkinet Mov (N Y). 2012;2:1-15. doi:10.7916/D8WM1C41
  14. Thenganatt MA, Louis ED. Distinguishing essential tremor from Parkinson’s disease: bedside tests and laboratory evaluations. Expert Rev Neurother. 2012;12(6):687-696. doi:10.1586/ern.12.49
  15. Jiménez MC, Vingerhoets FJG. Tremor revisited: Treatment of PD tremor. Parkinsonism Relat Disord. 2012;18:S93-S95. doi:10.1016/S1353-8020(11)70030-X