, Alberto J. Espay2, Alfonso Fasano3 and Francesca Morgante4
(1)
Neurology Department, King’s College Hospital NHS Foundation Trust, London, UK
(2)
James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA
(3)
Division of Neurology, University of Toronto Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease Toronto Western Hospital, UHN, Toronto, Ontario, Canada
(4)
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
5.1 An Introductory Note
Tremor is the most common movement disorder and denotes a rhythmic involuntary movement of one or several regions of the body [1]. Many conditions might be characterized by a tremor and the related disabilities are as diverse as their clinical appearance, pathophysiology and etiologies. A low-amplitude, high-frequency physiologic action tremor can be instrumentally detected in all normal subjects (physiological tremor). Pathologic tremor mostly interferes with normal motor function and is visible to the naked eye.
5.2 How to Recognize
A careful clinical examination focused on the following features classifying the tremor leads to the diagnosis in almost all patients.
Condition of activation. The patient should be examined under all the possible conditions capable of eliciting the tremor (Fig. 5.1 and Table 5.1). The following types of tremor can be seen:
Fig. 5.1
How to assess tremor. This figure and Table 5.1 show the possible combinations between activation and topography when assessing a tremor patient. Indeed, not all the body parts can be assessed during the same activation tasks (e.g. the tremor of the vocal cord can only be assessed during action, i.e. speaking). The Tremor Rating Scale proposed by Fahn, Tolosa and Marin in 1988 is the most used scale and comprises of three sections. Section A takes into account the aforementioned combination of activation tasks (rest, posture and kinetic tremor) and the different topography according to a 0–4 scale (total score is 84). Section B evaluates specific goal-directed tremors (handwriting for the dominant side, drawing spirals and lines and pouring water for both hands) according to a 0–4 scale (total score is 36) (l). Section C is a questionnaire addressing the functional disabilities resulting from the tremor (e.g. speaking, eating, drinking, etc.) according to a 0–4 scale (total score is 32). A general assessment of the functional limitations is provided by the examiner and the patient at the end of the scale (additional 8 points), thus resulting in a maximum score of 152, with higher scores representing worse tremors. More recently, the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) has been designed specifically for the clinical measurement of ET severity; it comprises of a 12-item activities of daily living subscale and a 9-item performance subscale that quantifies the tremor in the head, face, voice, limbs and trunk
Table 5.1
The possible combinations between activation and topography when assessing a tremor patient
Topography
Activation
Rest
Posture
Intention
Head
Lying down (A)
Lifting the head (B) or sitting (C) or standing
Face
Lying down (A) or sitting (C)
Tongue
Opening the mouth (D)
Protruded
Voice
Saying prolonged vocals aloud
Upper limbs (R and L)
Lying down or sitting with the hands on their lap (E) or the armchair
Arms out-stretched, wrists mildly extended, fingers spread apart (F)a or ‘bat-wing position’ (G)b
Finger to nose test (H)
Trunk
Lying down (A)
Sitting (C) or standing
Lower limbs (R and L)
Sitting with their feet on their heels or lying down (I)
Legs flexed at the hips and knees, foot dorsiflexed (J)
Heel to knee test (K) or toe to examiner’s finger
Orthostatic
Trunk/legs when standing
1.
Resting tremor occurs when the muscles of the affected body part are not voluntarily activated; the tremor usually ceases when a voluntary movement is initiated or performed.
2.
Action tremor is any tremor that is produced by voluntary contraction of muscles and covers five types:
(a)
Postural tremor is present while voluntarily maintaining a position.
(b)
Kinetic tremor occurs during voluntary movement and is further subdivided into:
Simple kinetic tremor (during purposeless voluntary movements)
Goal-directed tremor (during target reaching; historically labelled as ‘intention tremor’)
(c)
Task-specific tremor is a rare form only occurring during the performance of specific highly skilled, goal-oriented tasks such as handwriting or speaking.
(d)
Position-specific tremor is a rare form only occurring during the maintenance of certain postures.
(e)
Isometric tremor occurs during a voluntary muscle contraction that is not accompanied by any movement.
Topography. Tremors can occur in any joint or muscle that is free to oscillate (Fig. 5.2). By far, the upper limb is the most common location for a tremor to occur, but it can be spared or accompanied by a tremor in other regions. Symmetry is also important to take into account.
Fig. 5.2
Topography of tremor guides clinicians in the diagnosis. The figure shows the conditions (listed from the most to the least common) able to cause a tremor based on the specific body segment taken into account. By far, the upper limb is the most common location but it can be spared or accompanied by a tremor in other regions
Frequency. With some experience, three main frequency ranges can be distinguished on visual inspection: high (>7 Hz), medium (4–7 Hz) and low (<4 Hz).
Additional signs and symptoms. Additional patient’s features are important diagnostic hints, e.g. co-occurrence of dystonia for ‘tremor associated with dystonia’ (see below). Age should be also taken into account as tremor can also present during childhood (Table 5.2).
Table 5.2
Tremor conditions in newborns and during childhood
Physiologicala
Drugs
Mother’s drugs in newborn (direct effect or abstinence) see Table 5.8
See Table 5.8
Metabolic
See Table 5.7
Inborn errors of metabolism
Sepsis
Vitamin B12 deficiency
Neurodegenerative
Ataxias
Fragile X pre-mutation
Dystonia (e.g. DYT1 or DYT6)
Mitochondrial encephalopathy
Neuropathy (paediatric CMT)
Spinal muscular atrophies (e.g. Kennedy)
Westphal variant of Huntington’s disease
Wilson’s disease
Other organic conditions
Chromosomal disorders (e.g. 48XXYY, 47XYY)
Dopamine responsive dystonia
Geniospasm
Essential tremor
Structural problemsb
Abscesses
Hydrocephalus
Myelin disorders
Trauma
Tumours
Vascular lesions
Others
Functional
Psychological stress
5.3 How to Distinguish from Related Disorders
The use of any rational approach to make the final etiologic diagnosis is based on the assessment of the specific clinical features (activation, frequency and topography) used for the tremor classification (Table 5.3).
Table 5.3
Clinical features of the most common tremor syndromes
Diagnosis | Definition | Sym. | Activation | Freq. (Hz) | Additional symptoms | Familial history | Treatment | |||
|---|---|---|---|---|---|---|---|---|---|---|
R | P | GD | TP | |||||||
Essential tremor | Bilateral tremor of the hands or forearms with predominant kinetic tremor and resting tremor only in advanced stages with the absence of other neurological signs (with some exceptions) Isolated head tremor without evidence of abnormal posture may occur (see Table 5.5 for diagnostic criteria) | + | ± | + | + | 4–11 | Cogwheel phenomenon (no rigidity) Abnormal tandem gait (missteps) | ++/− | See text | |
Enhanced physiologic tremor | Abnormally increased amplitude of the normal physiological tremor. Other neurological symptoms or diseases that could cause the tremor must be excluded | + | + | + | 6–13 | – | – | It is typically only short-lived and improves once the cause is corrected (see Table 5.7). A single dose of a beta-blocking agent (e.g. propranolol 30–100 mg) can help to suppress this transient tremor that may interfere with important (e.g. professional) functions | ||
Parkinsonian tremors | ||||||||||
Type I | Unilateral (or asymmetric) resting tremor that increases in amplitude under mental stress and is suppressed during initiation of a movement and often during the course of a movement. ‘Re-emergent’ tremor is the same tremor occurring after some latency under postural and action conditions | – | ++ | ± | ± | 4–7 | Other parkinsonian features (rigidity, bradykinesia) | ± | Dopaminergic medications are effective but sometimes high doses are needed. Alternative approaches are the use of anticholinergics, clozapine and BoNT. Surgery and particularly DBS is highly effective when targeting either Vim, GPi or STN | |
Type II | Tremor coexisting with type I (frequency should be at least 1.5 Hz higher than type I); bilateral (usually asymmetric) postural/kinetic tremor of the hands | ± | + | + | 6–13 | ± | See the treatment of ET | |||
Type III | Postural/kinetic tremor of the hands without a resting component | ± | + | + | 6–13 | ± | Usually not needed | |||
Dystonic tremors | ||||||||||
Dystonic tremor | Postural/kinetic tremor, rarely at rest, occurring in the body region affected by the dystonia. Usually focal with irregular amplitudes and frequencies; antagonistic gestures lead to a reduction of the tremor amplitude | – | ± | + | + | ± | 5–10 | Dystonic posturing of affected region; other neurological signs (myoclonus, parkinsonism) in dystonia plus syndromes | ± | Drug efficacy is generally disappointing and a moderate effect is only found with anticholinergics, tetrabenazine, clonazepam, β-blockers and primidone. The largest amount of data available is for BoNT injections, which provide a marked improvement, particularly for the management of midline tremors (head or vocal cords) Refractory cases have been successfully treated with DBS of the Gpi. Vim DBS can also alleviate the tremor drastically but does not improve postures |
Tremor associated with dystonia | Postural/kinetic tremor in a body region not affected by dystonia but dystonia is present elsewhere (e.g. spasmodic torticollis with ‘ET-like tremor’) | + | + | + | 6–12 | Dystonia elsewhere in the body | ± | See the treatment of ET | ||
Dystonia gene-associated tremor | Postural/kinetic tremor usually affecting the hands (‘ET-like tremor’). No signs of dystonia but dystonia is present in relatives | + | + | + | 6–12 | – | + | See the treatment of ET | ||
Task- and position-specific tremor | Focal and irregular task-specific tremor. Tremor predominantly or only occurs during specific motor task (type A) or position (type B) | – | ± | ± | + | 5–10 | – | – | See the treatment of dystonic tremor. Orthotic device has been used with anecdotal success | |
Orthostatic tremors | ||||||||||
Primary OT | High-frequency trunk tremor only present during standing. None of the patients have problems when sitting and lying. Tremor may also involve upper limbs | + | ±* | + | 13–18 | – | ± | According to small double-blinded studies, gabapentin seems to have an excellent and most consistent beneficial effect and thus it is used as the first drug of choice for OT (1800–2400 mg daily). The drug of second choice is clonazepam. Primidone or L-dopa has not consistently shown efficiency as well. Some patients have been reported to improve with Vim DBS, particularly if performed bilaterally | ||
OT-plus and symptomatic OT | The association of OT and other primary neurological disorders (OT-plus) or a structural lesion (symptomatic OT) | + | ± | ± | + | 13–18 | Depending on the associated condition | – | Depending on the underlying aetiology | |
Slow-OT | Three sub-types can be recognized: (1) primary forms; (2) secondary forms, in the context of cerebellar and pontine lesions; (3) ‘pseudo’ forms corresponding to a parkinsonian type 1 tremor | ± | ± | + | 4–9 | Depending on the associated condition | – | Primary form: see the treatment of OT Secondary forms: intravenous immunoglobulin in autoimmune cases or chemotherapy in paraneoplastic forms Pseudo forms: L-dopa | ||
Cerebellar tremor | Pure or dominant intention tremor; a postural tremor (>5 Hz) resembling ET may be present. Titubation is a slow-frequency tremor involving the axial body parts (head or trunk) | ± | + | ++ | <5 | Other cerebellar signs (gait ataxia, dysmetria, hypotonia) | ± | Generally the drugs used for ET are used but satisfactory results are rare. New treatments for MS have been associated with an improvement of tremor in open-label studies: natalizumab, dalfampridine (the sustained release form of the potassium channel blockers 4-aminopyridine) and levetiracetam | ||
Holmes’ tremor | A slow-frequency and irregular resting tremor combined with an intention tremor of the same frequency as the resting component. Postural tremor may occur | – | + | + | + | 3–6 | Possible parkinsonian and cerebellar features | – | The effect of medication is generally poor. It is usually used for the treatment of parkinsonian tremor type 1 combined with the treatment for cerebellar tremor. Possible positive effect of onabotulinumtoxinA in patients variably injected into teres group muscles, shoulder adductor (pectoralis major) or shoulder abductor (deltoid). Some patients have dramatically responded to levetiracetam or zonisamide | |
Neuropathic tremor | A variable postural/kinetic tremor affecting limbs; the frequency can be higher in proximal arm muscles Two criteria should be fulfilled: confirmed diagnosis of neuropathy (abnormal joint position sense need not be present) and exclusion of other neurological diseases associated with tremors | + | ± | + | + | 5–10 | Peripheral sensory loss (and peripheral weakness) | ± | Successful treatment of the underlying neuropathy may improve the tremor in some of the patients. A number of patients have been successfully treated with pregabalin (see also the drugs used for ET). Some patients have also been successfully treated with Vim DBS, but long-term habituation to stimulation has been also reported | |
Palatal tremors | ||||||||||
Essential palatal tremor | Rhythmic movement of the roof of the soft palate due to contractions of the tensor veli palatine muscle (cranial nerve V) and rarely other pharyngolaryngeal muscles | + | + | 2–5 | Ear click | – | Low BoNT dosages (e.g. 4–10 units of Onabotulinumtoxin A) have been injected under EMG guidance into the tensor veli palatini See also the treatment of functional tremor | |||
Symptomatic palatal tremor | Rhythmic movement of the edge of the soft palate due to contractions of the levator veli palatine muscle (cranial nerves IX and X). Other muscles innervated by cranial nerves may be involved (eye, tongue, pharynx). More rarely, patients have a synchronous diaphragmatic tremor or a postural/kinetic tremor of the arms | ± | + | ± | ± | 1–7 | Cerebellar and brainstem signs | ± | Discomfort or disability is minimal except when the eye muscles are involved, causing oscillopsia, or when the tremor has extended to a limb. Treatment for oscillopsia includes clonazepam, gabapentin, trihexylphenidyl, valproate and especially BoNT injected into the retrobulbar fat tissue or specific extra-ocular muscles | |
Functional tremor | Irregular tremor with variable frequency and amplitude. Decrease of tremor amplitude during distraction and/or positive ‘coactivation sign’ (see text for details) | – | ± | + | + | 4–9 | Somatizations or other psychiatric disorders (not always present) | – | First step is disclosing the diagnosis and reassuring the patient. One small study in patients also presenting with depression has shown some improvement with antidepressant medication. Transcranial magnetic stimulation has also been proposed as well as psychotherapy based on the response to the entrainment test | |
5.3.1 Essential Tremor
Essential tremor (ET) is a slowly progressive tremor disorder, capable of causing severe disability (up to 25 % of the patients seeking medical attention must change careers or retire from work altogether). The traditional view of ET as a mono-symptomatic disorder has been revised as it may include motor signs other than tremor as well as non-motor symptoms (Table 5.4). A physiologic or laboratory test for the validation of the diagnosis is still lacking; therefore, the heterogeneity may partly be due to diagnostic uncertainty. Currently, different sets of diagnostic criteria only use medical history and clinical findings (Table 5.5). Due to the application of imprecise and variable diagnostic criteria, prevalence estimates range from 0.008 to 22 %, with a substantial increase with age. The condition may begin in childhood but the incidence increases above the age of 40 years with a mean onset of 35–45 years in different studies [17]. Young-onset ET is very often familial and probably represents a different subtype than the classical and senile ET forms [18].
Table 5.4
Several studies have described clinically subtle and less subtle motor and non-motor features. These are often signs of cerebellar dysfunction and are important for the pathophysiology of ET
Motor features | |
Clinically visible signs of cerebellar dysfunction | Overshoot and slowness of hand movements [3] Mediolateral instability (missteps during tandem gait) [4] |
Instrumental-only signs of cerebellar dysfunction | Hand and elbow movements [3] Gait [4] Eye movements [5] Rhythm generation [6] Motor learning (eyeblink conditioning) [7] Temporal discrimination task [8] |
Non-motor features | |
Cognition | Attention and executive dysfunctions, such as deficits on tests of verbal fluency, naming, mental set-shifting, verbal and working memory, complex auditory attention, visual attention and response inhibition (for a review, see [9]) |
Neurosensorial | Hearing deficit (primarily caused by cochlear involvement) [10] Olfaction deficit [11]a |
Psychiatric | Distinct personality profile (more tender minded and less aggressive than the normal population with a trend toward social introversion, higher scores in the harm avoidance scale of the tridimensional personality questionnaire) [12, 13] |
Othersb | Poor sleep quality Reduced body mass |
Table 5.5
Movement Disorder Society consensus criteria for the diagnosis of essential tremor
Inclusion criteria a |
1. Bilateral, largely symmetrical postural or kinetic tremor involving the hands and forearms that is visible and persistent |
2. Additional or isolated tremor of the head might occur but in the absence of abnormal posturing |
Exclusion criteria |
1. Other abnormal neurological signs; especially dystoniab |
2. Presence of known causes of enhanced physiological tremor, including current or recent exposure to tremorogenic drugs or presence of a drug withdrawal state |
3. Historical or clinical evidence of functional tremor |
4. Convincing evidence of sudden onsetc or evidence of stepwise deterioration |
5. Primary orthostatic tremor |
6. Isolated voice tremor |
7. Isolated position-specific or task-specific tremors, including occupational tremors and primary writing tremor |
8. Isolated tongue or chin tremor |
9. Isolated leg tremor |
ET often starts with a postural tremor that can still be suppressed during goal-directed movements. This tremor is not disabling and, accordingly, many ET patients are never seen by a neurologist. The topographic distribution shows a hand tremor in 94 %, head tremor in 33 %, voice tremor in 16 %, leg tremor in 12 %, jaw tremor in 8 %, facial tremor in 3 % and a tremor of the trunk in 3 % of the patients [19]. Head, voice or chin might be involved in isolation (i.e. with no or minimal limb involvement) but these tremors are considered dystonic in nature by many researchers (and are rarely seen in familial forms of ET). In fact, most of these midline tremors occur in patients with long-standing ET affecting upper limbs with older age and female gender appearing to be risk factors. Notably, 50–90 % of the patients with ET improve with ingestion of alcohol (Fig. 5.3).
Fig. 5.3
Alcohol responsiveness of the tremor is particularly common in patients with ET (e.g. spirals drawn by an ET patient at baseline and 15, 30 and 45 min after the ingestion of two glasses of wine) and can be used as a supportive criterion for the diagnosis. However, the finding is not specific for ET because other tremors (e.g. ET-like tremors seen in patients with dystonia) might respond as well
Tremor slowly progresses over time; predictive factors of greater severity include older age, longer disease duration and the presence of voice tremor [20]. Intention tremor develops at various intervals between 3 and 30 years after the original onset of postural tremor [3]. The occurrence of an intention tremor is characterized by a decrease in frequency and a tendency to develop larger amplitudes, along with signs of cerebellar dysfunction such as movement overshoot and slowness of movements (Table 5.4) [3]. Up to 20 % of patients, particularly those with advanced disease, may develop a tremor at rest [21]. This tremor can usually be separated from other resting tremors as it is not or only mildly suppressed at movement onset [22].
Patients with ET were assumed to have mortality rates similar to those of the general population [23]. However, in retrospective studies they were found to live longer [24] while a longitudinal prospective population-based study found the risk of mortality to be slightly increased [25]. The large NEDICES Study Project, which was a survey of major neurological disorders in people age ≥65 years living in 3 communities of central Spain, found an increased incidence and prevalence of dementia in senile ET patients (for a review, see [25]). However, given the high prevalence of enhanced physiological tremor in the elderly population, diagnostic difficulties are a specific concern for an age-related effect like the incidence of dementia. Nevertheless, several recent studies have highlighted subtle dysfunctions of several non-motor domains (Table 5.4), which are thought to mirror the dysfunction of frontal areas due to a remote effect within the cerebello-thalamo-cortical circuits.
5.3.1.1 Aetiology and Pathophysiology
The majority (60–80 %) of ET cases are hereditary, usually with an autosomal dominant inheritance pattern with an almost complete penetrance by the age of 60–70 years old. Twin studies suggest a heritability of up to 95 % [18]. As of yet, however, no clear genetic or environmental cause has been found (Table 5.6). While brain MRI of ET patients is usually normal, more sensitive techniques (i.e. spectroscopy, voxel-based morphometry and diffusion-tensor imaging) consistently disclose the involvement of the cerebellum and its connection with the brainstem, thalamus and the frontal cortex (for a review, see [44]).
Table 5.6
The genetic and environmental causes for ET described so far
Genetic factors a | |
Locus (chromosome localization)/gene (product) | Evidence |
ETM1 (3q13) [26]/DRD3 (dopamine D3 receptor) | The only locus independently replicated Ser9Gly variant associated with risk and age of onset of ET Protein expressed in Purkinje cells No significant association in other population |
Ala265Gly rs11680700 variant of HS1BP3 exon 7 has been reported in families with ET but not replicated by others HS1-BP3Binds to motor neurons and Purkinje cells | |
ETM3 (6p23) [29] | No pathogenic mutation in the 15 genes selected as plausible candidates |
ETM4 (16p11.2)/FUS (RNA-binding protein FUS) [30] | Stop mutation (c.868C > T; p.Gln290a) in a large Franco-Canadian family Risk variant (Met392Ile) that increases susceptibility of ET among ethnic Chinese [34] If this is the first genetic variant of ET but it seems to be very rare |
(15q24.3)/LINGO1 (Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1) | GWAS in Icelandic people with ET [35] Replication studies with mixed results, a meta-analysis has suggested a relationship between rs11856808 polymorphism and the risk for both familiar and sporadic ET, while rs9652490 polymorphism was only related with the risk for familial ET [36] Protein levels of LINGO1, but not LINGO2, were significantly increased in the cerebellar cortex of ET patients compared with controls [37] |
(11p13)/SLC1A2 (Excitatory amino acid transporter 2) | Found in a GWAS [38] Highly expressed in the inferior olive No replication study published to date |
Environmental factors | |
Agent | Evidence |
Beta-carboline alkaloids (harmine and harmane) | Known to cause tremor in animals [39] Blood levels elevated in patients with either sporadic or familiar ET [40] |
Lead | Blood levels elevated in ET patients Possible interaction with allele status for d-amino-levulinic acid dehydratase, a principal enzyme involved in lead kinetics [41] |
Alcohol | Larger use seems to be a risk factor The regular consumption of small quantities of alcohol seems to be protective [42] |
Smoking | One study reported a protective role |
At the cortical level, tremor-related activity can be detected with electrophysiological techniques. Coherence tests have shown consistency between activity in the motor cortex and the contralateral hand tremor, indicating a transcortical pathway of these tremor-related signals. These findings have been interpreted as representing a spatio-temporal pattern of intermittent synchronization within a complex cortical network responsible for the tremor [45]. The cause for this oscillation is unknown but several lines of evidence suggest that the oscillator is located within the Guillain–Mollaret triangle (Fig. 5.4), with the assumption that the tremor may result from abnormal intrinsic oscillations originating in the inferior olive or the cerebellum and spreading throughout the olivocerebellar network [46]. Accordingly, positron emission tomography (PET) studies have provided evidence for bilateral overactivity of cerebellar connections in ET and other tremors. No consistent pathology has been found. One research group has found two pathology types, one with Lewy bodies in the locus coeruleus and another with a cerebellar pathology characterized by torpedoes and a reduction of Purkinje cells [47]. The latter seems to be more frequent but two other groups have been unable to reproduce these findings [48, 49]. One study failed to find pathological changes in the inferior olive [50], whereas another found a significant reduction of GABAergic neurons containing parvalbumin without any reduction of the enzymes involved in the metabolism of dopamine and noradrenaline, particularly in senile cases [49]. These findings are in keeping with the reduction of the density of GABA-A and GABA-B receptors found by another postmortem study [51] which further strengthens the ‘GABA hypothesis’ [52]. Indeed, this theory is supported by the GABA-A1 knockout tremor-producing mouse [53], hyperactivity of GABA receptors as measured by PET studies in ET patients using [11C] flumazenil [54] and the response of ET patients to GABAergic drugs.
Fig. 5.4
The CNS circuits of tremor. Shadowed area represents the Guillain–Mollaret triangle, composed of the connections between the rubral, olivary and dentate nuclei
5.3.2 Enhanced Physiological Tremor
An increase in the amplitude of normal physiological tremor leads to the visibly enhanced PT (EPT) (Table 5.3). EPT is the most common tremor disorder with a cross-sectional population-based study finding the prevalence of EPT to be 9.5 % in subjects over 50 years of age [55]. EPT relies on the same mechanism as normal physiological tremor, which mainly comprises of peripheral mechanisms (mechanical properties of body segments and stretch reflex) and, in less than 10 % of subjects, a central component with oscillations around 8–10 Hz (Fig. 5.5). Table 5.7 lists the causes of EPT, the majority of which are related to drugs or toxins enhancing the peripheral or central component of PT (Table 5.8).
Fig. 5.5
Tremor analysis. (a) Spectral analysis of four different postural hand tremors with the accelerometer spectrum and the EMG spectrum of the wrist extensors unloaded and with a load of 1000 g mounted on the back of the hand. In PT, the tremor is detectable on accelerometer but there is no EMG activity and a load-dependent mechanical resonance peak is present (note the shift of the frequency). In EPT, a reflex-activated tremor might be detectable because the EMG frequency peak decreased with the accelerometer peak during loading. The third example is from a normal subject having a central, frequency-invariant component in addition to the load-dependent mechanical component. In ET, like most pathological tremors, there is a central component with a frequency-invariant EMG peak (from [56]). (b) A very easy and rapid measurement of tremor frequency is to use the built-in accelerometer of smartphones via an application. Accuracy closely matches the more sophisticated tremor analysis
Table 5.7
Causes of enhanced physiologic tremor
Toxins | Mercury, lead, manganese, alcohol, DDT |
Metabolic disturbances | Hyperthyroidism, hyperparathyroidism, hypoglycaemia, hypoxia, hepatic encephalopathy, magnesium deficiency, hypocalcaemia, hyponatraemia |
Drugs | See Table 5.8 |
Others | Anxiety, fatigue, fever, infections (e.g. rabies), hypothermia, sleep deprivation, sympathetic reflex dystrophy, withdrawal of alcohol or drugs |
Table 5.8
Toxic and drug-induced tremors
Anti-arrhythmics | Amiodarone, mexiletine, procainamide |
Antibiotics, antivirals and antimycotics | Amikacina, amphotericin B, co-trimoxazole, gentamicina, itraconazole, pentamidinea, vidarabine |
Antidepressants and mood stabilizers | Tricyclicsb (e.g. amitriptyline), lithium, SSRIsb |
Antiepileptics | Benzodiazepinesc, lamotrigine, valproic acid |
Bronchodilators | Salbutamol, salmeterol |
Chemotherapeutics | Cisplatina, cytarabine, ifosfamide, tamoxifen, thalidomide |
Diuretics | Loop and thiazide diureticsa |
Drugs of misuse | Cocaine, ethanolc, MDMA, MPTP, nicotine |
Gastrointestinal drugs | Cimetidine, metoclopramide |
Hormones | Epinephrine, calcitonind, insuline, thyroxinef, medroxyprogesterone, parathyroid hormoneg |
Immunosuppressants | Cyclosporinea, interferon-α, tacrolimus |
Methylxanthines | Caffeine, theophylline, ‘energy drinks’ |
Neuroleptics and dopamine depletersh | Cinnarizine, flunarizine, DRBA (e.g. haloperidol, thioridazine), reserpine, tetrabenazine |
Toxins | Ammoniai, copperj, DDT, lead, linden, manganese, mercuryk |
Others | 4-Aminopyridine, donepezil |
5.3.3 Parkinsonian Tremor
Parkinsonian tremor has been defined as a tremor occurring in parkinsonism, especially in Parkinson’s disease (PD) [1]. The clinical classification encompasses three types of tremors (Table 5.3):
1.
Type I: classical parkinsonian tremor (see also Chap. 1). This is the typical resting tremor affecting up to 80 % of all patients at any time of their disease. It may be seen in the hands during walking or when sitting as the characteristic ‘pill-rolling’ tremor of the hand or a pronation–supination oscillation at the wrist. Tremor frequency is usually 4–7 Hz but can be higher especially in early PD. Patients with type I tremor may also display a ‘re-emergent tremor’, which is a postural/kinetic tremor occurring after some latency under postural and action conditions. Re-emergent tremor has clinical characteristics similar to a rest tremor, including having a similar frequency, asymmetry and response to levodopa, and is therefore thought to have the same pathophysiologic mechanism as rest tremor [57]. A classic PD type I tremor (e.g. involving one limb or the jaw) for more than 2 years with otherwise no symptoms sufficient to diagnose PD characterizes the so-called monosymptomatic tremor at rest or benign tremulous parkinsonism, a specific variant of PD. The occurrence of ocular tremor in PD is a novel assumption still debated. Duval and Beuter [58] and later Gitchel et al. [59] have reported the occurrence of ocular oscillations with the same frequency features of resting tremor. However, others have pointed out that this ocular tremor could simply be due to the vestibuloocular reflex induced by head movements caused by a tremor elsewhere in the body or in the head itself [60]. In any case, the amplitude of these oscillations is too small to induce oscillopsia but it might contribute to visual symptoms sometimes reported by patients.
Type I tremor is typical of PD compared to other degenerative or secondary parkinsonisms (with the exception of the parkinsonian subtype of progressive supranuclear palsy, PSP-P). Moreover, type I tremor does not correlate with disease progression or with the amount of dopaminergic degeneration measured with PET or single-photon emission computed tomography (SPECT). Animal experiments (e.g. micro-recording in MPTP model) and human data (e.g. micro-recording during deep brain procedures) converge to suggest that parkinsonian tremors are generated by abnormally synchronized ‘tremor cells’ topographically organized within the basal ganglia loops [61]. According to Helmich et al. [62] this oscillation originates in the subthalamus or globus pallidus, wherein loss of dopaminergic input is required to cause an abnormally phasic neuronal discharge which is then amplified in the cerebellothalamic network and transmitted to the motor cortex (‘dimmer-switch’ model). This model is in keeping with microelectrode recordings in awake PD patients with tremor, showing that pallidal neurons (the ‘switch’) are only transiently and inconsistently coherent with the tremor while thalamic neurons (the ‘dimmer’) are highly synchronous with it. The model also explains why surgical lesions in different parts of the basal ganglia-thalamo-cortical loop might suppress the tremor. In addition, pathology suggests that in patients with tremor-predominant PD, the retrorubral A8 part of the substantia nigra (which mainly projects to the pallidum) specifically degenerates. The degeneration of neurotransmitter systems other than dopamine may be responsible for the erratic behaviour of tremor. Indeed, a reduction in 5-HT1A binding in the midbrain raphe region has been correlated with tremor severity but not with rigidity or bradykinesia [63]. Accordingly, the administration of agents acting on the 5-HT system (tryptophan or ritanserin) has been anecdotally reported to be beneficial in PD tremor.
2.
Type II: action tremor with a different frequency from resting tremor (at least 1.5 Hz above the resting frequency). In addition to their resting tremor, less than 15 % of PD patients might have a predominant action tremor, which can be very disabling. This action tremor has a higher and non-harmonically related frequency to the resting tremor. Some of these patients developed their postural tremor long before the onset of other symptoms of PD, further challenging the debated relationship between ET and PD.
3.
Type III: high-frequency action tremor in patients without resting tremor. 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 parkinsonisms.
5.3.4 Dystonic Tremor
Three forms of tremors can be associated with dystonia (Table 5.3; see also Chap. 6).
1.
Dystonic tremor (DT) occurs in the body region affected by dystonia. DT is defined as a postural/kinetic tremor usually not seen during complete rest [64]; it is usually a focal tremor with irregular amplitudes and variable frequencies (mostly below 7 Hz). Virtually every dystonic syndrome may present with DT with typical examples including head tremor in torticollis, hand tremor in writer’s cramp and jaw tremor in orofacial dystonias. The prevalence of dystonic tremor in adult-onset primary dystonia is between 17 % [65] and 55 % [66]. The proportion seems not to differ between primary and secondary dystonias but appears to be more common in cervical dystonia than in other locations. In a survey among patients from a large Indian movement disorder centre, DT accounted for approximately 20 % of all patients presenting with non-parkinsonian and non-cerebellar/ET tremors [67]. Some patients exhibit focal tremors even without overt signs of dystonia, thus challenging the diagnostic abilities of neurologists, especially when the tremor is present at rest. These patients are often diagnosed with PD but do not progress and have normal dopamine transporter imaging (DAT-SPECT) results, labelled in clinical trials as subjects without evidence of dopaminergic deficit (SWEDD) [68]. In many patients with DT, a geste antagoniste leads to a reduction in the tremor amplitude. Particular types of DT are (at least some of) the task-/position-specific tremors (see below) and ‘thalamic tremor’, when a posterolateral thalamic lesion, usually a stroke, also induces dystonic posturing with or without ballistic jerks (see also Holmes tremor, for comparison). In the setting of a well-recovered severe hemiparesis, the combination of a jerky tremor with an intentional component, dystonia and a severe sensory loss seems to be the important clue to suspect a preceding stroke as the source of the abnormal movements. A latency of several weeks to months between the thalamic stroke and the appearance of the tremor is characteristic. Proximal segments are often involved.
2.
Tremor associated with dystonia (TAD) is a more generalized form of tremor in body sites that are not affected by dystonia, but which is present elsewhere in the same subject. This is a relatively symmetric, postural and kinetic tremor usually showing higher frequencies than actual DT and often seen in the upper limbs in patients with spasmodic torticollis [69]. TAD was considered a forme fruste of ET; however, it is not yet clear if they share common genes and the pathophysiologic mechanisms seem to be different in some of the patients [8, 69]. On the basis of clinical and neurophysiological work, it has been recently proposed that that there is a subgroup of patients with male preponderance and early-onset arm tremor who later develop cervical dystonia without further segmental spread of symptoms. During ballistic wrist flexion movements, the latency of the second agonist EMG burst occurs later in ET than in patients with tremor associated with cervical dystonia [69]; in addition, reciprocal inhibition between forearm muscles differ in patients with tremor preceding torticollis or when tremor started simultaneously with torticollis [69]. As patients with prominent tremor may develop dystonia late in the course of the disease, additional tests may be needed to distinguish this tremor from ET. Preliminary data suggest that thresholds for temporal discrimination of movement might provide such a test [8].
3.
Tremor associated with dystonia genes shares the same features and pathophysiology of TAD but dystonia is only present in other family members. This ‘ET-like’ tremor further complicate the nosology of ET, since many investigators erroneously include ET among the expression of dystonia (e.g. in the context of genetic studies).
5.3.5 Primary Writing Tremor and Other Task-Specific Tremors
Primary writing tremor (PWT) is a condition in which tremor predominantly or exclusively occurs during writing [70]. No other neurological signs are evident except for a slight postural and terminal intention tremor. PWT can be exclusively task-induced (type A) or position-sensitive (type B).
The epidemiology and the natural course of PWT are not well known. The age of onset is variable with reported cases presenting even during childhood. The disorder typically begins slowly, progresses for many years and then stabilizes [71]. Some patients report that at the onset they only had difficulties with specific letters but their condition might progress in terms of severity, topography (also involving the non-dominant side) or type of tremor (e.g. becoming a resting/action tremor) [72]. Familial history is generally negative.
PWT is the most common variant among many task-specific tremors frequently associated with specialized motor skills, such as musician tremor or golfer tremor. PWT is considered to be a focal task-specific tremor but has been described to belong amongst the ET syndromes, focal dystonias, both or neither category. The focal task-specific nature and a lack of response to propranolol, along with a well-documented effect of anticholinergic drugs [71], have suggested that PWT may be more closely related to focal dystonia than ET. Abnormal co-activation of antagonist muscles on EMG recordings has been used to support this claim. PWT, however, is distinguished from focal task-specific dystonia (‘writer’s cramp’) by the lack of excessive overflow of EMG activity into the proximal musculature along with an abnormal reciprocal inhibition of the median nerve H-reflex on radial nerve stimulation [73, 74]. The cumulative data, thus far, supports the contention that PWT is a distinct disorder with some features of ET and many of DT but fulfilling complete criteria for neither disorder [75].
5.3.6 Orthostatic Tremor
Orthostatic tremor (OT) is a unique tremor syndrome [76] characterized by a subjective feeling of unsteadiness during stance eventually occurring during gait in severe cases. Some patients might have sudden falls. OT is the only tremor syndrome with a pathognomonic frequency on surface electromyography (EMG) of legs while standing (13–18 Hz) [77]. The tremor cannot be seen with the naked eye and sometimes the only clinical finding is a palpable fine-amplitude rippling or an auscultable ‘helicopter sign’ (a stethoscope over the muscles of the thigh and calf may reveal a repetitive thumping sound) of leg muscles [78]. Consequently, the diagnosis is suspected mainly based on the complaints of the patients rather than the clinical findings.
OT is a rare condition and epidemiological data are lacking. The condition only occurs in patients above the age of 40 years with the mean age of onset lower for women (50 years) compared with men (60 years) [79]. It is not typically considered a hereditary disease albeit familial cases have been described in twins or in families with ET [79, 80]. Interestingly, OT has been described in patients with spastic paraplegia 31. The pathophysiology is largely unknown but the high frequency on EMG and the complete coherence between all weight-bearing muscles suggest that a single, bilaterally descending system must generate the pathologic oscillations of OT. The generator for this tremor is assumed to be located within the brainstem or cerebellum, yet a recent study found evidence for an oscillation coupled with the tremor in the thalamus and cortex [81]. It is unclear what the significance of the reduction of dopaminergic terminals in the striatum is, which is rarely reported in this condition [82].
Table 5.3 summarizes the classification of OT, which is based on the associated conditions and frequency characteristics. Four types are described:
1.
Primary OT is considered an idiopathic condition and may be further subdivided into two subgroups: patients with or without a postural arm tremor [79]. Such an arm tremor may occur in roughly half of the patients and is usually more evident during stance. There has been much debate as to whether OT is a separate entity or a variant of ET since it may be associated with such upper limb postural tremor. However OT, unlike ET, shows synchrony between different muscles and rarely responds to therapeutic agents such as propranolol and alcohol [83].
2.
OT-plus is the nomenclature given to OT when co-occurring with other primary neurological disorders. So far, OT has been found to be associated with restless leg syndrome, orobuccal dyskinesias of uncertain aetiology, cerebellar ataxia, progressive supranuclear palsy and PD [84].
3.
Symptomatic OT has been described in non-tumoral aqueduct stenosis, following head trauma, vascular lesion and abscesses.
4.
Slow-OT (<12 Hz) has been rarely reported and it is still an unclear entity. It corresponds to a similar history to that of OT but with surface EMG-documented frequency below the diagnostic range. Three types can be recognized: ‘primary’ forms (without overt etiologies), ‘secondary’ forms (in the context of cerebellar and pons lesions or autoimmune processes of the CNS, e.g. anti-Hu and anti-Yo antibodies) and ‘pseudo-OT’. The latter has been described in PD, Lewy body dementia and SCA3, but given a frequency of 4–6 Hz, the asymmetry of the tremor and the adequate response to levodopa, it is considered a different expression of a parkinsonian resting tremor made more overt during standing [85].
5.3.7 Cerebellar Tremor
The classical cerebellar tremor is a slow (<5 Hz) intention tremor ipsilateral to the underlying cerebellar abnormality. Simple kinetic and postural tremor may also be present but a rest tremor does not occur unless the patient is unable to completely relax. Titubation is another tremor manifestation of cerebellar disease and is a low-frequency oscillation (around 3 Hz) of the head and trunk depending on postural innervation.
One of the most common causes of cerebellar tremor are demyelinating lesions in multiple sclerosis (MS); it is observed in up to 75 % of cases and is a predominant source of disability [86]. Cerebellar tremor may also be the consequence of head trauma, cerebellar strokes or degeneration. It can be an early feature of spinocerebellar ataxias (SCA) type 8, 12, 15, 16 and 27, but it is typically seen in SCAs 1 and 12 while is rather underrepresented in SCAs 3 and 6. Autosomal recessive cerebellar ataxias might also feature postural or kinetic tremor. In particular, a tremor can occur in ataxia with vitamin E deficiency, late-onset Tay–Sachs disease, mitochondrial recessive ataxia syndrome, ataxia–telangiectasia (see below), ataxia with oculomotor apraxia type 1 and 2, Cayman ataxia and Marinesco–Sjögren syndrome. The broad clinical spectrum of Friedreich’s ataxia may also demonstrate a bilateral intention tremor of the upper limbs.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
