The Essential Tremors: A Family of Neurodegenerative Disorders?

Abstract

Essential tremor (ET) is the most common pathological tremor in humans. The traditional view of ET, as a mono-symptomatic condition, is being replaced by an appreciation of the spectrum of clinical features, with both motor and non-motor elements. These features are not distributed homogeneously across patients. In addition, post-mortem studies are now demonstrating distinct structural changes in ET. There is growing evidence that ET may be a family of diseases rather than a single entity. Further, this aging-associated, progressive disorder is associated with neuronal loss and postmortem changes that occur in traditional neurodegenerative disorders.

Introduction to Essential Tremor and Questions Posed

Essential tremor (ET), the commonest pathological tremor in humans, is among the more ubiquitous neurological diseases, with a prevalence (age ≥40 years) of 4.0%.^{1, 2} Its most recognizable clinical feature is an 8–12 Hz kinetic tremor of the arms (i.e., tremor during voluntary movement)(Figure 1), which often is later accompanied by head and voice tremors. The condition is global, affecting human beings in a variety of settings, ranging from the remote Okapa sub-district of Papua New Guinea to the urban Washington Heights-Inwood community in northern Manhattan, New York.^{1, 2} The traditional view of ET as a mono-symptomatic condition characterized only by kinetic or postural tremor has been supplanted in recent years. First, the tremor phenomenology is broad and many patients have other motor manifestations³ and non-motor features, including cognitive and psychiatric.^{3, 4} Furthermore, this expanded constellation of clinical features is not distributed homogeneously across patients. For example, some patients develop head tremor while others do not. Some dement while others do not; some develop Parkinson’s disease (PD) while others do not.⁵ Recent studies of the pathology of ET have demonstrated several distinctive structural changes, including neuronal loss.^6–10 With evidence of clinical and pathological heterogeneity emerging, several important questions arise. First, is ET a single disease entity or a family of diseases? Second, is ET neurodegenerative?

Figure 1.

Kinetic tremor is apparent in an ET patient’s drawing of an Archimedes spiral.

Essential Tremor or the Essential Tremors?

Neurology is replete with historical examples in which clinical-pathological investigations have resulted in the partitioning of disease entities and the refinement of classification. For example, many patients with upper motor neurons signs were clinically lumped together, yet in the 1800s, Charcot and others, observed that among such patients who had sclerosis on postmortem examination, one sub-group had a pattern that could be characterized as ‘amyotrophic lateral sclerosis’ (ALS) while a second sub-group had a pattern that could be characterized as ‘multiple sclerosis’ (MS). We now know that ALS and MS are different diseases with distinct mechanisms, clinical features, and treatments. Likewise, in the mid-twentieth century, advances in neuropathology and careful clinical-pathological studies re-defined the concept of parkinsonism as a family of disease entities rather than a single disease. Idiopathic Parkinson’s disease (PD) could be distinguished from other entities such as progressive supranuclear palsy and corticobasal ganglionic degeneration. It is conceivable that we are now arriving at such a primary juncture in our understanding of ET. Evidence of clinical heterogeneity and pathological heterogeneity is emerging, raising the question as to whether it is possible to re-formulate ET as a cluster of separable clinical-pathological entities, that is, a family of diseases – “the essential tremors”.

Heterogeneity (Clinical, Therapeutic Response, Pathological, and Etiological)

Although clinical phenotypic variability by itself is not an argument for separate diseases, its presence further opens that possibility. Clinically, the view of ET as a single neurological sign no longer seems tenable. First, the tremor phenomenology itself is multifaceted. Although kinetic and postural tremors are the core features upon which diagnostic criteria are generally based (Table 1), intention tremor,¹¹ and tremor at rest¹² may also occur in subsets of patients. The relative severity of different tremor types (kinetic > postural ¹³), the favored sites of anatomical involvement (arm more often than head, and head more often than jaw ¹⁴), and the typical direction of spread over time (from arms to head rather than the converse)¹⁵ are distinctive, adding a degree of subtlety and complexity to the recognition and diagnosis of a disorder that is often viewed as relatively ordinary and featureless. Indeed, perhaps due to a lack of familiarity with these features, mis-diagnosis is exceedingly common; 30–50% of patients diagnosed with ET do not have ET,¹⁶ which may make this one of the most commonly mis-diagnosed neurological disorders. Moreover, kinetic tremor of the arms, though not the head, may be a side-effect of many medications, which further contributes to this diagnostic difficulty (Table 2). There are motor features aside from tremor. In a large number of studies,^{11, 17} postural instability and mild to moderate gait ataxia, beyond that observed in normal aging, have been demonstrated in subgroups of ET patients. In addition to these gait problems, eye motion abnormalities (impaired smooth pursuit initiation and pathological suppression of the vestibulo-ocular reflex time constant) were recently described in a study of 17 ET cases.¹⁸ Third, there is a growing appreciation of the existence of a variety of non-motor features, including cognitive, psychiatric, and sensory. Cognitive features, especially mild problems with executive function and memory, were first reported in 2001¹⁹ and soon after by numerous other investigators.²⁰ Furthermore, a population-based study in Madrid²¹ first demonstrated in 2006 that the odds of prevalent dementia were nearly twice as high among the subset of ET cases with older onset disease when compared with age-matched controls. The same group later demonstrated ⁵ that the risk of developing incident dementia was nearly twice as high in the ET cases than controls. Also, a number of psychiatric correlates have been observed. The presence of specific personality traits^{22, 23} has been demonstrated. In one such study, ²² the observed personality profile was not related to functional disability or tremor severity, suggesting that it could be a primary disease feature rather than a response to disabling tremor.²² Anxiety,²⁴ depressive symptoms,²⁵ and social phobia ²⁶ have been shown to occur in ET patients more often than in controls. Traditionally, these have been viewed as psychiatric responses to disabling tremor. Yet in one recent prospective study,⁴ depressive symptoms preceded the onset of the tremor by several years (i.e., the presence of baseline self-reported depression was associated with an increased risk of developing incident ET during follow-up). Sensory abnormalities, including olfactory deficits in some studies²⁷ and hearing loss in others,²⁸ have been reported in ET cases compared with age-matched controls, further drawing attention to the domain of non-motor manifestations. Although a single disease may be have a broad array of clinical manifestations (e.g., Huntington’s disease), such clinical variety can also be an indication that one is dealing with a group of diseases (e.g., parkinsonisms such as PD, progressive supranuclear palsy, and corticobasal ganglionic degeneration).

Table 1.

Two sets of clinical diagnostic criteria for definite essential tremor. The Movement Disorder Society has proposed consensus criteria for ET.⁵², ⁵³ The Washington Heights–Inwood Genetic Study of Essential Tremor criteria⁵⁴ specify the minimal severity of tremor that is required, and are also widely used in genetic and epidemiological studies.¹, ⁵⁵–⁵⁸

Consensus statement of the Movement Disorder Society on tremor52, 53

Inclusion criteria

Bilateral postural tremor with or without kinetic tremor, involving hands and forearms, that is visible and persistent Duration greater than 5 years

Exclusion criteria

Other abnormal neurological signs (except Froment’s sign) Presence of known causes of increased physiological tremor Concurrent or recent exposure to tremorogenic drugs or the presence of a drug withdrawal state Direct or indirect trauma to the nervous system within 3 months before the onset of tremor Historical or clinical evidence of psychogenic origins Convincing evidence of sudden onset or evidence of stepwise deterioration

Washington Heights Inwood Genetic Study of Essential Tremor criteria54

On examination, a +2 postural tremor* in at least one arm (a head tremor might also be present, but is not sufficient for the diagnosis) On examination, there must be a +2 kinetic tremor during at least four tasks, or a +2 kinetic tremor on one task and a +3 kinetic tremor on a second task. Tasks include pouring water, using a spoon to drink water, drinking water, finger-to-nose maneuver, and drawing spirals If on examination the tremor is present in the dominant hand, then by report it must interfere with at least one activity of daily living (eating, drinking, writing or using the hands). If on examination the tremor is not present in the dominant hand, then this criterion is irrelevant Medications, hyperthyroidism, ethanol, and dystonia are not potential etiological factors Symptoms are not psychogenic (e.g. bizarre features, features inconsistent in character, the patient is distractable, or other psychiatric features on examination)

^*0 to +3 tremor ratings: 0, no visible tremor; +1, tremor is of low amplitude, barely perceivable, or intermittent; +2, tremor is of moderate amplitude (1–2 cm) and usually present, and is clearly oscillatory; +3, tremor is of large amplitude (>2 cm), violent, and jerky, resulting in difficulty completing the task because of spilling or inability to hold a pen to paper

Table 2.

Medications that may produce kinetic tremor

Amiodarone

Bronchodilators

Cyclosporin

Lithium

Methylphenidate

Phenylpropanolamine

Procainamide

Pseudoephedrine

Selective serotonin reuptake inhibitors

Steroids

Theophylline

Thyroxine

Tricyclic antidepressants

Valproic acid

It is important to emphasize that these clinical features are heterogeneously distributed across ET patients. Although some patterns are now becoming apparent (e.g., patients with intention tremor have more gait difficulties and eye motion abnormalities,¹⁸ patients with rest tremor generally have longstanding disease with severe kinetic tremor,¹² dementia is associated with older age of onset of ET,⁵ older age of onset and unilateral onset are associated with more rapid progression^{29, 30}), a clear separation of distinct clinical subtypes has yet to emerge.

The mainstays of therapy for ET are propranolol and primidone, although several promising new agents have been introduced in recent years (Table 3); surgical treatment (deep brain stimulation) is also highly effective.³ One re-occurring feature of pharmacotherapeutic trails in ET is that the response to a particular medication is usually patchy, with approximately one-half of the patients evidencing some degree of tremor reduction and others none at all;³¹ this phenomenon is frequently observed by practitioners as well. Among other possibilities (e.g., differences in disease duration across treated patients), this heterogeneity of response could be a marker of different underlying disease mechanisms in subsets of patients, although this remains to be demonstrated.

Table 3.

Medications used to treat ET

Medication	Dosage	Potential side effects
Acetazolamide	Up to 500 mg/d	Weakness, fatigue
Alprazolam	0.125–3 mg/d	Sedation, fatigue, potential for abuse
Atenolol	50–150 mg/d	Lightheadedness, nausea, cough, dry mouth, sleepiness
Botulinum toxin A (hand tremor)	50–100 U	Hand/finger weakness, reduced grip strength, pain at injection site, stiffness, cramping, haematoma, paraesthesias
Botulinum toxin A (head tremor)	40–400 U	Neck weakness, post-injection pain
Botulinum toxin A (voice tremor)	0.6–15 U	Breathiness, weak voice, swallowing difficulty
Clonazepam	0.5–6 mg/d	Drowsiness
Clozapine	Up to 200 mg/d	Sedation, potential agranulocytosis (0.8% at one year)
Flunarizine	10 mg/d	Sedation, weight gain, depression, dystonia, parkinsonism
Gabapentin	1,200–1,800 mg/d	Lethargy, fatigue, decreased libido, dizziness, nervousness, shortness of breath
Levetiracetam	Up to 3,000 mg/d	Depressed mood, drowsiness, fatigue
Methazolamide	Up to 300 mg/d	Somnolence, nausea, paresthesias, headache
Nimodipine	120 mg/d	Headache, heartburn
Nadolol	120–240 mg/d	None
Olanzapine	20 mg/d	Drowsiness, sedation, weight gain, diabetes
1-octanol	1 mg/kg/d	Lethargy, asthenia, headache
Phenobarbital	Up to 150 mg/d	Drowsiness, fatigue ataxia
Pregabalin	Up to 600 mg/d	Dizziness, somnolence
Primidone	Up to 750 mg/d	Sedation, drowsiness, fatigue, nausea, giddiness, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, acute toxic reaction
Propranolol	60–800 mg/d	Reduced arterial pressure, reduced pulse rate, tachycardia, bradycardia, impotency, drowsiness, exertional dyspnoea, confusion, headache, dizziness
Long-acting propranolol	80–320 mg/d	Skin eruption, transient dizziness
Sodium oxybate	Up to 7.5 g/d	Dizziness, headache, sedation, ataxia
Sotalol	75–200 mg/d	Decreased alertness
Topiramate	Up to 400 mg/d	Appetite suppression, weight loss, paraesthesias, anorexia, concentration difficulties
Zonisamide	Up to 200 mg/d	Ataxia, dizziness, somnolence, agitation, anorexia

Disease mechanisms in ET have been elusive. Despite its high prevalence, until recently, few ET brains were examined and little information was available about the pathology. An intensive effort was launched in 2003 to bank ET brains.⁶ In contrast with previous studies, these brains were systematically examined to quantify cerebellar and other brainstem pathologies and were compared to control brains. These analyses, based on 33 ET brains, indicated that the structural pathological changes appeared to be of two types.^{6, 7, 9, 32} Most commonly (75%), brains were characterized by clear cerebellar degenerative changes, including a 40% reduction in number of Purkinje cells, a six-fold increase numbers of torpedoes (i.e., swellings of the Purkinje cell axon that likely represent a cellular response to injury), and Purkinje cell heterotopia and dendrite swellings. These brains did not have Lewy bodies. The remaining brains were characterized by Lewy bodies confined mainly to the locus ceruleus with relative to total sparing of other brainstem structures (see Table 2 in⁶). The prevalence of Lewy bodies was significantly greater than that observed in similarly-aged controls, indicating that they were not likely to be incidental.⁶ Furthermore, this particular pattern of Lewy body involvement in ET has not been described in series of “atypical” Lewy body brains (i.e., brains that do not follow the Braak staging scheme).³³ The ET brains with Lewy bodies did not have excessive torpedoes or Purkinje cell loss.⁶ These two pathological patterns were labeled “cerebellar ET” and “Lewy body variant of ET” [LBVET]).^{6, 34} Other recent series of ET brains have also confirmed a heterogeneous pathology involving Purkinje cell loss in the cerebellum in some cases and changes, including cell loss, in the locus ceruleus in others.⁸ These recent postmortem studies have helped identify degenerative structural alterations in the cerebellum and its connecting pathways in ET. How changes in the locus ceruleus could produce ET is less clear, although neurons of the locus ceruleus synapse with cerebellar Purkinje cell dendrites.³⁵ These projections are important for the normal development and maintenance of Purkinje cells.³⁶ Impaired activity in the locus ceruleus could result in a diminution of stimulatory output from that locus to the Purkinje cells.

On an etiological level, ET is often considered to be genetic.³⁷ There are many examples of families in which the proband and multiple relatives have ET and in which the pattern of inheritance is consistent with an autosomal dominant model. In 1997, linkage was demonstrated to a region on chromosome 2p ³⁸ and, in that same year, to chromosome 3q in other families.³⁹ A third study demonstrated linkage to a region on chromosome 6p in several families.⁴⁰ Aside from these three studies, other studies that have failed to demonstrate linkage to these three regions, indicating that there will likely be more than three genes responsible for this disease.^{37, 41} It is important to note, however, that the genetic studies have not progressed further and the specific ET genes have been not yet been identified.^37–40 In the absence of a specific genotype for ET, there are as yet no specific genotype-phenotype correlations, although is appears that young onset cases are generally familial (i.e., likely to have a genetic susceptibility).⁴² Aside from genetic factors, there is also a growing understanding that environmental factors are likely to contribute to the etiology of ET as well, indicating that there is further heterogeneity on an etiological level. Several lines of evidence support the role of these factors. First, while commonly stated that 50% or more of ET cases have a genetic basis, the precise derivation of this estimate is unclear and its validity is also doubtful.⁴³ Indeed, some estimates are as low as 17%.⁴³ In twin studies ^{44, 45} concordance in monozygotic twins was only 60% in one study and 63% in another. Second, the well-known existence of intra-familial differences in age of onset, location of tremor, and severity of tremor ⁴⁶ also suggests that environmental (or perhaps other genetic) factors may be serving as modifiers of underlying susceptibility genotypes. In terms of environmental factors, a growing number of case-control studies ⁴⁷ has implicated several specific toxins, namely β-carboline alkaloids (e.g., harmine and harmane, a group of highly tremorogenic dietary chemicals) and lead; and further studies of these putative environmental toxins are needed.

Organizing the Heterogeneity

Information presented in the previous section may be organized by etiologies, pathologies and the clinical features (Figure 2). Given the sheer prevalence and ubiquity of this condition, the historical tendency to split disease entities as new knowledge arises, the appreciation of a broader variety of clinical features in several separate domains (e.g., tremor, other motor, cognitive, psychiatric), the observation that these are not uniformly present in ET patients, the evidence that multiple genes will likely be responsible for this disease, and preliminary evidence of distinct pathological patterns, it is likely that ET will turn out to be a family of diseases rather than a single disease entity. It is likely that this family of diseases, united by the presence of kinetic tremor, would be separable on the basis of etiological, clinical, therapeutic response and pathological features, although further work is needed to explore these relationships.

Figure 2.

The heterogeneity in ET may be organized by (1) disease etiology, (2) tissue-level changes that occur after the disease process is initiated and as it develops, and (3) clinical features that are the end product of these underlying pathological processes. Here is one such possible schema.

Is ET Neurodegenerative?

A question implicitly raised in the above discussion is whether this disease (or these diseases) are neurodegenerative. The idea that ET could be neurodegenerative is not new. In 1948, Critchley and Greenfield wrote: “Although anatomical proof is as yet lacking, there are at least a number of clinical points to make question whether “essential tremor” may not, at times any rate, represent an incomplete or a premature variant of one of the cerebellar atrophies.”⁴⁸ Although not further elaborated by those authors, these clinical points include its insidious onset, association with advanced aging (i.e., both incidence and prevalence increase with aging), gradual yet progressive nature, and the presence of “cerebellar” features (e.g., intention tremor and ataxia) on examination.

Neurodegenerative diseases traditionally have been defined as diseases that begin insidiously, pursue a gradually progressive course that may continue for many years, and are characterized by the selective involvement of anatomically and physiologically related systems of neurons due to intrinsic processes rather than an identifiable outside influence (e.g., vascular, auto-immune). Cell loss is also considered by many to be a prominent feature of these diseases.⁴⁹ Furthermore, their occurrence often increases markedly with advancing age. What is the evidence that ET is neurodegenerative? The clinical points noted above are important. ET has an insidious onset^{46, 50} and then follows a gradual yet progressive clinical course.^{29, 30} There is a marked and continued rise in disease occurrence in advanced ages.^{1, 2} This clinical constellation is somewhat compelling; however, none of these features in isolation is specific to neurodegenerative diseases. On a tissue-based level, the evidence is more compelling. Selective involvement of an anatomically and physiologically related system of neurons, Purkinje cells, has been reported in ET cases both in our recent series (Figure 3)^{6, 7} and in the other large recent series.⁸ When quantified using different methods, Purkinje cell loss is significant. There is an approximate 40% loss of these cells compared to age-matched control brains,^{6, 7} which persists even when one adjusts for age and other confounding pathologies (e.g., mild Alzheimer’s type changes). Additional evidence that the Purkinje cells are diseased is that there are significantly more torpedoes in the ET brain, where their numbers are six-times higher than expected for age, and a preponderance of displaced (i.e., heterotopic) Purkinje cells as well as Purkinje cells with dendritic swellings.⁶ In contrast to these cases, the ET cases with normal cerebella have Lewy bodies,^{6, 9} which are lesions that have long been considered important in the pathogenesis of another neurodegenerative tremor disorder, namely, PD. While none of these pathological changes in the cerebellum are disease-specific (e.g., other forms of cerebellar degeneration may be characterized by Purkinje cell loss and torpedo formation), this just indicates that the changes seen in the cerebellum in ET occur more broadly in the cerebellar degenerations. Aside from this structural-pathological evidence suggesting a neurodegenerative process, other evidence suggests that ET is neurodegenerative. While many of these features in isolation are not specific to neurodegenerative diseases, the constellation of findings, all present in the same disease, is more compelling (Table 4). For example, there is a longstanding clinical association between ET and PD; indeed, having ET increases the risk of developing incident PD four to five-fold.⁵¹ Furthermore, having older onset ET increases the risk of developing Alzheimer’s disease nearly two-fold.⁵ This association between ET and subsequent development of these neurodegenerative diseases suggests that ET may share pathogenic mechanisms with these disorders.

Figure 3.

When quantified using different methods, Purkinje cell loss in ET is significant compared to age-matched controls. Bielschowsky-stained section (50× magnification) of the cerebellar cortex in a 79 year old ET case showing normal Purkinje cellularity (right) vs. a region with segmental loss of Purkinje cells (left).

Table 4.

Evidence suggesting that ET is neurodegenerative

Evidence	Comment/Rationale	PD*	AD*	Cautionary Caveat
Purkinje cell loss or Lewy bodies on postmortem studies	Selective involvement of anatomically and physiologically related systems of neurons is considered an important feature of neurodegenerative disorders. Lewy bodies are a feature of PD, a neurodegenerative disease.	Yes	Yes1	Additional postmortem studies are needed to confirm the results of currently-emerging large postmortem series.6, 8
Clinical resemblance to other cerebellar atrophies and Purkinje cell loss	This suggests shared disease mechanisms.	No	No
Marked rise in occurrence with advanced age	PD and AD are associated with advanced age	Yes	Yes
Clinically progressive in most patients	PD and AD are relentlessly clinically-progressive	Yes	Yes	Diseases that are not neurodegenerative may sometimes be clinically-progressive.
Somatotopic spread of tremor over time	Tremor often begins in one body region, and as the disease worsens, spreads to others.	Yes	Yes2
Olfactory Deficit	Olfactory deficits are reported in PD and AD	Yes	Yes	Not specific to neurodegenerative disorders. Not a consistent finding across all studies of ET.
Loss of body mass index59	Neurodegnerative diseases are often associated with loss of body mass index	Yes	Yes	Not specific to neurodegenerative disorders. Not a consistent finding across all studies of ET.
Increased risk of mortality60	Neurodegenerative disorders are associated with increased risk of mortality	Yes	Yes	Not specific to neurodegenerative disorders. Not a consistent finding across all studies of ET.
Increased risk of AD	This association with ET suggests that ET may share pathogenic features with this neurodegenerative disease.	Yes
Increased risk of PD	This association with ET suggests that ET may share pathogenic features with this neurodegenerative disease.		Yes

^*This feature or a similar feature is a characteristic of PD or AD.

AD = Alzheimer’s disease, PD = Parkinson’s disease, ET = essential tremor

¹Neuronal loss in the hippocampus and neocortex are features of AD.

²As AD progresses, different cortical regions may become involved.

Conclusion

There is some evidence to suggest that ET is a family of diseases rather than a single entity (Table 5). These disorders, perhaps better termed “the essential tremors”, are aging-associated, progressive, and associated with cell loss and other types of changes (Lewy body formation) that traditionally occur in neurodegenerative disorders. Future study is needed to continue to shape our evolving notion of the entity that we currently refer to as “essential tremor”.

Table 5.

Key Points

Essential tremor (ET), a progressive disorder of the central nervous system, traditionally has been characterized by kinetic tremor of the arms. This view of ET as a mono-symptomatic condition has been supplanted in recent years. Evidence of clinical heterogeneity and pathological heterogeneity is emerging, raising the question as to whether it is possible to re-formulate ET as a cluster of separable clinical-pathological entities, that is, a family of diseases – “the essential tremors”. The tremor phenomenology is broad and many patients have other motor manifestations and non-motor features, including cognitive and psychiatric. Furthermore, this expanded constellation of clinical features is not distributed homogeneously across patients. Differences in therapeutic response phenotype provide yet another example of clinical heterogeneity and this could be a marker of different underlying disease mechanisms in subsets of patients. Disease mechanisms in ET have been elusive, yet recent postmortem studies have demonstrated a heterogeneous pathology, with ET cases clustered into two groups: those with cerebellar degenerative changes (“cerebellar ET”), and those with brainstem Lewy bodies (“Lewy body variant of ET”). The etiology of ET is often genetic; although specific genes associated with ET have not yet been identified, susceptibility loci have been found on chromosomes 3q, 2p and 6p. Also, several environmental toxins, including harmane and lead, have been tentatively linked with ET. ET is aging-associated, progressive, and associated with neuronal loss and other types of changes that traditionally occur in neurodegenerative disorders, indicating that ET is likely to be a neurodegenerative disease. The mainstays of therapy for ET are propranolol and primidone, although several promising new agents have been introduced in recent years. Surgical treatment (deep brain stimulation) is also highly effective.