ESSENTIAL TREMOR WITHIN THE BROADER CONTEXT OF OTHER FORMS OF CEREBELLAR DEGENERATION

Abstract

Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it within the context of these diseases. Here we compare the clinical and postmortem features of ET to other cerebellar degenerations, thereby placing it within the broader context of these diseases. Action tremor is the hallmark feature of ET. Although often underreported in the spinocerebellar ataxias (SCAs), action tremors occur, and it is noteworthy that in SCA12 and 15, they are highly prevalent, often severe, and can be the earliest disease manifestation, resulting in an initial diagnosis of ET in many cases. Intention tremor, sometimes referred to as “cerebellar tremor”, is a common feature of ET and many SCAs. Other features of cerebellar dysfunction, gait ataxia and eye motion abnormalities, are seen to a mild degree in ET and more markedly in SCAs. Several SCAs (e.g., SCA5, 6, 14, and 15), like ET, follow a milder and more protracted disease course. In ET, numerous postmortem changes have been localized to the cerebellum, and are largely confined to the cerebellar cortex, preserving the cerebellar nuclei. Purkinje cell loss is modest. Similarly, in SCA3, 12 and 15, Purkinje cell loss is limited, and in SCA12 and 15, there is preservation of cerebellar nuclei and relative sparing of other central nervous system regions. Both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration.

Introduction

Essential tremor (ET) is a chronic, progressive neurological disease whose hallmark clinical feature is kinetic tremor of the upper limbs (1, 2). It is among the most prevalent movement disorders and is the most prevalent tremor disorder (3), with an estimated 7 million affected people in the United States (i.e., approximately 2.2% of the entire population of the United States) (4) and high estimates of prevalence (i.e., number of cases per 100,000 population) in numerous countries (3).

Despite being so common, the underlying patho-mechanisms of ET remain surprisingly enigmatic (5–7). Even localizing the site of primary pathology within the brain has been a major challenge. There had been no systematic collection of ET brains until 2003 (8, 9). During the 100-year period from 1903 to 2003, there were only 15 published postmortems (8), mainly comprising isolated case reports with no conclusive findings (10–16). These studies lacked rigor as none used quantitative or immunohistochemical approaches, nor compared ET to control brains (8, 9). The field faced the curious situation in which ET was one of the most prevalent neurological diseases, yet there was nearly no knowledge about its underlying pathobiology (8, 9). A popular disease model, proposed in the 1970s (17), linked ET to an abnormal inferior olivary nucleus; however, empiric support for that model is limited (18–20) and it has recently fallen out of favor (21, 22). More recent research in the field has focused on the cerebellum, where clinical, neuroimaging, and postmortem studies suggest that ET originates within that brain region (23–30). Indeed, there has been a reconceptualization of the disease as one of cerebellar degeneration (7, 23, 31–40).

While the disorders of cerebellar degeneration share numerous clinical and postmortem features (e.g., gait ataxia and Purkinje cell loss), they are not a monolithic unit. Indeed, these many disorders are chacterized by clinical, pathomechanistic, and pathological heterogeneity (41–45). For example, they do no all follow the same natural history – in some life span is quite truncated whereas in others, there is a normal life span (41–51). In some, the main features are cerebellar, and in others there is a range of additional clinical features referable to lesions in the cerebral cortex, brainstem and cranial nerves, and peripheral nervous system (41–45).

Although ET has recently been conceptualized by many as one of the degenerative diseases of the cerebellum (7, 23, 31–40), no one has critically evaluated it within the context of these diseases. How does ET compare to these diseases? Are there other degenerative diseases of the cerebellum that share clinical and pathological features with ET? The goal of this paper is to place the clinical and postmortem features of ET within the context of other forms of cerebellar degeneration; that is, to look for overlapping features and points of clinical and pathological intersection. The paper builds on recent postmortem studies that have begun this comparative process (39).

Selection of Specific Cerebellar Diseases for Comparision to ET

The list of degenerative conditions of the cerebellum is extensive (41–45, 52). For this review, we carefully selected the following 12 diseases, which we compared with ET: spinocerebellar ataxia (sca)1, 2, 3, 5, 6, 7, 12, 14, 15, 17, Friedreich’s ataxia and multiple system atrophy with cerebellar features (MSA-C). Our choice of diseases was based on the following considerations: (1) detailed information has been published on the clinical features of the disorder (41, 43, 45), (2) postmortem features of the disorder have been described in some detail (42, 53, 54), (3) the presence of certain clinical features (e.g., more prominent kinetic and postural tremor in SCA12 and 15, as is seen in ET) (50, 55–59), (4) the presence of natural history features that overlap with what is seen in ET (e.g., SCA5, SCA6, SCA14, SCA15) (51, 55, 60, 61), (5) the presence of certain postmortem features (e.g., relative preservation of the Purkinje cell population in SCA3, thereby mirroring the modest Purkinje cell loss observed in ET) (42, 53), and (6) the relatively high prevalence of the condition (e.g., Friedreich’s ataxia, SCA1, SCA2, SCA3, SCA6 and SCA7) (41, 43, 45, 53). We considered including fragile X-associated tremor/ataxia syndrome, in which intention tremor is common, but a detailed clinical characterization of the various types of tremor (e.g., kinetic, postural) has not been undertaken to any large degree in that syndrome (62).

Methods

One of the authors (E.D.L.) conducted a PubMed search on May 5, 2020, searching abstracts of publishing papers, crossing the term “essential tremor” with a series of second terms, which yielded the following numbers of papers: essential tremor + clinical (n = 1,891), essential tremor + pathology (n = 547), and essential tremor + postmortem (n = 89). Similarly, “spinocerebellar ataxia” was crossed with tremor (n = 179), clinical (n = 1,430), pathology (n = 1,304) and postmortem (n = 46); “multiple system atrophy” was crossed with clinical (n = 1,927), tremor (n = 218), pathology (n = 1,752), and postmortem (n = 151); and Friedreich’s ataxia was crossed with clinical (n = 602), tremor (n = 14), pathology (n = 435), and postmortem (n = 17). All of these papers were reviewed for relevant content and cited in this paper if pertinent.

Clinical Features of ET in Comparison with Other Forms of Cerebellar Degeneration

Tremor and Cerebellar Signs

Tremor is likely underreported in most cerebellar degenerative disorders, as the focus in these disorders is often on the multitude of other features of cerebellar degeneration that can be more clinicially obvious or disabling (e.g., gait ataxia, eye movement abnormalities, dysmetric limb movements (Table 1). Furthermore, tremor may be difficult to separate from dysmetria, further complicating and obscuring its evaluation. When tremor is reported in these disorders, much of the attention is on intention tremor (i.e., tremor that worsens when approaching a target), as this is regarded as a form of cerebellar tremor, or rest tremor (i.e., tremor that occurs when a body part is supported against gravity and is inactive), as this can be a feature of the parkinsonism that can accompany some forms of cerebellar degeneration. Hence, kinetic tremor (i.e., tremor occurring during voluntary movements such as writing or eating) and postural tremor (i.e., tremor occurring when a body part is held motionless against the force of gravity) are likely to be relatively underreported forms of tremor.

Table 1:

ET compared with other forms of cerebellar degeneration in terms of motor features

	Tremor (type not specified)	Other type of tremor	Kinetic (also action) tremor	Postural tremor	Intention tremor	Rest tremor	EOMA or nystagmus	Gait ataxia	Other cerebellar features (e.g., dysmetria, over-shoot, dysarthria)
ET		Head tremor (17.9% – 52.0%)(213) Jaw tremor (7.5% – 41.2%)(213) Voice tremor (15.1% – 40.1 %)(213)	369/369 (100%)(1)	305/369 (82.7%)(1)	101/228 (44.3%)(78–81)	2/105 (1.9%)–77/166 (46.4%) (90)	+(mild and subclinical)( 107–109)	159/379 (42.0%)(93– 98)	Not present
SCA1			0/10 (0.0%)(63)	3/52 (5.8%)(68), 4/40 (10.0%)(69),	1/8 (12.5%)(160), 3/16 (18.8%)(83), 2/3 (66.7%)(182)	0/40 (0.0%) (69)	+(63, 83, 160, 182)	+(63, 160, 182)	+(63, 160, 182)
SCA2		Lip tremor 2/28 (7.1 %)(69) Head tremor 1/1 (100%)(214) Chin and head tremors 1/1 (100%)(215)	5/21 (23.8%)(63), 5/21 (23.8%)(64), 1/1 (100%)(214), 1/1 (100%)(216), 1/1 (100%)(215)	6/28 (21.4%)(69), 5/21 (23.8%)(64), 19/69 (27.5%)(68), 3/4 (75.0%)(73), 1/1 (100%)(214), 1/1 (100%)(216), 1/1 (100%)(215)	15/21 (71.4%)(64), 4/4 (100%)(194), 1/1 (100%)(215)	4/28 (14.3%)(69), 4/8 (50.0%)(132), 1/1 (100%)(214), 1/1 (100%)(216), 1/1 (100%)(215)	+(63, 64, 132, 183, 194, 214, 216, 217)	+(63, 64, 132, 183, 214–217)	+(63, 64, 194, 214–217)
SCA3		Lip tremor 1/17 (5.9%)(69) Truncal tremor 1/1 (100%)(218)	2/60 (3.3%)(63), 1/1 (100%)(122)	2/72 (2.8%)(71), 14/126 (11.1 %)(72), 16/129 (12.4%) (68), 3/17 (17.6%)(69), 2/8 (25.0%)(73)	7/53 (13.2%)(82), 2/9 (22.2%)(194)	0/17 (0.0%)(69), 5/72 (6.9%)(71), 4/53 (7.6%)(82), 2/4 (50.0%)(219)	+(63, 82, 122, 194, 219–221)	+(63, 72, 82, 122, 194, 218–221)	+(63, 82, 122, 194, 218–220)
SCA5			−(178), 0/6 (0.0%)(179), 0/77 (0.0%)(51), 2/15 (13.3%)(70)	−(178), 0/6 (0.0%)(179), 0/77 (0.0%)(51), 2/15 (13.3%)(70)	− (178), 0/6 (0.0%)(179), 0/77 (0.0%)(51), 5/15 (33.3%)(70)		+(51, 70, 178, 179)	+(51, 70, 178, 179)	+(51, 70, 178, 179)
SCA6	12/140 (8.6%)(22 2)		1/27 (3.7%)(63)	11/65 (16.9%)(68), 3/7 (42.9%)(223)**, 3/4 (75.0%)(73)	11/48 (22.9%) (84)*,+(224)	0/12 (0.0%)(225), 1/17 (5.9%)(91)	+(63, 91, 193, 220, 222–224, 226, 227)	+(63, 91, 180, 193, 220, 222–224, 226, 227)	+(63, 91, 220, 222–224, 226, 227)
SCA7	1/26 (3.8%)(228), 2/19 10.5%)(92), 2/16 (12.5%)(186), 3/12 (25.0%)(2 29)	Head tremor 1/26 (3.9%)(228), 1/19 (5.3%)(92), 1/8 (12.5%)(230) Head, truncal and limb tremors even at rest 1/1 (100%)(231)		1/50 (2.0%)(86), 1/6 (16.7%)(73)	1/16 (6.3%)(186), 2/26 (7.7%)(228), 45/50 (90.0%)(86)	1/19 (5.3%)(92)	+(86, 92, 133, 186, 187, 228, 230–234)	+(86, 92, 133, 186, 187, 228–234)	+(86, 92, 133, 186, 187, 228–234)
SCA12	2/4 (50%)(235	Head temor 13/21 (61.9%)	19/25 (76.0%)(66), 5/6	17/21 (81.0%)(59)	1/10 (10.0%)(67),	10/21 (47.6%)(59)	+(59, 65, 67, 77, 163)	+(59, 65, 67, 77, 163,	+(59, 65, 67, 77, 235)
	), 4/6 (66.7%)(77),1/1 (100%)(163)	(59) Voice tremor 2/21 (9.5%)(59) Orofacial tremor 3/21 (14.3%)(59)	(83.3%)(65), 10/10 (100%)(67)		12/21 (57.1 %)(59)			235)
SCA14		Head tremor 2/18 (11.1 %)(164), 1/1 (100%)(236) Truncal tremor on standing 1/6 (16.7%)(48) Head, arm or leg tremor which was not well- characterized and could be myoclonus rather than tremor 5/5 (100%)(165)	1/3 (33.3%)(123)	2/7 (28.6%)(76)			+(47–49, 76, 123, 124, 164)	+(47–49, 60, 76, 123, 124, 164, 165, 236, 237)	+(47–49, 76, 123, 124, 164, 165, 236)
SCA15		Trunk or neck tremor 6/10 (60.0%)(56)	4/10 (40.0%)(56), 7/10 (70.0%)(55)	1/7 (14.3%)(58), 2/10 (20.0%)(57), 3/13 (23.1 %)(50), 4/10 (40.0%)(56),	10/10 (100%)(55)		+(50, 55–58, 181, 238)	+(50, 55, 56, 58, 181, 238, 239)	+(50, 55–58, 181, 238)
				7/10 (70.0%)(55)
SCA17	1/15 (6.7%) (16 8)		1/1 (100%)(216)	1/15 (6.7%)(125), 1/1 (100%)(216)	1/3 (33.3%)(126), 1/1 (100%)(216)		+(125, 126, 216)	+(125, 126, 168, 216)	+(125, 126, 216)
Friedreich’s ataxia		Head tremor 32/103 (31. 1 %) (240), 1/1(100%) (24 1)	2/2 (100%)(127)	5/29 (17.2%)(73), 1/2 (50.0%)(127)	1/1 (100%)(242)		+(240)	+(127, 240–242)	+(127, 240–242)
MSA-C			12/119 (10.1 %)(74), 2/18 (11.1 %)(75)	14/119 (11.8%)(74), 4/18 (22.2%)(75)	49/203 (24.1 %)(85), 6/18 (33.3%)(75), 14/31(45.2%)(24 3)	3/119 (2.5%)(74), 3/18 (16.7%)(75), 6/24 (25.0%)(244), 8/31 (25.8%)(243), 79/203 (38.9%) (85)	+(74, 75, 85, 243, 244)	+(74, 75, 85, 244)	+(74, 85, 243, 244)

EOMA = extraocular motion abnormalities, ET = essential tremor, MSA-C = multiple system atrophy with cerebellar features, SCA = spinocerebellar ataxia

^*intention tremor in the limbs and/or axial tremor in the head and trunk.

^**In the neck in one patient and in both the neck and upper limbs in two patients.

⁺feature is present.

Kinetic tremor occurs in 100% of ET patients (Table 1) and as the sine qua non of ET (1). A review of the data on other forms of cerebellar degeneration (Table 1) shows that kinetic tremor is rarely-reported in some forms of SCA (e.g., SCA1 [0.0%] (63), SCA3 [3.3%] (63), SCA6 [3.7%] (63)), is reported in a moderate percentage of patients with several other forms of SCA (e.g., approximately 20 – 25% in SCA2 (63, 64)) and has been reported in a high percentage of patients with two forms of SCA (e.g., SCA15 [40% – 70%] (55, 56) and SCA12 [76% – 100%] (65–67)).

Postural tremor is a feature of a majority although not all ET patients (e.g., 82.7%, Table 1) (1). By comparision, in patients with cerebellar degenerations, postural tremor is reported to occur in a relatively higher percentage of patients than is kinetic tremor, with percentages ranging from those that are low (5% – 15% [SCA1 (68, 69), SCA5 (70)], 3% – 25% [SCA3 (68, 69, 71–73), Friedreich’s ataxia (73), MSA-C (74, 75)], to those that are in the moderate range (20% – 30% [SCA2 (64, 68, 69), SCA14 (76)], 40% [genetically undefined SCA (73)], 14% – 70% [SCA15 (50, 55–58)]) to those that are higher (80% [SCA12 (59)]). As is the case with kinetic tremor, postural tremor seems to be highly prevalent among patients with SCA12 and SCA15 (Table 1) (50, 55–59, 65–67, 77).

Below, more detail is provided on SCA12 and SCA15, as in these forms of SCA, kinetic and postural tremors seem to be a predominating feature (50, 55–59), as they are in ET (1). Action tremor (i.e., postural or kinetic tremors) of the arms or head was present in 10/10 (100%) affected family members in one SCA12 kindred (67). Tremor was the first neurological sign in 8/10 (80.0%) affected family members in this SCA12 kindred (67); tremor also affected the jaw and voice in two patients and in the protruded tongue of one patient (67). The patients in this kindred were often initially diagnosed as ET (67). In another series of seven SCA12 cases in China, six of whom had clinical information, action tremor was present in 5/6 (83.3%) (65); of the three kindreds reported, action tremor was the initial presenting symptom in one, was a subsequently-reported feature in one, and was not seen in the one patient that comprised the third kindred (65). In a study of 25 SCA12 cases in India, 19 (76.0%) presented with upper limb tremor (66); interestingly, the authors reported that all affected individuals had mild or no gait ataxia (66). In a study of six patients in India with SCA12, four (66.7%) presented with tremor in the hand and the two remaining presented with gait ataxia and dysarthria (77). In a study of ten Japanese patients with SCA15, postural and action tremor was noted in the upper limbs in 4/10 (40%) (56). In a study of ten German patients with SCA15, action and postural tremor of the hands was found in 7/10 (70.0%) patients, and the patients perceived tremor as one of the most compromising impairments of activities of daily living (55). In summary, in these two disorders, SCA12 and SCA15, action tremor (i.e., kinetic and postural tremor) is highly prevalent, often severe, and it can be the earliest disease manifestation, resulting in an initial diagnosis of ET (50, 55–59, 65–67, 77).

With respect to intention tremor, this has been reported in approximately one-half (44.3%) (78–81) of ET patients (Table 1). In other forms of cerebellar degeneration, intention tremor occurs in varied proportions of patients - 0.0% in large cohort of 77 patients with SCA5 (51), 13.2% in a cohort of 53 patients with SCA3 (82), 18.8% in a cohort of 16 patients with SCA1 (83), 22.9% in a cohort of 48 patients with SCA6 (84), 24.1% in a large cohort of 203 patients with MSA-C (85), 57.1% in a cohort of 21 patients with SCA12 (59), 71.4% in a cohort of 22 patients with SCA2 (64), 90% in a cohort of 50 patients with SCA7 (86), and 100% in a cohort of 10 patients with SCA15 (55) (Table 1). Thus, with respect to prevalence of intention tremor, ET falls at a midpoint with respect to these other disorders, with some forms of SCA having lower reported prevalences of intention tremor and some having higher reported prevalences. It is difficult to comment on the severity of intention tremor, as this is generally not reported in the SCA literature; in ET, intention tremor can range from mild to severe (2, 87). Furthermore, in ET, intention tremor is not restricted to the upper limbs, but is also observed in the lower limbs (88) and head (89).

In ET, the proportion of patients with rest tremor depends on the characteristics of the sampled cohort and more specifically, the duration of illness, but it ranges from 1.9% – 46.4% in carefully assessed cohorts (Table 1) (90). Similarly, rest tremor has been reported in a number of other cerebellar degenerative disorders, with the prevalence generally being low (e.g., in larger cohorts of patients: 14.3% of SCA2 (69), 7.6% of SCA3 (82), 5.9% of SCA6 (91), 5.3% of SCA7 (92), Table 1), but its prevalence is reported to be particularly high in some forms of SCA in which tremors of different types are generally more common (e.g., 10/21 patients [47.6%] with SCA12 (59), Table 1).

While some signs typical of cerebellar degeneration other than tremor have not been reported in ET, such as dysarthria and dysmetria, a number of other cerebellar signs have been reported. Thus, gait ataxia has been reported in numerous studies of ET (Table 1) (93–98). Although this ataxia is generally mild in ET, it can be more marked (99). When defined as taking 2 or more tandem gait mis-steps, as is common in prior gait and balance studies, ataxia has been reported in 42.0% of patients with ET vs. only 22% of similarly-aged controls (93). As described elsewhere (93), ET results in significant impairments in gait speed, asymmetry, dynamic balance, and variability, and these may lead to functional consequences for ET patients, including reduced balance confidence and increased risk of falls (100, 101). The impairments that are observed in ET are qualitatively similar to those reported in patients with other forms of cerebellar ataxia (102–104). Thus, classic cerebellar ataxic gait is characterized by slow gait speed, short step length, wide base of support, deviations in the walking path, and increased step-to-step variability (93, 102–105). Increased step-to-step variability, in particular, may be the result of poor timing and scaling of joint movement (93, 105, 106). As discussed elsewhere, gait impairments in ET do not include a wide base of support and deviations in the walking path, both considered key characteristics of ataxic gait (93). Therefore, gait impairments in ET share several features with cerebellar ataxia, but it is important to note that not all features are shared, and the presentation in ET is typically not as severe (93).

Another feature of SCAs is eye motion abnormalities; to some extent, these are likely the result of involvement of cerebellar pathways but they may also be the result of involvement of the brainstem and cranial nerve nuclei in these disorders. In several studies, such abnormalities have been reported in ET (e.g., reflexive saccadic dysmetria and slowing of smooth pursuit), but in terms of their severity, they are far milder than seen in many patients with SCA; indeed, in ET they are not readily detectable on a standard neurological examination (107–109). Limited range of eye motion is not a reported feature of ET in clinical settings.

There are other motor abnormalities in ET that point to a more pervasive underlying abnormality of cerebellar function. Several studies have revealed abnormalities in limb motor behavior in ET in studies of eye-hand coordination and repetitive finger tapping movements (110–113).

Dystonia and Other Involuntary Movement Disorders

Although in the past, dystonia was regarded as a disorder of the basal ganglia, recent studies have posited a role of the cerebellum as well (114–120). In this context, it is of interest that dystonia has been reported in numerous cerebellar degenerative disorders (SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA14, SCA17, Fridreich’s ataxia); the extent to which this is the result of cerebellar or extra-cerebellar (e.g., basal ganglia) pathology, as is found in some of these disorders, remains to be determined. When present, the location of this dystonia can be variable from patient to patient, and the prevalence can be high in some studies. In a study of the natural history of 345 SCA patients from 12 centers in the United States, 7/58 (12.1%) SCA1, 13/72 (18.1%) SCA2, 33/134 (24.6%) SCA3 and 6/70 (8.6%) SCA6 patients had dystonia (121). In a study in India, 5/40 (12.5%) SCA1 patients, 5/28 (17.9%) SCA2 patients, and 3/17 (17.6%) SCA3 patients had dystonia; dystonia included generalized dystonia, torticollis, facial dystonia, lingual dystonia and foot dystonia (69). In a series of SCA3 patients in France, 2/6 (33.3%) had dystonia (one facial dystonia and one hand dystonia) (71), and an 11 year old girl with SCA3 was reported to have lingual dystonia (122). In Taiwan, 19/53 (35.8%) SCA3 cases had dystonia (82). In a study of 126 SCA3 patients from two large cohorts, one in China and one in North America, 32/126 (25.4%) had dystonia (72). A study in Japan of 48 individuals with SCA6 reported the presence of dystonia in 7 (15%) (84). In African families with SCA7, individuals with dystonia were noted (92). Focal dystonia was reported in 2/10 (20%) patients with SCA12 (67). Axial dystonia was noted in 2/25 (8.0%) of patients with SCA12 in India (66) and 1/12 (8.3%) patients with SCA12 in another report from India (77). A patient with SCA14 in a Japanese kindred was reported to have cervical dystonia (123). Two of 13 affected family members with SCA14 in a Dutch kindred had focal dystonia (writer’s cramp) (124). In a study of 15 SCA17 patients in Italy, 7 (46.7%) had dystonia (125); the authors of this report noted that the dystonia in SCA17 was diverse - blepharospasm, torticollis, writer’s cramp, foot dystonia (125). Indeed, in a kindred in Germany, all three affecteds had different types of dystonia: foot, writer’s cramp, cervical (126). A patient with Friedreich’s ataxia had writer’s cramp and dystonia in both feet; in the same report, another patient with the same disease had dystonic postures in the left hand (127). Furthermore, 13/29 (44.8%) patients with Friedreich’s ataxia in Spain were reported to have dystonia.

With respect to ET, there is increasing evidence that advanced patients may develop some dystonia (2, 128–130). Thus, patients with bone fide ET, and especially longstanding and severe ET, may develop subtle dystonic postures or dystonic movements (128). It is debated whether these dystonic postures or movements are simply a manifestation of their advanced ET or whether their presence predicates a second diagnosis or a retraction of the longstanding ET diagnosis (128). There is evidence that it is merely a manifestation of their ET, as it involves their cerebellum (128). The recent consensus classification of tremor similarly acknowledged that patients with ET may exhibit some degree of dystonia (131). However, there is uncertainty as to how much dystonia may be present in a patient with ET. It is not apparent how severe the dystonic postures in ET may be, where these may be located (e.g., limb, neck), and whether they should relate to limbs that do or do not have tremor. Beneath all of this uncertainty, however, is the acknowledgment that some degree of dystonia does not necessitate the removal of the ET diagnosis, although some have suggested referring to these patients as having “ET-plus” (128).

We discussed the occurrence of rest tremor in ET and SCAs above; however, a full parkinsonian syndrome occurs in certain forms of SCA, for example, SCA2 (69), and it can be quite common. For example, in a Japanese SCA2 kindred, 7/8 (87.5%) patients had features of parkinsonism (e.g., rest tremor, bradykinesia, masked face) (132). Parkinsonism has been reported, although more rarely, in other forms of SCA. Thus, a patient with SCA7 and parkinsonism was also reported (133). ET is reported to be a risk factor for incident Parkinson’s, such that some patients with ET will eventually develop co-morbid PD (134–138). In this sense, a full parkinsonian syndrome can be an eventual stage in the evolution of the disease (134–138). Whether the presence of Lewy bodies in some ET patients is a pathomechanistic avenue for such an evolution is not clear (139, 140).

Cognition

Although the hallmark clinical feature of ET is kinetic tremor (1), there is growing appreciation that cognitive impairment is a disease-linked feature (32, 141–143). In particular, clinical studies show that ET patients have poorer cognitive performance than age-matched controls (141, 144). While in many patients the problem is mild, in some it reaches more severe proportions (141, 145, 146). Results of clinical research are consistent with epidemiological studies demonstrating that ET patients have a higher prevalence of mild cognitive impairment (MCI) than controls, and they are also at increased risk of developing dementia (141, 145–147). Early studies examining cognition in ET, as well as the majority of cognitive studies in ET to date, have primarily highlighted deficits in executive functioning (141). Given the documented role of the cerebellum in supporting executive functioning (141, 148, 149), and the known compromise of the cerebellum in ET (24–27, 39, 141, 150, 151), executive deficits in ET have generally been conceptualized as the result of inefficient or impaired cerebellar-cortical networks, and particularly those projecting to and from the prefrontal cortex (141, 152–157). It should be pointed out, though, that the cognitive deficits in ET are not restricted to executive dysfunction, as other domains of cognition may be affected (141, 143, 158).

The cerebellum is involved in a broad array of cognitive processes (152). As with ET, cognitive impairment is a described feature of a variety of SCAs, and the deficits may be profound (159). For example, 2/8 (25%) SCA1 patients were demented; their ages were 40 and 56 years (160). Five of 21 (23.8%) SCA2 patients in a German kindred were reported to have mild dementia; their ages were 22, 40, 55, 63 and 68 years (64). Dementia was noted in 4/17 (23.5%) SCA2 patients in Germany; their mean age was 52.0 ± 12.2 years (161). Dementia and delirium were reported in 4 patients in Japan with SCA3 (162). Nine of 19 (47.4%) SCA7 patients were reported to have dementia; 7 (77.8%) of the 9 were between the ages of 20 and 36 (92). Two of 6 (33.3%) affecteds in an SCA12 family in India were reported to be demented (163), and cognitive decline was reported in 2/6 (33.3%) SCA12 patients in 3 Chinese kindreds with clinical information (65). Thirteen of 18 (72.2%) SCA14 patients in a kindred of French ancestory had cognitive complaints or abnormal cognition; in several of these, the cognitive complaint preceded motor signs of cerebellar dysfunction (164). Five of these 13 were under the age of 40 years and ten were under the age of 60 years (164). In a cohort of 15 French or German SCA14 patients, 5/15 (33.3%) had cognitive deficits or dementia (165). Two of five (40%) SCA14 patients in Japan had cognitive deficits; their ages were 30 and 49 (123). In twelve SCA15 patients in Italy, 2 (16.7%, ages 50 and 60 years) had cognitive impairment (57). In SCA17, dementia is common (159, 166, 167); 7/15 (46.7%) SCA17 patients were noted to have dementia (125). Eight of 15 (53.3%) SCA17 patients in Italy had cognitive impairment, which was of moderate severity in six; their ages ranged from 25 – 62 years (168).

In summary, although defined as motor disorders, both ET and a range of SCAs are characterized by cognitive impairments that can range from mild to severe. The pathomechanism for some of these deficits may involve inefficient or impaired cerebellar-cortical networks, and particularly those projecting to and from the prefrontal cortex.

Non-cerebellar signs

SCA6 is often viewed as a predominantly cerebellar syndrome, with few non-cerebellar signs (41, 63). However, many of the SCAs are accompanied by neurological signs that are not referable to cerebellum degeneration and which reflect a more widespread involvement of the nervous system. For example, SCA7 is distinguished from other SCAs by the high prevalence of retinal degeneration (41). One of these signs, hearing loss, will be highlighted as it represents an area of overlap with ET. A number of the SCAs have an associated hearing loss. Thus, a study of two SCA14 cases indicated hearing loss in both; in the one who could be tested, the results supported a sensorineural hearing loss suggesting that the inner ear or cochlear nucleus were impaired (169). A study of central auditory processing in patients with spinocerebellar ataxia noted that 12/43 (27.9%) reported hearing loss and 14/43 (32.5%) had abnormal audiological findings, including 4/12 (33.3%) with SCA3, 3/6 (50.0%) with SCA10 and 1/1 with SCA4, 1/1 with SCA6 and 1/1 with SCA7 (170). Hearing loss, in excess of what is observed in age-matched controls, has now been reported in numerous studies of ET as well; the cause is unclear although there is more evidence in favor of cochlear rather than retrocochlear pathology (171–175). It hints at involvement in ET of structures outside of the cerebellum and traditional tremor pathways (e.g., cerebellar-thalamic tract), thus in some ways mirroring the situation that occurs more broadly in the SCAs.

Natural History

While ET is generally a progressive disease, it is slowly progressive, with estimates of progression being less than 5% per year (176). Patients live to advanced ages. In this respect, in the past, ET was often referred to as “benign essential tremor” (177). By contrast, many forms of cerebellar degeneration follow a more rapidly progressive course (41), leaving some to wonder whether a disease that advances as slowly as ET does could really be a form of cerebellar degeneration. However, a number of SCAs are also slowly progressive (51). Thus, SCA5 (70, 178, 179), SCA6 (180), SCA14 (60, 61), and SCA15 (46) generally do not shorten lifespan and follow a relatively mild disease course (51). Several of these will be discussed in more detail below.

In a Japanese SCA14 kindred, all affected individuals, including a woman with a 30-year history, remained ambulatory without assistance (47). In an Australian SCA14 family, the authors noted that progress of the condition had been slow and that some had even been symptomatic for decades (48). Indeed, in an initial report of a four-generation SCA14 family of English and Duch ancestry with fourteen affected members, the authors noted that symptoms were subtle and slowly progressive and that lifespan did not appear to be decreased (49). In a Dutch SCA14 kindred, the authors noted that life-span appeared to be unaffected, as evidenced by the fact that three affected men were 80 years of age or older (124). In a study of fourteen SCA14 patients in the US, the authors similarly reported that there was no evidence of shortened life span (60).

With respect to SCA15, the investigators noted that in a large kindred, the rate of progression was slow, and some family members remained ambulatory without walking aids five decades after onset” (46). In a paper that reported thirteen SCA15 patients of French origins, the progression of the disease was noted to be “particularly slow” and the two patients with disease of more than 40 years duration needed help to walk but were still ambulatory (50). Another sign of benign disease can be late onset. A report of an Italian SCA15 kindred noted that ages of onset were quite late - 60, 66 and 73 years (181). In another two Italian SCA15 kindreds, ages of onset were quite late - 60 or older in 5/12 (41.7%) affecteds and 70 or older in 2/12 (16.7%) affecteds (57).

Summary (Clinical Features)

In summary, our goal in this paper is to examine ET within the context of other disorders of cerebellar degeneration and review the clinical features of ET relative to those in these other disorders. A consideration of the clinical features of ET should be first and foremost centered on tremor. Kinetic tremor occurs in 100% of ET patients (1) and is the sine qua non of ET. Postural tremor is also very common in ET (1). Although tremors are often underreported in the various SCAs, both types of tremor do occur in the SCAs and their prevalence ranges from rare (e.g., <10%), to moderate percentages (e.g., 20% – 70%) to high percentages (>70%). It is highly noteworthy that in two disorders, SCA12 and SCA15, kinetic and postural tremors are highly prevalent, often severe, and they can be the earliest disease manifestation, actually resulting in an initial diagnosis of ET (50, 55–59, 65–67, 77). Aside from kinetic and postural tremor, intention tremor, often referred to as “cerebellar tremor”, has been reported in 44.3% (78–81) of ET patients. With respect to prevalence of intention tremor, ET falls at a midpoint with respect to the SCAs. Other features of cerebellar dysfunction or degeneration are also quite common in ET, with a mild gait ataxia reported in as many as 42% of ET cases (93) and mild eye motion abnormalities in smooth pursuit and saccades in ET as well (107–109). Although the hallmark feature of ET is kinetic tremor (1), there is growing appreciation that cognitive impairment also occurs (32, 141–143). The cerebellum is involved in a broad array of cognitive processes (152), and as with ET, cognitive impairment may be a feature of a variety of SCAs (159). Non-cerebellar signs such as auditory problems occur in ET (171–175) as well several of the SCAs (169, 170), thereby hinting at involvement in ET of structures outside of the cerebellum and traditional tremor pathways (e.g., cerebellar-thalamic tract), thus mirroring the situation that occurs more broadly in the SCAs. Finally, while ET is generally a progressive disease, it is slowly progressive, with estimates of progression being less than 5% per year (176). Patients live to advanced ages and, in the past, ET was referred to as “benign essential tremor” (177). By contrast, many forms of cerebellar degeneration follow a more rapidly progressive course (41), leaving some to wonder whether a disease that advances as slowly as ET could really be a form of cerebellar degeneration. However, a number of SCAs are also slowly progressive (51). Thus, SCA5 (70, 178, 179), SCA6 (180), SCA14 (60, 61), and SCA15 (46) generally do not shorten lifespan and follow a relatively mild disease course. In summary, in multiple regards, the clinical features of ET do overlap with those of the SCAs, with several forms of SCA evidencing tremor-predominant and more benign phenotypes.

Pathological Features of ET in Comparison with Other Forms of Cerebellar Degeneration

Pure Cerebellar Degeneration vs. Widespread Involvement of Extra-Cerebellar Regions

In ET, the main postmortem changes have been observed in the cerebellar cortex (7, 39, 139). Yet in many forms of SCA, involvement of the nervous system is often diffuse, involving numerous extra-cerebellar regions as well as the cerebellum (54, 182–187). This may in part account for the more severe and widespread clinical findings in these disorders, and the involvement of pre-cerebellar and deep cerebellar nuclei, in addition to the cerebellar cortex, could account for the often greater severity of the clinical cerebellar syndrome noted in these disorders relative to that seen in ET (185).

Many of the SCAs are accompanied by diverse extracerebellar neurodegeneration patterns (e.g., cerebral cortex, basal ganglia, thalamus, midbrain, pons, and medulla) (54, 182–187). However, there are differences, and the pathology is not monotonously the same. For example involvement of the basal forebrain is more a feature of SCA1 and SCA2 than SCA3, SCA6, SCA7 and SCA17 (54, 182), and involvement of basal ganglia, thalamic and midbrain structures are similarly differently involved across this set of six disorders, with severe affection of the pallidum and subthalamic nucleus, for example, in SCA3 (54). Pontine atrophy is more marked in SCA2 than in SCA6 (54). The inferior olivary nucleus is reportedly more involved in SCA1 and SCA2 than in SCA3, SCA6, SCA7 and SCA17 (54, 183). It should also be pointed out that these neurodegenerative patterns overlap considerably, particularly as the diseases pass on to advanced stages (54). In ET, studies to date have not shown such a widespread pattern of degeneration.

Several forms of SCA either have clinical features (e.g., type of tremor, natural history) that more resemble ET. Drawing a parallel with ET, several of these will be discussed below with respect to the limited extent of their associated extra-cerebellar pathology.

As noted above, SCA12 patients have prominent kinetic tremor and may initially be diagnosed as ET (65–67). There is limited knowledge of the pathology of SCA12, with only one published postmortem examination; this patient died at age 66 years of age and had presented initially with action tremor of both arms in her 30s and later developed ataxia and dementia (188). Consistent with the more benign ET-like clinical picture of these patients is that the extent of the pathology (188) was less than that seen in many other forms of SCA (e.g., SCA1, 2, 3, 6) (54). The changes were most evident in the cerebral cortex and cerebellum (188). In the cerebral cortex, there was generalized atrophy that was more marked in parietal and posterior frontal regions (188). Numerous other brain regions appeared normal (e.g., thalamus, subthalamic nucleus, cranial nerves) whereas several others showed mild atrophy (i.e., hippocampus, midbrain, pons, medulla) but without microscopic cell loss or changes (188). Mild cerebellar cortical atrophy was noted (188). Purkinje cell loss was moderate in degree and was patchy and segemental with only occasional torpedoes (188). The deep cerebellar nuclei appeared normal in size and cytology (188). Alzheimer-type neuronal plaques and tangles were rare, and thus could not explain the dementia. Neuronal intranuclear ubiquitin-positive inclusions were rarely detected in motor cortex and in Purkinje cells; more abundant inclusions were identified in the substantia nigra, most consistent with Marinesco bodies. The inclusions identified in this brain did not stain for long polyglutamine tracts (1C2 antibody), nor with alpha-synuclein, tau or TDP-43; their significance in disease pathogenesis remains undefined. SCA12 is caused by an expanded noncoding CAG repeat in a functional promoter region of the PPP2R2B gene, and longer repeats increase expression of PPP2R2B splice variants (188). As the CAG repeats appear not to be significantly transcribed, consistent with the absence of 1C2 immunostaining, SCA12 is not a typical polyglutamine disease.

In SCA15, action and postural tremor of the hands is very common and the patients may perceive tremor as one of the most compromising impairments of activities of daily living (55). To our knowledge, however, there are no published postmortem brain examinations of SCA15. MRI studies have shown cerebellar atrophy, either global or predominant in the vermis, with sparing of brainstem structures (50, 55, 57).

SCA14 tends to follow a more benign course than many of the other SCAs and in this sense resembles ET (47–49, 60). Only two reported cases have come to postmortem examination. The first was a 66 year old woman; clinical information was not published, although family members were reported to have “pure ataxia” (49). The postmortem examination revealed a reportedly normal cerebral cortex, basal ganglia and pons (49). On magnetic resonance imaging, the cerebellar cortex had shown midline atrophy; on postmortem examination, the cerebellar cortex showed patchy loss of Purkinje cells with empty baskets that were hypertrophic (49). The medulla showed mild gliosis in the inferior olives without appreciable neuronal loss (49). The second postmortem was a 90-year old man who died of natural causes, from a 4-generation British family having 18 affected family members (189). MRIs of family members demonstrated moderate to severe generalized cerebellar atrophy. Specific clinical features for this patient were not described, although the family was described as having “pure ataxia”. Mild Braak II/III neurofibrillary Alzheimer type pathology was present, but no Lewy body or TDP-43 proteinopathy was identified. P62 sequestosome antibody did not identify any other protein aggregates. There was severe loss of Purkinje cells in all lobules of the neocerebellum (estimated to be 80%), associated with Bergmann gliosis. However, Purkinje cells in the cerebellar tonsils and adjacent flocculonodular lobe were relatively preserved. There was no apparent neuronal loss in cerebellar nuclei, pons or inferior olive. Thus, in both of these postmortem examinations, the neuropathology of SCA14 was predominiated by Purkinje cell loss, consistent with strong protein expression limited to cerebellar Purkinje cells for the disease affected protein kinase C-γ (189).

Extent of Purkinje Cell Loss: Marked vs. Modest

In ET, Purkinje cell loss, when described, has been significant when compared to age-matched controls, but the degree of loss is moderate and patchy (39, 139, 190). There is no reported thinning of the molecular layer in ET. Many SCA subtypes evidence marked cerebellar cortical atrophy, and marked and even subtotal Purkinje cell loss with thinning of the molecular layer (53, 54, 125). Similarly, in MSA, Purkinje cells may be severely depleted (191). However, in some forms of SCA, this is less marked. Examples of the latter will be discussed below, within the context of their clinical similarities to ET.

SCA12 patients have prominent kinetic tremor and may initially be diagnosed as ET (65–67). There is limited knowledge of the pathology of SCA12 as there has been only one published postmortem examination (188). As described above, in this case, there was moderate loss of Purkinje cells in the cerebellar vermis and cerebellar hemispheres, which occurred in patches of up to 10 cells (188). In this sense, the Purkinje cell loss was not total and occurred to a moderate and patchy degree, similar to the segemental loss of Purkinje cells that is observed in the ET brain (190). Of further interest is that the individual had an expansion of 73 repeats, which is at the high end of the pathogenic range and the patient had an unusually severe clinical course (188). As noted by the authors, it is conceivable that the neuropathological changes observed in this individual were more marked than might be observed in a more typical patient with fewer repeats (188). Of additional note is that torpedoes (i.e., swellings of the Purkinje cell axon) were noted to be “occasional” rather than abundant (188). While neuroimaging findings of other individuals with more modest expansions have also demonstrated atrophy predominantly in cerebellum and cerebral cortical regions (54, 192), additional confirmatory postmortem studies are needed.

SCA14 tends to follow a more benign course than many of the other SCAs and in this sense resembles ET (47–49, 60). As described above, two cases have come to postmortem. The first was a 66 year old woman in whom magnetic resonance imaging of the cerebellar cortex had shown midline atrophy; on postmortem, the cerebellar cortex showed patchy loss of Purkinje cells with empty baskets that were hypetrophic (49). The second case (189) was a 90 year old man in whom pathology was also limited to the cerebellum, which showed more severe Purkinje cell loss (estimated at 80% of Purkinje cells) throughout the cerebellum associated with Bergmann gliosis, except for relative Purkinje cell sparing in cerebellar tonsils and adjacent flocculonodular lobe. Torpedoes were not mentioned in either of these case studies.

Aside from SCA12 and SCA14, there are other forms of SCA in which the Purkinje cell layer is relatively preserved. In SCA3, for example, both the Purkinje cells and the inferior olives are relatively preserved (39, 53, 54, 185, 193–195). Similarly, in Friedreich’s ataxia, involvement of the dentate nucleus is more marked and there is relative preservation of the cerebellar cortex (53).

Types of Changes Within the Cerebellum

One differentiating point for these disorders is the manner in which the cerebellum is involved. A point of discussion is the cerebellar nuclei. In the bulk of ET cases, the dentate nucleus appears normal, although in two cases there was degeneration (139, 196). The SCAs themselves do not unformly involve the cerebellar nuclei, with the most marked involvement reported in SCA1 when compared to SCA2, SCA3, SCA6, SCA7 and SCA17 (54, 183, 184). In Friedreich’s ataxia, involvement of the dentate nucleus is also marked (53). Hence, involvement varies across these disorders.

It is also important to consider the range of other changes in the cerebellar cortex across these various disorders and in doing so, compare ET to these disorders. In recent postmortem studies, we and others have identified a growing number of morphological changes in the ET cerebellum, predominantly centered in and around the Purkinje cell population (197–209), distinguishing ET from age-matched control brains. These changes are observed in the Purkinje cell dendritic arbor and Purkinje cell axonal compartment as well as the connections between Purkinje cell and neighboring neuronal populations (i.e., climbing fibers and basket cells); studies have also detected Purkinje cell loss (197–206). More specifically, changes include swelling and thickening of axons; swellings, regressive changes and loss of spines in Purkinje cell dendrites; remodelling of Purkinje cell axons; Purkinje cell death; remodelling of basket cell axons; heterotopic Purkinje cells; reorganization of climbing fibres; and alterations in astroglia (197–206). By contrast, overt changes have not been observed in other brain regions, such as the thalamus, inferior olivary nucleus and red nucleus (210, 211). In a recent study (39), we contextualized the neuropathological changes observed in ET within a broader degenerative disease spectrum, performing a comparative analysis of quantitative morphologic changes in cerebellar cortex in a postmortem study of 156 brains (50 ET, 23 SCA, 15 MSA, 29 Parkinson’s disease, 14 dystonia, 25 controls), with 37 metrics reflecting alterations in the cell body, dendritic and axonal compartments of PCs, basket neuron axons and afferent climbing fiber synaptic inputs. Within the SCAs and MSA, there was a marked spectrum of change, with ET generally at the low end and SCA1, SCA2, SCA6, or MSA at the high end of severity (39). In this sense, the changes observed in ET fell on the mild end of what is observed in cerebellar degenerations (39). Thus, in large part, these comprised differences of degree rather than kind, likely reflecting a stereotypic repertoire of cellular reactions that characterize cerebellar degeneration (39). In addition, features distinctive to specific disorders were also identified, including a unique redistribution of climbing fiber synapses to the outer Purkinje cell dendritic arbor in ET and aggregation of calbindinD_28k-positive puncta around the Purkinje cell soma most prominently in SCA1, SCA2 and SCA6 (39). Each of these disorders had a different signature with respect to cerebellar degeneration, as evidenced by our metric “scores” that combine categories of morphologic features and a skyline plot, which showed that different patterns emerged for ET, SCA3, and SCAs 1, 2, and 6, indicating that these disorders of cerebellar degeneration do not form a homogeneous entity (39). In this sense, there were differences not only of degree, but also differences of kind (39).

Summary (Postmortem Features)

In ET, the main observed postmortem changes have been in the cerebellum (7, 39, 139). Yet in many forms of SCA, involvement of the nervous system is often diffuse, besides the cerebellum also involving numerous extra-cerebellar regions (54, 182–187). In the SCAs however, the pathology is not monotonously the same, and a spectrum of changes exists. Most relevant to the current discussion, which attempts to place ET within the context of these disorders, is that one may see similarities between ET and several SCAs. Several of the SCAs (e.g., SCA12 and SCA15) have clinical features (e.g., prominence of tremor, more benign natural history) that resemble ET. Consistent with the more ET-like clinical picture of these patients is the relative sparing of other regions of the central nervous system outside of the cerebellum as well as the sometimes moderate rather than total nature of Purkinje cell loss and the preservation of deep cerebellar nuclei (49, 188).

In ET, Purkinje cell loss, when described, has been significant when compared to age-matched controls, but the degree of loss is moderate and is patchy (39, 139, 190), and this has raised some concerns when considering this disease as degenerative. However, as noted above, Purkinje cell loss is similarly moderate and not subtotal or total in SCA12 and some cases of SCA14 (49, 188, 189) and furthermore, there are other forms of SCA in which the Purkinje cell layer is relatively preserved (e.g., SCA3) (39, 53, 54, 185, 193–195), as is the case in Friedreich’s ataxia (53). In many senses, the changes observed in ET fell on the mild end of what is observed in cerebellar degenerations (39). A recent analysis further explored numerous metrics of cerebellar cortical pathology in ET relative to other disorders of cerebellar degeneration and reported that there was a marked spectrum of change, with ET generally at the low end and SCA1, SCA2, SCA6, or MSA at the high end of severity (39). In addition, each of these disorders had a different signature with respect to cerebellar degeneration, indicating that these disorders of cerebellar degeneration do not form a homogeneous entity; in this sense, there were differences not only of degree, but also differences of kind (39).

Other Intersection Points

In this paper, we review the numerous intersection points between ET and the degenerative diseases of the cerebellum. These do not as yet extend to specific genetic etiologies. Thus, a study of 10 common degenerative ataxia genes in 323 ET cases and 299 controls indicated that pathogenic repeat expansions in SCA loci were not associated with ET (212).

Summary

Although ET has recently been conceptualized as one of the degenerative diseases of the cerebellum (7, 23, 31–40), there has been no attempt to assess it within the context of these diseases. Are there other degenerative diseases of the cerebellum that share clinical and pathological features with ET? The goal of this paper is to place the clinical and postmortem features of ET within the context of other forms of cerebellar degeneration; that is, to look for overlaps and intersections.

We reviewed the clinical features of ET relative to those of these other disorders. A consideration of the clinical features of ET should be first and foremost centered on kinetic and postural tremors. Although often underreported in the various SCAs, both types of tremor do occur in the SCAs and it is noteworthy that in two disorders, SCA12 and SCA15, kinetic and postural tremors are highly prevalent, often severe, and they can be the earliest disease manifestation, actually resulting in an initial diagnosis of ET (50, 55–59, 65–67, 77). Intention tremor, reported in 44.3% (78–81) of ET patients, is also a common features of many of the SCAs. Other features of cerebellar dysfunction or degeneration are also quite common in ET, albeit often mild - gait ataxia (93) and subclinical eye motion abnormalities (107–109). There is also a growing appreciation that cognitive impairment also occurs in ET (32, 141–143). The cerebellum is involved in a broad array of cognitive processes (152), and as with ET, cognitive impairment may be a feature of a variety of SCAs (159). Finally, many forms of cerebellar degeneration follow a more rapidly progressive course (41), leaving some to wonder whether a disease that advances as slowly as ET does could really be a form of cerebellar degeneration. However, a number of SCAs are also slowly progressive (51). Thus, SCA5 (70, 178, 179), SCA6 (180), SCA14 (60, 61), and SCA15 (46) generally do not shorten lifespan and follow a relatively mild disease course. In summary, in multiple regards, the clinical features of ET do overlap with those of the SCAs, with several forms of SCA evidencing tremor-predominant and more benign phenotypes.

In ET, the main observed postmortem changes have been in the cerebellum (7, 39, 139). Yet in many forms of SCA, involvement of the nervous system is often diffuse, besides the cerebellum also involving numerous extra-cerebellar regions (54, 182–187). In the SCAs however, the pathology is not monotonously the same, and a spectrum of changes exists. Most relevant to the current discussion, which attempts to place ET within the context of these disorders, is that one may see similarities between ET and several SCAs. Several of the SCAs (e.g., SCA12, SCA14 and SCA15) have clinical features (e.g., prominence of tremor and/or more benign natural history) that more resemble ET. Consistent with the more ET-like clinical picture of these patients is the relative sparing of other regions of the central nervous system outside of the cerebellum as well as the moderate rather than total nature of Purkinje cell loss and the preservation of deep cerebellar nuclei (49, 188). In ET, Purkinje cell loss, when described, has been significant when compared to age-matched controls, but the degree of loss is moderate and is patchy (39, 139, 190), and this has raised some concerns when considering this disease as degenerative. However, as noted above, Purkinje cell loss is similarly moderate and not subtotal or total in SCA12 and some cases of SCA14 (49, 188, 189) and furthermore, there are other forms of SCA in which the Purkinje cell layer is relatively preserved (e.g., SCA3) (39, 53, 54, 185, 193–195), as is the case in Friedreich’s ataxia (53). In many senses, the changes observed in ET fell on the mild end of what is observed in cerebellar degenerations (39).

In summary, both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration.