Background Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features.
Methods All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody.
Results All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident.
Conclusions In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.
- Essential tremor
- rest tremor
- movement disorders
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- Essential tremor
- rest tremor
- movement disorders
Kinetic tremor is the hallmark feature of essential tremor (ET)1; however, rest tremor, which may also occur during the illness, has been observed in as many as 20–30% of cases in some series.2 3 Rest tremor has been reported to occur with greater prevalence in ET cases with more advanced disease (ie, tremor of longer duration and greater severity)2 and it generally occurs in isolation of other hallmark features of Parkinsonism such as bradykinesia and rigidity.2 4 In contrast to this common situation of isolated rest tremor in ET, other ET cases may manifest full-blown Parkinson's disease (PD) (ie, ET-PD).5–9 Yet in ET patients with isolated rest tremor, it remains unclear whether their rest tremor is a marker for Lewy body pathology in the basal ganglia.
The post-mortem study of ET cases allows one to further explore this issue. Yet there is a dearth of published cases. One series, which was published prior to identification of α-synuclein related pathology in PD, reported three ET cases who had rest tremor in the absence of other parkinsonian features; all had normal brains in which no Lewy bodies were found.5 A second series by the same investigators10 reported four additional ET cases with isolated rest tremor and normal post-mortem findings; whether α-synuclein antibody was used was not specified. Hence, the sum total in the current literature is seven cases. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features. In each case, tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody, thereby increasing the likelihood of detecting Lewy body pathology.
Selection of cases
The study was conducted at the Essential Tremor Centralised Brain Repository (ETCBR), Columbia University, New York,11–13 a centralised repository for the prospective collection of ET brains from donors throughout the USA. In July 2009, the ETCBR database was queried regarding the presence of rest tremor among harvested donors. Nine (22.0%) of 41 donors had had rest tremor on neurological examination. The post-mortem brain tissue of these nine donors was selected for these analyses; two had been included in an earlier series.12 In one comparative analysis, we also examined post-mortem tissue in nine age-matched ETCBR ET cases without rest tremor. The study was approved by the Columbia University Ethics Committee, and signed, written, informed consent was obtained from all cases during life.
During life, clinical data were collected on all prospective ETCBR brain donors. Each donor had a standardised videotaped neurological examination, which included an assessment of postural tremor (sustained arm extension) and five tests of kinetic tremor (pouring, drinking, using spoon, finger–nose–finger manoeuvre and drawing spirals). Each of these six tests was performed with each arm (12 tests total). Videotaped action tremor was rated by a senior neurologist specialising in movement disorders (EDL) during each test using a scale from 0 (no tremor) to 3 (large amplitude tremor),14 resulting in a total action tremor score (range=0–36). Head (ie, neck), voice and jaw tremors were noted as present or absent on videotaped examination. The motor portion of the Unified Parkinson's Disease Rating Scale (UPDRS)15 was videotaped, which included assessments of facial expression and blink frequency; speech; rest tremor evaluated while seated, standing and then walking; rapid alternating movements; rising from a chair; standing with arms at sides; and gait and arm swing. The presence of rigidity was assessed by review of treating neurologists' clinical records. The videotaped motor UPDRS was reviewed (EDL) and UPDRS scores assigned15; this videotape-based method has previously been shown to be a valid means of assessing and diagnosing PD (sensitivity=91.3% and specificity=98.8%).16 Features of dystonia were also noted if present on the videotaped neurological examination.
The clinical diagnosis of ET, initially assigned by treating neurologists, was confirmed (EDL) using ETCBR clinical criteria, as described.12
Assessment of rest tremor
The videotaped motor UPDRS included rest tremor evaluated while seated, standing and walking. Assessment of rest tremor while lying down was later added to the protocol. Rest tremor was rated in each arm while seated (0–4) and while upright (standing and walking) (0–4) using UPDRS scores.15 Ratings were very conservative, and as previously documented,2 rest tremor was not coded as present unless the limb appeared to be completely at rest. In particular, the senior neurologist specialising in movement disorders (EDL) was careful to distinguish true rest tremor from postural tremor that manifested when the ‘resting’ arm or hand was held tensely or stiffly (ie, it was not fully at rest). The UPDRS total rest tremor score was the sum of the four individual UPDRS ratings (right seated, left seated, right upright, left upright) (range=0–16). Rest tremor was also rated (0–4) in the legs.
All brains had a complete neuropathological assessment (J-PGV) as described.12 Each brain had standardised measurement of brain weight (g), and post-mortem interval (hours between death and placement of brain in a cold room or upon ice) was recorded.12 Tissue was examined microscopically by a senior neuropathologist (J-PGV) blinded to clinical information.
Substantia nigra pars compacta (SNc)
Bilateral sections of midbrain were used containing the SNc. Whenever possible, three levels of the midbrain were included. Luxol fast blue/haematoxylin and eosin (LH&E)-stained and α-synuclein-immunostained sections were used to assess Lewy bodies.12 Lewy neurites were assessed with α-synuclein-immunostained sections. A reliable semiquantitative scale was used to assess Lewy bodies (LH&E and then α-synuclein) and Lewy neurites (α-synuclein): 0 (absent or not discernible), + (rare or slight), ++ (moderate) and +++ (severe).12 In addition, a reliable semiquantitative scale17 was used to grade neuronal loss in the SNc (grade 0=none, grade 1=sparse, grade 2=moderate, grade 3=severe); in many instances, the presence of macrophages that included pigmented material was used as supportive evidence of neuronal loss.
Caudate, putamen and globus pallidum
Tissue from both sides of the brain was used, and these structures sampled on at least two levels. Lewy bodies and Lewy neurites were assessed, as in the SNc.12 In addition, selected sections were stained by the Bielschowsky method, mouse monoclonal antibodies to phosphorylated τ and β-amyloid. Neurofibrillary tangles (NFTs) were assessed on AT8 labelled sections and graded (0=0/100× field, 1=1–2/100× field, 2=3–6/100× field, 3=7–15/100× field, 4 >15/100× field). Plaques were assessed on Bielschowsky stained and β amyloid stained sections and graded (0=0/100× field, 1=1–5/100× field, 2=6–10/100× field, 3=11–20/100× field, 4>20/100× field). The presence of other changes (eg, lacunes, criblures, infarcts, vascular changes) was also noted.
A standard 3×20×25 mm parasagittal neocerebellar block was harvested from each brain.12 Paraffin sections (7 μm thick) were stained with LH&E as described previously. Purkinje cells in five 100× fields (LH&E) were counted and averaged. Using the standard cerebellar section, torpedoes in the entire section were counted using an LH&E-stained section.
Each brain received a Braak & Braak Alzheimer's disease (AD) stage for NFTs18 and Consortium to Establish a Registry for AD (CERAD) ratings for neuritic plaques.19 National Institute on Ageing—Reagan Institute (NIA—RI) criteria for AD were assigned.20 Using α-synuclein and LH&E-stains, sections were examined at two to four levels of the pons with the locus ceruleus, the medulla (with dorsal vagal nucleus, nucleus raphé magnus, gigantocellular reticular nucleus), hippocampus, cingulate gyrus, temporal cortex, prefrontal cortex and motor cortex. Lewy bodies and Lewy neurites were assessed using the previously noted semiquantitative scale.12 PD staging, consistent with Braak,21 was also assigned.
Analyses were performed in SPSS (version 17.0; SPSS, Chicago, Illinois). Pearson correlation coefficients were used to assess the associations between the UPDRS total rest tremor score and total action tremor score, age at death, age of tremor onset and disease duration.
The mean age at death was 81.8±9.3 years (median=84 years, table 1).
The age of onset of action tremor ranged from 23 to 70 years (median=41 years), and onset was before age 60 years in seven (77.8%) of nine cases. All cases had longstanding ET (median action tremor duration=42 years, range=17–61 years). Eight (88.9%) cases were right-handed. Seven (77.8%) reported a first-degree relative with ET. None had taken neuroleptics. Two had clinical diagnoses of dementia (table 1); in one, memory problems were first noted 8 years after onset of action tremor, and in the other more than 40 years after the onset. The precise age of onset of rest tremor was not known in our cases.
On examination, the median total action tremor score was 27, and all cases had moderate to severe arm involvement, with one or more tests of kinetic tremor receiving a rating of 3. All had cranial (head (neck), voice or jaw) tremor. None had decremental bradykinesia, slowness of rapid alternating movements or rigidity on examination, and none had clinical diagnoses of PD. None had dystonic posturing in their tremulous limbs, in other limbs or in the neck. None had a dystonic component to their tremor (ie, jerky tremor, irregular tremor or directional component to tremor).
Rest tremor involved both arms in most cases (seven of nine (77.8%)) (table 2) and, in each case, involved the fingers (including thumb) in flexion–extension movements or the wrist in pronation–supination movements.
In all cases, rest tremor was present in at least one arm while seated, and in seven (77.8%), it was present in at least one arm while standing or walking. In one case, rest tremor in the arms was assessed while lying down, and it was present. Most UPDRS tremor scores were two (ie, either ‘mild and persistent’ or ‘moderate and intermittent’). No cases exhibited rest tremor in the legs (table 2). We examined whether rest tremor and action tremors were more severe in the right or left arm. In five (55.6%) cases, there was concordance (ie, the side with more severe rest tremor also had more severe action tremor). Among the remaining four, action tremor was symmetrical, but rest tremor was unilateral (one case); action tremor was symmetrical but rest tremor was asymmetrical (two cases), and action tremor was asymmetrical, but rest tremor was symmetrical. There were no cases in which action tremor was more severe in one arm and rest tremor was more severe in the contralateral arm. The UPDRS total rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04), but not with age at death (r=0.33, p=0.39), age of tremor onset (r=0.48, p=0.19) or disease duration (r=−0.26, p=0.51).
The mean number of torpedoes per LH&E-stained section of the cerebellar cortex was 20.8±19.9 (median=12). The mean number of Purkinje cells per 100× field was 7.3±1.3 (median=7.8). Published normative control values are 1.7±1.4 and 9.6±3.4, respectively.12
Post-mortem changes in the SNc were minimal (table 3).
Neither Lewy bodies nor Lewy neurites were evident in the SNc. Sparse neuronal loss was present in the SNc in seven (77.8%) cases. In a group of nine age-matched ETCBR ET cases (mean age=83.1±8.7 years) who had no rest tremor on examination, sparse neuronal loss was present in the SNc in a similar proportion (6 (66.7%)).
Changes in the caudate, putamen and globus pallidum were mild (table 3). No Lewy bodies or Lewy neurites were evident in these structures. Rare neostriatal, globosum neuronal tangles were present in these structures in five cases and rare plaques in four cases. They were not found within the paleostriatum. One case had two microscopic lacunes (caudate and putamen). Two cases (no 3 and no 9) met NIA-RI criteria for AD. Two cases (no 2 and no 9) had rare (+1) Lewy bodies in the dorsal vagal nucleus and locus ceruleus on α synuclein-immunostained sections, although notably not in the nucleus raphé magnus or gigantocellular reticular nucleus; neither of these cases had Lewy bodies in the SNc on α synuclein-immunostained sections.
In this study of nine new ET cases, tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody. The study presents data on the clinical–pathological relationship between isolated rest tremor in longstanding ET and underlying Lewy body pathology in these brains at autopsy. No Lewy bodies or Lewy neurites were evident in the basal ganglia on α-synuclein-immunostained sections in these nine ET cases with upper-extremity rest tremor. Other pathological changes in the basal ganglia were minimal and of the type that commonly accompany normal ageing.
In terms of clinical implications, these data indicate that the isolated upper-extremity rest tremor in longstanding and severe ET cases is in the majority of cases not accompanied by Lewy body pathology in the SNc or elsewhere in the brain. In two cases, however, rare Lewy bodies were present in the dorsal vagal nucleus and locus ceruleus. It is not known whether these cases were in the process of developing an ascending Lewy body pathology that, had the patient lived long enough, would have become full-blown clinical PD as well as pathological PD (Braak Stage III). The notable absence of Lewy bodies in the nucleus raphé magnus or gigantocellular reticular nucleus, which is most typically observed early in the evolution of PD pathology (ie, Stage 2),21 argues against this possibility but does not fully exclude it. In summary, the weight of evidence suggests that the majority (and possibly all) of these cases did not have evolving PD.
There are seven previously published ET cases with isolated rest tremor and, on post-mortem examination, neither Lewy bodies nor other changes involving the basal ganglia were detectable, although the use of α-synuclein antibody was not specified.5 10 Based on their data, the authors concluded that isolated rest tremor in ET was not a marker of early or evolving Lewy body pathology in the basal ganglia. To our knowledge, there are no other clinical–pathological reports addressing this issue.
What was the cause of the rest tremor in our cases? This question has scientific implications, particularly with regards to the underlying basis for rest tremor in ET and perhaps more broadly. Could rest tremor in our ET cases be due to coexisting AD? This is unlikely. First, only two of our ET cases had AD. Also, although rest tremor has been reported to occur in 11–13% of AD cases,22–25 when present, it is usually accompanied by bradykinesia, rigidity and postural-gait changes, which occur more commonly in AD.24 These clinical signs were not present in our cases.
A second possibility is that Lewy body pathology in the basal ganglia underlies rest tremor in ET. Yet only two of our cases had Lewy body pathology, and in none were Lewy bodies or Lewy neurites evident in the basal ganglia (caudate, putamen, globus pallidum, SNc at multiple levels) on α-synuclein-immunostaining, strongly arguing against this explanation.
Third, a subgroup of patients with prominent rest tremor and ET-like action tremor has recently been identified. Although initially thought to have PD, these patients have been found to have normal presynaptic nigrostriatal dopaminergic imaging and have been termed ‘subjects with scans without evidence of dopaminergic deficits’ (SWEDDs).26 Many of these patients have dystonic tremor26 and other signs of parkinsonism (eg, bradykinesia, rigidity, gait and postural changes),27 which our patients did not have.
One final possibility is that pathological changes in the cerebellum or cerebellar system account for the occurrence of rest tremor in ET. Degenerative changes in the cerebellum, including torpedoes and Purkinje cell loss, have been observed in ET12 28 and were also present in these nine cases. A study in monkeys showed that bilateral electrolytic lesions in the cerebellar dentate and interpositus nuclei resulted in tremor at rest.29 The Vim thalamic nucleus, targeted in the surgical treatment of ET, receives cerebellar afferents but none from the basal ganglia, and this surgery results in improvements in rest tremor in ET.30 This possibility deserves further exploration.
This study had limitations. We do not know the duration of rest tremor in these cases. Even if rest tremor had been of very short duration in some of our cases, our pathological analysis indicates that it did not result from Lewy bodies in the SNc. In this study, we examined the SNc bilaterally and at multiple levels, with both LH&E and α-synuclein immunostains, thereby increasing the sensitivity of our survey. Second, rigidity was assessed by outside neurologists rather than study neurologists, and it is conceivable that it could have been present but overlooked. Even if this were the case in some of our patients, it would simply imply that rest tremor and rigidity had no evident pathological correlate in the basal ganglia in these cases. Strengths of this study included the use of α-synuclein-immunostained sections, the examination of brainstem structures bilaterally and at multiple levels, and our ability to assess clinical–pathological correlations.
In nine ET cases with upper-extremity rest tremor, Lewy body pathology was not evident on α-synuclein-immunostained sections of the SNc, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated upper-extremity rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.
Funding R01 NS042859 from the National Institutes of Health (Bethesda, MD); the Parkinson's Disease Foundation; the Arlene Bronstein Essential Tremor Research Fund (Columbia University).
Competing interests None.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the Columbia University.
Provenance and peer review Not commissioned; externally peer reviewed.