Website Edition: February/March 2013

Journal Featured Article

Movement Disorders
DOI: 10.1002/mds.25220

Neuropathological findings in benign tremulous Parkinsonism§
Marianna Selikhova MD1,3, Peter A. Kempster MD1,2,4, Tamas Revesz MD1, Janice L. Holton PhD1,2, Andrew J. Lees MD1,2,*

1 Queen Square Brain Bank for Neurological Disorders and Institute of Neurology, University College London, London, United Kingdom
2 Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom
3 Department of Neurology, Russian State Medical University, Moscow, Russia
4 Neurosciences Department, Monash Medical Centre and Department of Medicine, Monash University, Melbourne, Australia

* Correspondence to: Professor Andrew J. Lees, Reta Lila Weston Institute of Neurological Studies, 1 Wakefield Street, London, WC1N 1PJ, UK; andrew.lees@ucl.ac.uk

Funding agencies: J.L.H. and T.R. are supported by Parkinson's UK, the Multiple System Atrophy Trust, Alzheimer's Research UK, and the Progressive Supranuclear Palsy (Europe) Association. J.L.H. is supported by the Reta Lila Weston Institute for Neurological Studies. Part of this work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

Relevant conflicts of interest/financial disclosures: Nothing to report.

§ Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Benign tremulous parkinsonism, a tremor dominant syndrome with a relatively slow rate of deterioration, is recognized by clinicians although its pathological basis is not well understood. A systematic review of Queen Square Brain Bank donors was carried out to determine the natural history and pathology of individuals who had tremor dominant parkinsonism with mild non-tremor components and minimal gait disability for at least 8 years. We identified 16 cases of pathologically proved benign tremulous Parkinson's disease (PD); another 5 individuals conformed to the definition but did not have the pathology of PD. Patients with verified benign tremulous PD had less severe neuronal loss in the substantia nigra than controls (χ2: P = .003). Twelve of these had been correctly diagnosed with PD at their first neurological evaluation, whereas the other 4 were originally thought to have another tremor disorder. The only consistent distinguishing feature of the 5 pathologically disproved cases, who may have had either essential tremor with associated rest tremor or dystonic tremor, was a failure to develop unequivocal bradykinesia within a decade of onset of tremor at rest. Our findings support the existence of a distinct subgroup of benign tremulous PD. The slower rate of clinical progression correlates with less severe nigral cell loss at postmortem, although many of these patients transgress the benign tremulous parkinsonism definition by the final third of their disease course and develop the common features of advanced PD. © 2012 Movement Disorder Society

Clinical studies of benign tremulous parkinsonism (BTP) have claimed that it is a distinct clinical entity, unlike classical Parkinson's disease (PD) in several important respects. Josephs and colleagues1 describe the salient attributes of this syndrome as rest tremor, an early sign that consistently overshadows non-tremor parkinsonian deficits, with only mild deterioration (except for tremor) despite at least 8 years of parkinsonism. The main weakness of this and other recent surveys2–4 is a lack of pathological and longitudinal clinical correlation.

According to 1 view, there is a biological connection, not yet well understood, between essential tremor and PD, with a mixed essential tremor-PD phenotype that could compose the BTP syndrome.5 An opposing view is that BTP is separable into diagnostic subcategories (slowly progressive PD, essential tremor, and adult onset dystonic tremor) by careful clinical assessment assisted by functional dopaminergic imaging.6 These authors dismiss the essential tremor-PD phenotype with the explanation that these are only PD patients initially misdiagnosed with essential tremor, and essential tremor patients who subsequently developed additional coincidental PD. One of the reasons for the lack of clarity in this whole area of tremor classification is the known clinical diagnostic error rate, both for essential tremor7 and for PD.8 Each of these disorders is not infrequently mistaken for the other.

None of the questions about BTP can be properly addressed without pathological knowledge. We surveyed the large, pathologically ascertained Queen Square Brain Bank (QSBB) using a definition that would identify the same group of patients as the recent clinical studies.1,2 Our objectives were as follows: (1) to determine the clinical characteristics and natural history of pathologically confirmed benign tremulous PD; (2) to investigate the pathological basis of its benign course; and (3) to identify distinguishing clinical features of patients with a BTP phenotype who do not have the pathology of PD.

© 2012 Movement Disorder Society

Key Words: Parkinson's disease; benign tremulous; tremor; substantia nigra; parkin

Volume 28, Issue 2, pages 145–152, 2013

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Article Text

Patients and Methods

QSBB databases were searched for donors who conformed to the following definition: (1) rest tremor as an early, prominent and persistent clinical feature; (2) non-tremor parkinsonian signs present but mild; and (3) no more than mild progression except for tremor, and no gait disorder, within 8 years of developing parkinsonism. Twenty-one patients fulfilled this BTP definition; 16 had pathologically confirmed PD (group 1) and another 5 patients did not have the pathology of PD despite a diagnosis of PD when enrolled in the QSBB (group 2). Throughout this work we use the term BTP to refer to the clinical syndrome, and reserve benign tremulous PD for pathologically confirmed disease. QSBB databases on autopsy-proven PD were used as a source of comparative clinical statistics. All QSBB donors with a pathological diagnosis of PD had been previously screened for parkin and LRRK2 gene mutations. The London Multi-Centre Research Ethics Committee approved procedures for the donation of brains and retention of clinical records.

Cases without complete clinical records were excluded. Clinical details were abstracted by a single investigator blinded to the pathological data. The time of tremor onset, the pattern of other motor deficits, the time that parkinsonism was diagnosed, and the time at which a BTP definition ceased to apply were recorded. Tremor, bradykinesia, and rigidity were each graded semiquantitatively as mild, moderate, or severe. The files were checked for a family history of PD or another tremor disorder (affecting 1 or more first-degree relatives). The occurrence of clinical advanced disease milestones—frequent falling, visual hallucinations, and dementia—was determined using previous QSBB definitions.9

Pathological Methods

Pathological material was prepared using methods previously described.10 A standard definition of the neuropathological diagnosis of PD applied.11 Fifteen benign tremulous PD cases (stored brain tissue in 1 older case was unsuitable for restaining and cell counting) were compared with 15 PD controls, matched only for age at death and disease duration. Six subregions of the substantia nigra pars compacta12 were assessed by 2 experienced neuropathologists (J.L.H. and T.R.), blind to the clinical diagnosis. Using a consensus approach and previously published criteria,12 a score for pigmented neuronal loss (0, absent; 1, mild; 2, moderate; 3, severe) was agreed for each subregion and for the nigra as a whole. The assessment was repeated in 30% of cases to assess intrarater reliability. Sections from cortical regions were stained with a monoclonal anti-α-Synuclein antibody (Novocastra, Newcastle upon Tyne, UK) and assigned a Lewy-related pathology type according to the 2005 McKeith criteria.13 Braak PD staging was performed.14,15 The extent of any associated neurofibrillary tau pathology was characterized using tau immunohistochemical staining (AT8; Autogen Bioclear, Calne, UK) of standard sections.16 Alzheimer plaque pathology was analyzed by Amyloid-β immunohistochemistry (Dako, Ely, UK) with a 4-point semiquantitative grading11 based on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria.17 Four-point gradings were conducted for cerebral amyloid angiopathy18 and small-vessel cerebrovascular pathology.19 Cases in which a diagnosis of PD was not made were examined to exclude the pathological changes of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, other tauopathies, and TDP-43 proteinopathy.

Statistics

Group comparisons were made using χ2 for categorical and 2-tailed t test or the Mann Whitney U test, as appropriate, for continuous variables, using STATISTICA version 6.0. Intra-rater agreement on neuronal loss in the substantia nigra was tested using Cohen's Kappa measurement of agreement (SPSS, Chicago, IL).

Results

Clinical information on all 21 patients is shown in Tables 1 to 3, the pathological findings appear in Tables 4 and 5, and 2 illustrative case histories are presented. A previously published QSBB survey contains some data from 11 of the pathologically proven PD cases; that work examined a large tremor dominant group without specific analysis of benign tremulous PD.20

Table 1. Demographic and clinical information

Case number Sex (M/F)/age at tremor onset (y) Age at first documentation of parkinsonism (y) Initial diagnosis Age at death (y) Benign tremulous phenotype duration (y)a Disease duration from tremor onset (y) Family history
Group 1. Pathologically confirmed benign tremulous PD
1 M/48 57 PD 82 11 34 PD
2 F/53 61 PD 82 9 29
3 M/53 54 PD 76 18 22
4 M/56 56 PD 79 13 23
5 F/59 60 PD 82 8 23
6 F/59 65 PD 85 11 26
7 M/61 61 PD 73 10 12
8 F/69 72 PD 85 9 16 PD
9 M/70 71 PD 85 10 15
10 M/70 72 PD 88 9 18 PD
11 F/70 72 PD 95 10 24
12 M/72 75 PD 93 13 21
13 F/30 66 ET 80 10 50 ET and PD
14 F/53 61 Drug-induced tremor 73 10 21
15 M/55 63 Dystonic tremor 78 13 23
16 M/64 71 ET with rest tremor 84 10 21 Indeterminate tremor disorder
Group 2. Benign tremulous parkinsonism—not PD pathologically
17 F/50 71 ET with rest tremor 90 19 40
18 M/53 54 PD 77 13 24
19 M/60 67 PD 90 25 30
20 M/62 63 PD 74 11 12
21 M/66 66 PD 76 10 10
a
The benign tremulous phenotype duration column refers to the criteria for benign tremulous parkinsonism given in Patients and Methods.

PD, Parkinson's disease; ET, essential tremor.

Table 2. Treatment and later disease course

Case number Commencement of L-Dopa (y from tremor onset) Other drugsa Maximum L-Dopa dose (mg) L-Dopa response in first 8 yb Dyskinesia (y from tremor onset) Motor fluctuation (y from tremor onset) Advanced disease features (y from death)
Falls Hallucinations Dementia
Group 1. Pathologically confirmed benign tremulous PD
1 9 A, P, D 1250 + Y (14) Y (14) 11
2 8 A 800 + Y (16) Y (21) 6 5 3
3 7 A, P 750 0 Y (21) Y (21) 2 2
4 4 400 +/- Y (13) Y (15) 2
5 2 A 500 +/- Y (10) Y (14) 3
6 9 A, P 1200 + Y (15) Y (17) 5 4
7 2 A 450 + Y (10) Y (10)
8 4 D 675 +/- Y (8) N
9 2 A, P 1000 +/- Y (8) Y (14) 1 7 1
10 6 A, P 600 +/- N N 6 8
11 6 400 + Y (9) Y (10) 6
12 10 A, D 700 +/- Y (15) Y (15) 3 4 4
13 37 900 +/- Y (47) N 4 4 4
14 11 P 500 + Y (15) N
15 17 A, P 1500 0 N N 2
16 14 D 1000 0 N N
Group 2. Benign tremulous parkinsonism—not PD pathologically
17 19 A 750 +/- N N
18 10 300 0 N N
19 A, P N N -
20 1 A Uncertain 0 N N
21 2 500 +/- N N
a
Other drug treatments: A, anticholinergic agent; P, propranolol; and D, a dopamine receptor agonist.

b
Responses to L-Dopa: + definite response; +/- weak or equivocal response; 0 no response. In case 20, L-Dopa treatment was used briefly on 2 separate occasions, but the case files do not record dosages.

PD, Parkinson's disease.

Table 3. Tremor characteristics

Case number Initial tremor site Initial tremor patterna Anatomical spread of tremor Progression of tremor
Group 1. Pathologically confirmed benign tremulous PD
1 Left leg R Both arms, legs +++
2 Left hand R Both arms +++
3 Left hand R, P Both arms, leg +++
4 Right hand R Both arms ++
5 Left thumb R Both arms ++
6 Left hand R Both arms, legs ++
7 Right hand R, P, A Both arms, jaw ++
8 Left hand R Both arms ++
9 Right hand R Both arms, legs +++
10 Right hand R, P, A Both arms ++
11 Left hand R Both arms ++
12 Left hand R Both arms ++
13 Both hands P Both arms ++
14 Right hand R Both arms +++
15 Left fingers R, P Both arms, lips, jaw ++
16 Both hands, head R, P, A Both arms, head, jaw, chin ++
Group 2. Benign tremulous parkinsonism—not PD pathologically
17 Both hands P Head, jaw, legs ++
18 Right hand R Both arms ++
19 Both hands R. P Both arms, head ++
20 Both hands R, A Both arms +
21 Right hand R Both arms ++
a
Tremor pattern: R, resting tremor; P, postural tremor; and A, action tremor.
PD, Parkinson's disease.

Table 4. Pathological findings

Case n umber Mean substantia nigra cell loss Lewy body type Braak PD stage Braak and Braak tau stage Amyloid-β grade (diffuse) Amyloid-β grade (mature) Congophilic angiopathy gradeCerebrovascular disease grade
Group 1. Pathologically confirmed benign tremulous PD
1 2.4 Brainstema 5 I 1 0 0 1
2 2.8 Neocortical 6 III 1 2 1 1
3 3.0 Neocortical 6 II 2 2 1 1
4 2.4 Limbic 6 I 1 0 0 0
5 2.5 Neocortical 6 I 0 0 0 1
6 2.7 Limbic 6 III 1 0 0 1
7 2.6 Limbic 6 II 1 1 0 0
8 2.2 Neocortical 6 I 2 1 0 0
9 2.0 Limbic 6 II 0 0 0 0
10 2.3 Limbic 6 I 0 0 0 1
11 2.3 Neocortical 6 II 2 2 0 1
12 2.5 Limbic 5 I 0 0 0 1
13 N/A N/A N/A N/A N/A N/A N/A N/A
14 2.0 Brainstem 5 0 0 0 0 1
15 1.0 Brainstem 5 I 0 0 0 1
16 2.5 Limbic 6 V 1 1 2 1
Group 2. Benign tremulous parkinsonism—not PD pathologically
17 0.8 0b 0 II 1 1 1 0
18 0.2 Incidentalc 1 III 2 1 0 3
19 1.0 0 0 II 1 1 0 2
20 0.8 0 0 I 1 0 0 0
21 0.2 0 0 III 0 0 0 1
Arabic numeral scores 0 to 3 refer to the semiquantitative gradings absent, mild, moderate, and severe as defined in Pathological Methods. Substantia nigra cell loss is the mean of the 6 subregional scores.

a
Patient with compound heterozygous parkin gene mutations.

b
Subtle TDP-43 pathology (sparse fine threads and neuronal cytoplasmic inclusions) restricted to the CA1 subregion of the hippocampus and the subiculum.

c
α-Synuclein positive deposits in olfactory tubercle and piriform cortex, but not brainstem.

PD, Parkinson's disease; N/A, not available.

Table 5. Comparison of demographic and pathological data for pathologically proven benign tremulous PD and PD controls

Benign tremulous PD (n = 15) PD controls (n = 15) P
Age at death (y) 83 ± 6.2 82 ± 4.2 NS
Disease duration (y) 24 ± 8.8 22 ± 5.2 NS
Male/female (n) 8/7 10/5
Mean regional substantia nigra cell loss 2.3 ± 0.4 2.6 ± 0.4 Mann Whitney U: 0.046
Global substantia nigra cell loss mild = 1; moderate = 9; severe = 5 mild = 0; moderate = 2; severe = 13 χ2: 0.003a
Lewy body type brainstem = 3; limbic = 7; neocortical = 5 brainstem = 0; limbic = 7; neocortical = 8 NS
Braak PD stage 5.7 ± 0.5 5.9 ± 0.4 NS
Braak and Braak neurofibrillary stage 1.7 ± 1.2 1.5 ± 0.6 NS
Amyloid-β grade, diffuse deposits 0.8 ± 0.8 1.5 ± 1.2 NS
Amyloid-β grade, mature deposits 0.6 ± 0.8 0.9 ± 1.0 NS
Cerebral amyloid angiopathy grade 0.3 ± 0.6 0.7 ± 1.1 NS
Cerebrovascular disease grade 0.7 ± 0.5 0.7 ± 0.7 NS
Mean statistics shown with standard deviations. Pathological stages, grades, and typing as defined in Pathological Methods.

a
Mild or moderate compared with severe cell loss.

PD, Parkinson's disease; NS, not significant.

Group 1: Pathologically Confirmed Benign Tremulous PD (Cases 1–16)

The mean age of tremor onset was 59 ± 10 (range, 30–72) years, compared to 60 ± 8.3 years for other tremor dominant cases, and 60 ± 10 years for PD in general. Mean disease duration from tremor onset was 24 ± 8.8 (range, 12–50) years for benign tremulous PD, 18 ± 5.3 years for all other tremor dominant cases and 16 ± 7.3 years for all patients with PD. The time to initiation of L-Dopa treatment was 8.3 ± 8.0 years in benign tremulous PD, significantly longer than 3.0 ± 2.5 years for all other tremor dominant patients and 2.5 ± 2.4 years for all patients with PD (t test: P < .0001). Five patients (31%) had a family history of PD or another tremor disorder, compared with 7% for PD in general (χ2: P < .001).

Cases 1 to 12 had been diagnosed with PD when they first presented for neurological evaluation and this diagnosis was not called into question at any later stage. Eleven had presented with asymmetrical upper limb rest tremor, and 1 with unilateral leg tremor. Three had early postural/kinetic arm tremor as well. Unilateral arm tremor always became bilateral within 9 years of onset. Arm tremor spread to the ipsilateral leg in 3. One patient later developed jaw tremor. Early responsiveness to L-dopa was modest or equivocal in the majority, although there were 5 in whom L-dopa clearly seemed effective in the first 8 years. Most patients eventually developed common features of PD deterioration. The BTP definition was valid for 65% of the disease course calculated from tremor onset. Eleven developed dyskinesia; motor fluctuations, which did not exceed moderate degree, were present in 10. The mean onset of fluctuations in these patients was 15 ± 3.9 years after tremor, compared with 7.3 ± 4.6 years for PD in general (t test: P < .001). Features of the advanced disease state, though long delayed, eventually appeared in most. Of the 3 patients who became demented, all had preceding visual hallucinations. The mean time intervals between the advanced disease milestones and death were: regular falls 3.9 years (n = 8), visual hallucinations 4.8 years (n = 8), and dementia 2.7 years (n = 3), not significantly different from PD in general.9 One patient (case 1) had compound heterozygous parkin gene mutations (R275W point mutation and exon 6 deletion). Tremor had commenced at the age of 48 years, and there was a family history of PD. The clinical course over 34 years was typical of benign tremulous PD, although neither hallucinations nor dementia developed.

Cases 13 to 16 had initially been diagnosed with another tremor disorder, later revised to PD in 3. Two of these patients had presented with isolated tremor, and early non-tremor parkinsonism was very subtle in the other 2. The BTP criteria were met for 90% of their disease course. In case 13, upper limb postural tremor consistent with essential tremor preceded both rest tremor and the diagnosis of PD by many years; the disease pattern after diagnosis then followed a benign tremulous pattern. Case 14 still conformed to BTP definition at the time of death, and Case 16, although prone to some shuffling, had little non-tremor motor disability up to the final year of life.

Case 15: Initial Diagnosis of Adult Onset Dystonic Tremor

This man presented at the age of 55 years with asymmetrical upper limb rest and postural tremor. A diagnosis of dystonic tremor was made on the basis of dystonic hand cramping while playing the saxophone. At the age of 63 years he developed tremor of the lips and jaw, and mild bradykinesia was detected. He was treated with orphenadrine and propranolol. L-Dopa was tried later, but was ineffective. When aged 71 years, he had bilateral arm rest tremor, mild bradykinesia, and little impairment of gait. PD was suggested but there was still uncertainty about the diagnosis. Thereafter, he developed impaired postural reflexes with falls but there was no cognitive impairment. He died of cardiac disease at the age 78 years.

Group 2: Clinical Diagnosis of PD with Benign Tremulous Pattern, Not PD Neuropathologically (Cases 17–21)

A diagnosis of tremulous PD had been made after a variable period of uncertainty. Each patient had rest tremor at the time of the first documented neurological examination, although postural tremor probably came first in case 17. Case 20 also had early postural tremor whereas case 19 had an unusual combination of rest and kinetic tremor. These patients were all thought to have extrapyramidal rigidity and some degree of slowness of movement when diagnosed with parkinsonism, but none went on to develop unequivocal bradykinesia.

Case 18: Diagnosis of Tremulous PD with Equivocal Bradykinesia

At the age of 53 years this man developed rest tremor of the right hand. One year later, PD was diagnosed by a neurologist. Over the next 3 years, the tremor increased and became bilateral. Eight years after tremor onset, right arm cogwheel rigidity was documented, though it was noted that slowness of movement was minimal. While the tremor slowly progressed over the next decade, rigidity remained mild and it was uncertain whether bradykinesia was present. L-Dopa treatment had been tried during this period, but it was soon withdrawn because of lack of effect. Despite symptoms of disequilibrium, the patient retained good motor function, mobility, and cognition. By the time that he reached his 70s, it was clear that parkinsonism was not progressing and it was suspected that he might have essential tremor. The patient died when aged 77 years.

Pathological Findings

More patients with benign tremulous PD had mild or moderate global neuronal loss in the substantia nigra than pathological controls (χ2: P = .003). The mean score for regional nigral cell loss in benign tremulous PD was 2.3 ± 0.4, compared with 2.6 ± 0.4 for the control group (Mann Whitney U test: P = .046). All nigral subregions showed less cell loss in benign tremulous PD than controls. The most severe cell loss occurred in the ventrolateral nigra, whereas the medial nigra showed the greatest difference between the 2 groups (2.1 vs 2.7; P = .034). There was no significant difference in Lewy-related pathology according to McKeith typing or Braak PD stage, and there was no difference for any of the other pathologies that were graded. All brains from pathologically verified benign tremulous PD patients had Lewy bodies in the substantia nigra and other brainstem structures in the distribution characteristic of PD. There was overall good intrarater agreement for neuronal loss in the nigra, with Cohen's kappa coefficient varying from >0.5 to >0.8.

Case 1, with parkin gene mutations, had a mean nigral cell score of 2.4. There was scanty Lewy body deposition, which did not conform well to the Braak PD staging scheme (sparse Lewy bodies present in the transentorhinal cortex and cingulate gyrus but the density of brainstem Lewy bodies did not show the expected increase).

None of the group 2 patients had a specific pathological diagnosis. As shown in Table 4, small blood vessel disease of varying severity was present in 3 (1 severe and 1 moderate, each with basal ganglia involvement). Although only half brains had been examined histologically, no patient had focal ischemic damage in a strategic location that was likely to be the primary cause of the tremor disorder. Case 18 had α-Synuclein positive Lewy pathology in the olfactory tubercle and piriform cortex but not in the brainstem or neocortex, and neuronal loss in the substantia nigra was not observed. Moderate amounts of Amyloid-β and tau deposition were present in this group.

Discussion

Uncertainty about tremulous patients at the borders of the classification of PD has a long history. Gowers,21 writing in 1888, had recognized this problem and thought carefully about it. Comparing PD with senile tremor, he observed: “Senile tremor often commences on both sides, paralysis agitans always on one. There is not, however, any sharp line of demarcation between the two affections, and it is difficult to say in which category some cases should be placed.” Positron emission tomography research shows that there is benign tremulous variant of PD with dopaminergic deficit22 and clinical surveys have further defined the entity of BTP.1–4 While we agree with Josephs and colleagues1 that asymmetrical upper limb rest tremor is the usual presentation of benign tremulous PD, 5 of our 16 pathologically verified patients had simultaneous onset of rest and postural/ action tremor. Recent publications1,2 suggest that tremor in BTP is not strongly responsive to L-dopa in the early disease phase. This was true in more than one-half of our patients, and was probably the reason that many clinicians had attempted to treat the tremor with an anticholinergic drug or propranolol. But 6 patients did obtain an early benefit from L-dopa.

Cases 1 to 12, in whom the correct diagnosis was made at presentation, appeared to represent 1 end of the spectrum of tremulous PD.23–25 Despite a long disease course, all eventually transgressed the definition because of increasing non-tremor motor disability and gait impairment. Motor fluctuations, dyskinesia, and advanced disease milestones were later documented in most. The pathologically confirmed Cases 13 to 16 provide evidence that benign tremulous PD also encompasses an indeterminate gray clinical zone between PD and other tremor disorders such as essential tremor or dystonic tremor. Each went through an early stage of tremor without definite parkinsonism and these 4 patients had the most “benign” disease courses. Case 13 was the only instance of PD developing in a patient likely to have had preexisting essential tremor; all other group 1 patients had a resting tremor when first assessed by a neurologist.

At autopsy, benign tremulous PD patients had significantly lower scores for pigmented neuronal loss in the substantia nigra than the control group, suggesting more slowly progressive nigral cell degeneration. But these brains had only slightly less burden of regional Lewy-related and other pathologies, consistent with the fact that most eventually developed features of advanced PD. A family history of tremor or PD has previously been reported in more than 60% of patients with BTP, suggesting a stronger genetic effect than for PD in general.1,2 Two individuals with BTP and LRRK2 gene mutations have been reported before.2,26 We found 1 example with compound heterozygous parkin gene mutations. The earlier reports of autopsies on patients with PD associated with parkin mutations showed nigral cell loss without α-Synuclein pathology27–29; although, as in our case 1, sparse Lewy body deposition has been noted occassionally.30–32 Nigral cell reduction in our parkin mutation case was comparable in degree to other benign tremulous PD cases. Lewy bodies were scanty, corresponding best to brainstem predominant pathology, but their distribution did not follow the Braak staging scheme well.

In group 2, diagnoses of PD were negated by postmortem examination. Sundry pathologies—some cerebrovascular lesions in the basal ganglia, moderate amounts of tau deposition, incidental α-Synuclein pathology in 1 case—were present. All 5 of these patients had resting tremor at their first documented neurological examination. We considered 2 alternative diagnoses: essential tremor with rest tremor, and adult onset dystonic tremor. There is ample pathological evidence that essential tremor with rest tremor is a separate disorder from PD.33–35 Clinical studies of essential tremor suggest that rest tremor, if it occurs at all, is a later development,36 but Rajput and colleagues34 reported a patient labeled as BTP in life and reclassified as essential tremor with early rest tremor after postmortem examination. We found that the anatomical pattern of a tremor was not discriminative in BTP. Head tremor, usually considered to be an essential or dystonic tremor characteristic, and jaw tremor, seen more commonly as a parkinsonian tremor, was present in patients with and without proven PD. One clinical finding that sets group 2 apart from the pathologically proved cases is paucity of bradykinesia. The diagnosis of PD had been made on the basis of a resting tremor in association with cogwheel rigidity and equivocal slowness of movement, but none of the neurologists who attended these patients in life ever documented clear-cut bradykinesia in their medical records.

Between 4% and 15% of patients who comply with standard diagnostic criteria for PD have been found to have normal dopaminergic functional imaging.37,38 Many of these “scans without evidence of dopaminergic deficit” (SWEDDs) patients have tremor with equivocal bradykinesia.39,40 Although this technology shows promise for differentiating, at an early stage, patients with benign tremulous PD from those with other tremor disorders, there is as yet little clinicopathological data on the SWEDDs phenomenon. Extrapolating back from the relatively mild postmortem nigral cell loss in our study, some patients with benign tremulous PD may have a small dopaminergic deficit early in their disease course.

Clinicopathological research has the limitation of relying on retrospective analysis of clinical details from case files. Nevertheless, our findings suggest that there is a distinct subgroup of benign tremulous PD that is associated with less severe nigral cell loss at postmortem. Many patients with benign tremulous PD transgress its definition by the final one-third of the disease course, and develop the common features of advanced PD. The BTP phenotype also encompasses cases in which the initial diagnosis of PD is uncertain because of tremor characteristics that resemble atypical isolated rest or dystonic tremor associated with minimal bradykinesia, and caution is needed when diagnosing essential tremor in an older person with a relatively short tremor history. Failure to develop convincing bradykinesia a decade after the appearance of rest tremor was a consistent feature of the pathologically disproved cases, and should lead to a review of any diagnosis of benign tremulous PD.

Acknowledgments: A clinicopathological study of this type is only possible because of the generosity and goodwill of patients and their families. Ms. Susan Stoneham assisted with record keeping and data collection at the Queen Square Brain Bank for Neurological Disorders.

Author Roles:

1. Research project: A. Conception, B. Organization, C. Execution. 2. Statistical analysis: A. Design, B. Execution, C. Review and critique. 3. Manuscript: A. Writing of the first draft, B. Review and critique.

Selikhova M: 1ABC, 2ABC, 3AB.

Kempster PA: 1ABC, 2C, 3AB.

Revesz T: 1ABC, 2C, 3B.

Holton JL: 1ABC, 2ABC, 3AB.

Lees AJ: 1ABC, 2C, 3AB.

Financial Disclosures: Selikhova M: Stock Ownership in medically-related fields: none; Consultancies: none; Advisory Boards: none; Partnerships: none; Honoraria: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Institute of Neurology, London; Contracts: none; Royalties: none; Other: none.

Kempster PA: Stock Ownership in medically-related fields: none; Consultancies: none; Advisory Boards: none; Partnerships: none; Honoraria: none; Grants: none; Intellectual Property Rights: none; Expert Testimony: none; Employment: Southern Health, private neurological consulting practice; Contracts: none; Royalties: none; Other: none.

Revesz T: Stock Ownership in medically-related fields: none; Consultancies: none; Advisory Boards: none; Partnerships: none; Honoraria: Merck Serono 2011; Grants: Multiple System Atrophy Trust, ARUK, Parkinson's UK; Intellectual Property Rights: none; Expert Testimony: none; Employment: University College London; Contracts: none; Royalties: none; Other: none.

Holton JL: Stock Ownership in medically-related fields: none; Consultancies: none; Advisory Boards: none; Partnerships: none; Honoraria: Merck Serono 2011; Grants: Multiple System Atrophy Trust, ARUK, Parkinson's UK; Intellectual Property Rights: None; Expert Testimony: none; Employment: University College London; Contracts: none; Royalties: none; Other: none.

Lees AJ: Stock Ownership in medically-related fields: none; Consultancies: Genus; Advisory Boards: Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira, Roche; Partnerships: None; Honoraria: Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira, Roche; Grants: PSP Association, Weston Trust - The Reta Lila Howard Foundation; Intellectual Property Rights: none; Expert Testimony: none; Employment: UCLH/UCL; Contracts: none; Royalties: none; Other: none.

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