Article Text
PDF
Abstract
Objective To evaluate in detail the clinical features in a large series of pathologically confirmed cases of vascular Parkinsonism (VP).
Background In the absence of widely accepted diagnostic criteria for VP pathological confirmation of diagnosis is necessary to ensure diagnostic reliability, and has only been reported in a few small series.
Design/methods The archival records of the Queen Square Brain Bank (QSBB) have been used to identify cases of Parkinsonism where cerebrovascular disease was the only pathological finding. Clinical notes were scrutinised and milestones of disease progression were compared with other atypical Parkinsonian syndromes from previous QSBB studies.
Results Twenty-eight cases were included. Mean age of onset and disease duration were 70.6 (SD± 6.42) and 10.5 (SD± 66.1) years respectively. Bradykinesia was present in all cases, rigidity in 96%, falls in 76%, pyramidal signs in 54%, urinary incontinence in 50% and dementia in 39%.Visual hallucinations in 0%. Two-thirds had an insidious onset and a relentless rather than stepwise progression of disability. When compared with other Parkinsonian syndromes, VP had an older age of onset.
Conclusions In comparison with other Parkinsonian syndromes the patients were older and had an extremely low frequency of visual hallucinations compared with Parkinson's disease.
- Vascular Parkinsonism
- symptoms
- non-motor symptoms
- diagnosis and postmortem
- cerebrovascular disease
- dementia
- movement disorders
- neuropathology
- Parkinson's disease
Statistics from Altmetric.com
- Vascular Parkinsonism
- symptoms
- non-motor symptoms
- diagnosis and postmortem
- cerebrovascular disease
- dementia
- movement disorders
- neuropathology
- Parkinson's disease
Introduction
There are no widely accepted clinical diagnostic criteria for vascular Parkinsonism (VP). Because vascular lesions may coexist in patients with Parkinson's disease (PD), postmortem confirmation of the diagnosis is necessary to ensure diagnostic reliability.1–3
We have reviewed 28 cases from the archives of the Queen Square Brain Bank (QSBB) in which cerebrovascular disease (CVD) was considered to be the likely cause of Parkinsonism. We describe the clinical features and disease progression milestones and characterise the non-motor symptoms in these patients.
Methods
VP cases were collected at the QSBB between 1987 and 2011. In total, 1375 cases were screened. Seventeen cases were included in a previous publication.1 Tissue and medical records are archived at the QSBB under local and regional ethics approval, and with a full license from the UK Human Tissue Authority.
Cases were included if they met all the criteria below: (1) presence of long standing Parkinsonism recorded by a neurologist or a geriatrician with an interest in Parkinsonian disorders working in a hospital setting; (2) postmortem diagnosis of CVD and exclusion of other associated neurodegenerative diseases, including PD using standard neuropathological techniques; (3) no history of recent use of neuroleptics or significant head trauma; and (4) sufficient details in the medical records to clearly delineate the main clinical features.
All the brains were examined using the same standard staining and sectioning protocols available as given in online supplementary appendix 1.
The following variables were recorded: age at onset and at death, clinical diagnosis in life, postmortem diagnosis, presence of vascular risk factors, neuroimaging results, onset of symptoms, first symptom at presentation, predominance of lower body symptoms, presence of gait symptoms, time to the onset of gait problems, bradykinesia, rigidity, tremor, falls, time to falling, urinary urgency and incontinence, presence of indwelling catheter, dementia, pyramidal signs, cerebellar signs, eye movement abnormalities, history of stroke, response to levodopa treatment, motor fluctuations, dyskinesias, constipation, fatigue, mood and sleep disorders. For the following milestones of disease progression, the presence and the first-time record of the symptom were recorded: persistent visual hallucinations, multiple falls, cognitive decline and long-term admission to a nursing home (variables were recorded as missing data if not mentioned in the notes). Operational criteria for the definition of each variable are available in the online supplementary appendix 1.
Results
Overall, 28 cases of VP were found. During life, 14 had been diagnosed with PD, six with VP, four with progressive supranuclear palsy and two with multiple system atrophy. Two patients carried a label of unclassifiable Parkinsonism.
The clinical features are summarised in table 1. Figure 1 shows a comparison of our data with QSBB data on other causes of Parkinsonism (PD,4 multiple system atrophy and progressive supranuclear palsy5). The course of the disease is aggressive with early milestones and disease duration shorter than PD. Disease duration and age of onset were associated with each other (p<0.001) and both were associated with time to sphincter dysfunction and nursing home admission.
Summary of the clinical data in pathologically confirmed vascular Parkinsonism
Milestones of disease progression in our sample of vascular Parkinsonism cases (grey bar). Bars represent the time between average disease onset and average age at death (average disease duration). The vertical lines indicate the average time to reach each milestone. Data for Parkinson's disease extracted from Kempster et al4 and for the others from O'Sullivan et al.5
Two cases had dopamine transporter (DAT) SPECT during life. In one, the test was abnormal with bilateral decrease of striatal tracer uptake with no predilection for the putamen. In 12 cases who had CT, there was evidence of small vessel disease (SVD) of varied degrees. Four cases had brain MRI, with evidence of severe SVD in three, while in one the vascular changes were considered normal for the age group and only atrophy was reported.
Neuropathologically, three cases (10.7%) had moderate to severe cell loss in the substantia nigra (SN) beyond what is accepted as age-related changes. Only one case had incidental Lewy body (LB) pathology, and in this case there was no detectable neuronal loss in the SN. Other associated neuropathological changes found were Alzheimer's disease-related in two and argyrophilic grain disease of the temporal lobe in one case, none of which had significant nigral degeneration. There was no cell loss in the locus coeruleus in any case. Neuropathological findings are reported in online supplementary table 1.
A positive levodopa response was found in 20 of 26 (76.9%), rated as excellent in 5 (19.2%), good in 10 (38.4%), moderate in 5 (19.2%) and absent in 6 (23%). There was no significant difference in clinical features of the cases who responded and those who did not respond to levodopa. A positive response was seen in 11 of 15 (73.3%) of the lower body predominant group and in 9 of 11 (81.8%) of the remaining patients (p>0.99, Fisher two-sided exact test).
Discussion
This is the largest published series of pathologically confirmed VP. Most patients presented with an insidious onset and steadily progressive disease. Visual hallucinations were not reported in any case, suggesting that when present they are likely to point to a diagnosis of PD with associated cerebrovascular pathology. In contrast, dementia was present in half the patients. Urinary symptoms, constipation, mood disorders and sleep problems were also present in more than half of the patients, and a quarter had orthostatic hypotension. Although some patients had a postural tremor, rest tremor was rare supporting the general view that this is a supportive feature for the diagnosis of PD.
Frequent non-motor features have not been reported in pathologically confirmed series of VP. SVD has been shown to be a major source of disability in the elderly and both the severity and the distribution of white matter changes and lacunes probably play an important role in the development of different motor and non-motor symptoms.6
One case with a definitive postmortem diagnosis of VP had an abnormal DAT scan but was found to have no nigral loss at postmortem raising questions over the reliability of functional imaging. No study has assessed the accuracy of DAT imaging using postmortem confirmed cases and a normal DAT scan in a patient with suspected VP is considered to provide support for the clinical diagnosis. On the other hand, an abnormal result does not preclude the diagnosis of VP particularly if there is a history of lacunar stroke.7 MRI imaging is a crucial diagnostic and prognostic factor in patients with cerebral SVD. However, due to current clinical practice, at the time our cases were collected, only 4 of our 28 cases (14%) had had an MRI.
Although the exact prevalence of VP is not known, it is likely to be higher than the 2% figure (28 of 1375 cases) in this QSBB series. Foltynie and colleagues have estimated that 3%–6% of all cases of Parkinsonism may be due to VP,8 while Bower et al found that 5 out of 39 cases of Parkinsonism (12%) in a pathological series had VP.9
Lower body predominant VP is considered by many authors to be unresponsive to l-dopa therapy. Three-quarters of our patients, however, were reported to respond for at least several months to levodopa and we suggest that a therapeutic trial is worthwhile in all patients where VP is clinically suspected.10
VP remains a pathological diagnosis of exclusion, that is, even in the presence of significant CVD, Parkinsonism may be attributable to other causes of neurodegeneration. Three of our cases had significant nigral cell loss without LB pathology, probably due to ischaemic damage to the nigra or transneuronal degeneration.11 Parkin gene mutations can be associated with Parkinsonism and nigral degeneration in the absence of LB.12 Our three cases presented Parkinsonism at the ages of onset of 67, 70 and 79 years; all had significant vascular risk factors and, in all but one, the Parkinsonism was predominant in the lower body. Given that Parkin gene is typically associated with young onset Parkinsonism, excellent response to levodopa and early severe dyskinesias, monogenetic Parkinsonism therefore seems extremely unlikely although gene testing was not performed.
Only one of the cases had incidental LB pathology and there was no neuronal loss in the SN, a sine qua non for pathological diagnosis of PD. In this patient, the symptoms started at the age of 70 with gait and balance problem, and the patient had typical lower body predominant Parkinsonism with absent response to levodopa. Sixteen cases were diagnosed in life as having PD. A previous postmortem series highlighted the under-ascertainment of VP among Parkinsonian cases.9
An important limitation is the general term ‘vascular Parkinsonism’, as other authors use ‘lower body Parkinsonism’, ‘Binswanger's disease’, ‘leukoaraiosis’ or ‘small vessel disease’ to describe similar or overlapping clinical syndromes associated with CVD.13 Therefore, the lack of accepted international diagnostic criteria for this disease entity may hinder comparability with other studies.
We selected patients for inclusion only if they had CVD without evidence of other neurodegenerative changes. In clinical practice, it is likely that the presence of coexistent CVD in patients with PD is a much commoner scenario as these diseases frequently co-occur. There is evidence that the presence of CVD in patients with PD may contribute to modify the clinical picture, because patients with PD and comorbid CVD present more axial and levodopa unresponsive symptoms.14
Our findings in this large pathologically confirmed series support the notion that VP exists although it is rare. The presence of visual hallucinations makes VP very unlikely in the context of levodopa responsive Parkinsonism.
Acknowledgments
The authors would like to thank Professor Tamas Revesz and Dr Janice Holton for performing the postmortem analysis of the brains at the QSBB.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online supplement
Footnotes
Funding This work was supported by the Reta Lila Weston Trust for Medical Research.
Competing interests Dr Glass reports no disclosures. Professor Lees received honoraria for lecturing, advising or consultancies from Genus, Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira and Roche; received grants from PSP Association, Weston Trust—The Reta Lila Howard Foundation. Dr Bacellar received honoraria for lecturing, advising or consultancies from Roche, Merk Serono, Novartis and Lundbeck. Dr Zijlmans has received honoraria for lecturing or advising from GSK and Novartis. Dr Katzenschlager has received honoraria for lecturing or advising from GSK, Boehringer, UCB, Cephalon, Abbott, Novartis and Lundbeck. Dr Silveira-Moriyama works for the Reta Lila Weston Trust for Medical Research, UCL; received honoraria from Teva Lundbeck and grants from Parkinson's UK, UCB, Genus and Abbott.
Patient consent Obtained.
Ethics approval The London Multi-Centre Research Ethics Committee had approved procedures for the donation of brains to the Queen Square Brain Bank for Neurological Disorders as well as retention of and access to clinical records. Tissue is stored at the QSBB under a full license from the UK Human Tissue Authority.
Provenance and peer review Not commissioned; externally peer reviewed.