Clinical Correlates of Vascular Parkinsonism FREE

PARKINSONISM, a clinical syndrome of rest tremor, bradykinesia, rigidity, and postural instability, can result from a variety of causes. Idiopathic parkinsonism or Parkinson disease (PD) is characterized by the presence of Lewy bodies, and by degeneration of the lateral substantia nigra pars compacta, the cause of which is not yet known. The autopsy findings in 100 patients clinically diagnosed as having PD, reviewed by the London Parkinson's Disease Brain Bank Study, confirmed PD in 76 cases, but showed other pathologic findings in 24, including vascular disease in 3 cases.¹ This autopsy report underscores the clinical difficulty in distinguishing between patients with PD and those with secondary parkinsonism, and the need for identifying clinical characteristics that may improve diagnostic accuracy.

Parkinsonism attributable to strokes or other vascular causes has been described,^{2 - 18} although the validity of the concept has been questioned.^{19 - 22} The clinical correlates of vascular parkinsonism (VP) have not been fully characterized. The goal of our study was to evaluate a group of parkinsonian patients for evidence of vascular disease and compare the clinical features in vascular and idiopathic parkinsonism.

All patients were personally examined by one of us (J.J.) between 1978 and 1994 in the Movement Disorders Clinic at the Baylor College of Medicine, Houston, Tex. Parkinsonism was defined as the presence of at least 2 of the 4 cardinal signs of tremor at rest, bradykinesia, rigidity, and loss of postural reflexes. During this period, 2071 patients were classified clinically with PD and 133 with VP. Medical records of the last consecutive 288 patients diagnosed as having PD and of 96 with VP were reviewed. The following variables were recorded and analyzed: age, sex, duration of symptoms at time of initial visit, evidence of vascular disease, and distribution and asymmetry of findings. Furthermore, motor signs, such as tremor, rigidity, gait disorder, falling, and postural instability were scored on the Unified Parkinson's Disease Rating Scale (UPDRS).²³ The presence or absence of associated clinical findings of dementia, corticospinal signs, seizures, pseudobulbar signs (especially emotional incontinence), bowel or bladder incontinence, orthostatic hypotension, and psychiatric symptoms was also recorded. Response to the use of levodopa, as determined from the initial evaluation and from assessment on follow-up visits, was also recorded.

Evidence of vascular disease was assessed using a vascular rating scale previously described.²⁴ Two points were given for pathologically or angiographically proven diffuse vascular disease, 1 point for onset of parkinsonism within 1 month of clinical stroke, 1 point for history of 2 or more strokes, 1 point for history of 2 or more risk factors for stroke, and 1 point for neuroimaging evidence of vascular disease in 2 or more vascular territories. The following risk factors for stroke, based on the report of the Stroke Council of the American Heart Association,²⁵ were analyzed: hypertension, smoking, diabetes mellitus, hyperlipidemia, presence of heart disease associated with stroke (coronary artery disease, atrial fibrillation, congestive heart failure, valvular heart disease, mitral valve prolapse, or other arrhythmias), and other risk factors for stroke (family history of stroke, history of gout, or peripheral vascular disease). Patients with parkinsonism and a vascular score of 2 or more were categorized as having VP. The Hachinski Ischemic Scale²⁶ was also determined. Complete data sets for clinical (demographics and UPDRS) and neuroimaging (computed tomography or magnetic resonance imaging [MRI]) variables were available in 69 patients classified as having VP and 175 classifed as having PD.

Data were entered into a database (Paradox 4.0). The mean and SD of age and years of duration of symptoms were compared using the Student t test. Clinical characteristics were compared using the χ² statistic in a 2 × 2 matrix with the Yates correction. Statistical significance was assumed at P<.05.

Sixty-nine patients satisfied the above-mentioned criteria for VP; 58 of the 96 previously categorized as having VP, and 11 of the 288 previously categorized as having PD. Thus, 38 patients from the original VP group (n = 96) were excluded because they did not fulfill the diagnostic criteria for VP. The 69 patients categorized as having VP were compared with the remaining 277 with PD. The vascular score clearly separated the 2 groups in terms of evidence of cerebrovascular disease and vascular disease risk factors. Strokes were seen in both groups, but were more common in the vascular group (43.5% vs 2.9%; P<.00001); multiple strokes were noted only in the vascular group (15.9%). Onset of symptoms with stroke was noted in 24.6% of patients with VP compared with 0.7% in the PD group. Similarly, risk factors for stroke were significantly more common in the VP group. The greatest differences were seen in hypertension and heart disease (P<.00001), followed by diabetes and hyperlipidemia (P<.0005) and smoking (P<.01). Heart disease was more than 3 times more common in the VP group, particularly coronary artery disease (30.4% vs 6.9%; P<.00001) and congestive heart failure (11.6% vs 0.7%; P<.0001). Left ventricular hypertrophy was also more common in patients with VP (2.9% vs 0%; P<.05). The number of patients with atrial fibrillation, valvular heart disease, and artificial heart valves was too small to analyze. Evidence of carotid artery disease (presence of a bruit, or significant stenosis by carotid Doppler study or angiography) was seen in patients with VP, but not in patients with PD (7.2% vs 0%; P<.0005). Family history of stroke was more common in patients with VP (37.7% vs 17.9%; P<.001). No significant differences were noted in the presence of peripheral vascular disease or hyperuricemia. Hachinski Ischemic Scale scores were significantly higher in the VP group compared with the PD group (3.46 vs 0.39; P<.00001).

Patients in the vascular group were on the average 8.6 years older, 71.3 years compared with 62.7 years for patients with PD. This age difference was statistically significant (P<.00001). Symptom duration at initial evaluation was slightly shorter among patients with VP compared with patients with PD, 5.32 years compared with 6.14 years. Men predominated in both groups, although only slightly in patients with PD: 57.9% vs 50.9%. These differences were not statistically significant (P<.01).

Comparison of clinical features of parkinsonism showed significant differences between the 2 patient groups (Table 1). The differences in clinical features between the VP group and the PD group were similar irrespective of whether the entire PD group (n = 277) or only those patients who had neuroimaging studies (n = 175) was used for comparison. Lower body predominance, gait disorder, postural instability, and falling were more common in the vascular group, while tremor, asymmetry of involvement, and upper body predominance were features of the idiopathic group. These differences were highly statistically significant (P<.00001). Only 24.6% of the patients with VP treated with levodopa responded compared with 73.6% of patients with PD (P<.00001). Dementia, incontinence, corticospinal tract findings, and emotional incontinence were more common in VP. No significant differences were noted in the presence of rigidity, seizures, ataxia, orthostatic hypotension, or psychiatric symptoms.

Neuroimaging studies were performed in all 69 patients with VP: computed tomographic scans in 24, MRI in 60, both in 15 (Table 2). These studies were performed less frequently in the PD group: computed tomographic scans in 69, MRI in 129, both in 23, or a total of 175 (63.2%) of the 277. In addition, cerebral angiography was performed in 5 patients with VP and 2 patients with PD, carotid Doppler studies in 3 patients with VP and 5 patients with PD, and magnetic resonance angiography in 1 patient with VP and no patients with PD. Evidence of vascular disease was seen on neuroimaging studies in both groups, but was significantly more common in the VP group. No significant difference was seen in single vascular territory involvement, but involvement of multiple vascular territories, periventricular white matter changes, subcortical ischemic white matter changes, and ischemia of the basal ganglia and brainstem were all significantly more common in the vascular group. Atrophy was seen in both groups, but was more often described in the vascular group. Normal scans were described only in the idiopathic group, in 100 of the 175 scans performed. There were no normal scans in the vascular group.

The primary goal of this study was to seek evidence for or against cerebrovascular disease as a cause for the parkinsonian syndrome and to characterize VP. The underlying assumption is that, given a clinical syndrome with multiple underlying causes such as parkinsonism, clinically distinguishable subgroups represent patients with different causes. The hypothesis tested is that identifiable differences can be found in the pattern of parkinsonism between 2 groups of patients, 1 with idiopathic PD and 1 with clear evidence of cerebrovascular disease (VP). The finding of significant differences in clinical characteristics between these 2 patient groups suggests a distinct clinical entity in which cerebrovascular disease would be the likely cause of the parkinsonian syndrome, and supports the concept of VP.

We used a vascular score based on clinical, historical, and neuroimaging data. A similar method, the Hachinski Ischemia Scale, has been used in evaluating patients with dementia.²⁶ The validity of the Hachinski Ischemia Scale in differentiating vascular dementia from Alzheimer dementia has been supported by clinicopathologic studies.^{27 - 28} While our vascular score lacks such validation, criteria for inclusion in the vascular group are stricter. The Hachinski Ischemia Scale includes a history of a single stroke, or any stroke; the vascular score used in this study required a history of 2 or more strokes. Abrupt onset of symptoms is a feature of the Hachinski Ischemia Scale; our vascular score required onset within 1 month of a clinical stroke. Hypertension is the only risk factor for stroke included in the Hachinski Ischemia Scale; we included other risk factors for stroke, but required 2 or more risk factors for stroke for inclusion in our vascular group. Emotional incontinence and focal neurologic signs were analyzed separately and were increased in our VP group, consistent with a vascular cause. Neuroimaging studies^{29 - 30} have been incorporated into the criteria for diagnosis of vascular dementia; a recent study by Pullicino et al³¹ has further evaluated the validity of neuroimaging studies in the diagnosis of vascular dementia. This approach is similar to our own use of a vascular score combining clinical criteria and neuroimaging findings.

Our VP group shares many characteristics with those individuals presented in the original VP article by Critchley.² Critchley suggested that later age at onset would favor a vascular cause. Our patients with VP were significantly older than were patients with PD. Older age has also been noted in some studies of VP,¹³ although several other studies^{10 - 11} have not confirmed this finding. We observed a shorter duration of symptoms in our VP group, as did Critchley.² Similar to the original report by Critchley,² patients with VP were more likely to have gait difficulty, dementia, and corticospinal and pseudobulbar findings and were less likely to experience tremor. Unlike Critchley,² however, rigidity did not differentiate these 2 groups.

The presence of risk factors for stroke in patients with VP has been previously reported.^{11 - 12} The greater degree of upper body involvement in PD and lower body involvement in VP (lower body parkinsonism) was similar to the observations from previous series.^{2 ,11 ,32} Consistent with other reports,^{3 - 4 ,7 - 8 ,11 - 12} we also found that patients with VP were less likely to respond to the use of levodopa than patients with PD: 24.6% vs 73.6%. The predominant neuroimaging findings in our patients with VP were diffuse areas of increased signal intensity in the subcortical white matter on T₂-weighted MRI scans. Such findings have been frequently reported in magnetic resonance scans of the elderly.^{33 - 34} Many,^{35 - 40} but not all,⁴¹ studies have correlated the presence and severity of these lesions with age, history of stroke, and presence of vascular risk factors, especially hypertension, suggesting that these lesions may represent an index of chronic cerebrovascular disease. Fazekas et al⁴² found that deep white matter hyperintensities correlated pathologically with ischemic tissue damage. Our patients with VP also had a greater degree of atrophy of the hemispheres and involvement of the brainstem.

A few recent studies of MRI in patients with PD have discussed changes similar to those found herein. Durif et al⁴³ described a positive correlation between frontal atrophy on MRI with severity of gait disorder and postural instability in 30 patients with PD; however, all patients had typical PD and improved with the use of levodopa. Stern et al⁴⁴ compared MRI scans in 37 patients with PD and 34 with parkinsonian syndromes. The patients with parkinsonian syndromes were older and had a higher frequency of dementia, prior strokes, and vascular risk factors compared with patients with typical PD. Brainstem atrophy was more common in patients with parkinsonian syndromes compared with patients with PD. These findings are similar to those reported herein. White matter hyperintense lesions on T₂-weighted images were more common in those with parkinsonian syndromes compared with healthy controls; however, unlike our findings, no significant differences in white matter lesions were demonstrated between patients with PD and parkinsonian syndromes. In a study of 102 patients with PD by Piccini et al,⁴⁵ periventricular hyperintensities on MRI were correlated with greater disease severity and more rapid disease progression. Deep white matter hyperintensities showed no such correlation. However, patients with evidence of stroke and cerebrovascular disease risk factors were excluded from this study. Bonuccelli et al⁴⁶ categorized 129 patients with parkinsonian features into 3 groups based on MRI evidence of vascular lesions. Unlike our study, they found no significant differences in clinical parkinsonian features among the 3 groups. Zijlmans et al⁴⁷ compared MRI findings in patients with PD, suspected VP, and hypertensive controls. They found a greater volume of subcortical lesions and greater evidence of lesions of the subcortical gray nuclei in patients with suspected VP compared with both PD and hypertensive controls. These findings are similar to those of our study.

The mechanism by which ischemic lesions of the brain give rise to parkinsonian signs in VP has not been clarified. Vascular lesions of the basal ganglia themselves may account for some cases.^{4 - 9 ,14 - 15 ,47} Others^{17 ,48 - 49} have failed to find good correlation between vascular lesions of the basal ganglia and subsequent parkinsonism. Baloh et al^{50 - 51} suggested that the disequilibrium in a group of elderly patients with white matter lesions on MRI was due to impairment of long-loop reflexes traversing the white matter leading to disruption of sensorimotor integration. Thompson and Marsden⁵² suggested that the gait disorder of Binswanger subcortical arteriosclerotic encephalopathy is due to diffuse vascular lesions disrupting the interconnecting fiber tracts between the basal ganglia and the motor cortex. A similar mechanism could account for parkinsonism in patients with prominent subcortical white matter lesions in VP.

Roughly one quarter (24.6%) of our patients had onset of parkinsonism within 1 month of clinical stroke. Individual case reports have documented patients with acute onset of parkinsonism following infarction or hemorrhage of the basal ganglia.^{4 - 6 ,8 - 9 ,14 - 15} Zijlmans et al⁴⁷ noted 4 patients with acute onset of parkinsonism and subcortical gray matter lesions on MRI, and 11 patients with diffuse subcortical white matter lesions and insidiously progressive parkinsonism. This is similar to the suggestion of Bonucelli et al⁴⁶ that VP can be divided into "possible VP" in patients with vascular lesions on MRI and a history of stroke, and "probable VP" in patients with onset of parkinsonism shortly after acute stroke. Our findings, and those of others,^{12 ,47} suggest that there may be 2 forms of VP: 1 with acute onset, possibly associated with some basal ganglionic infarctions, and 1 with insidious progression, possibly associated with more diffuse subcortical white matter ischemia. Furthermore, cerebrovascular disease, however, can produce different types of parkinsonism. These include parkinsonism that is indistinguishable from idiopathic PD,⁵³ progressive supranuclear palsy that is clinically identical to the idiopathic variety,^{24 ,54} the lower body form of parkinsonsim,¹¹ and other parkinsonian gait disorders.⁵⁵

While the findings in this study support the concept that parkinsonism can be caused by cerebrovascular disease, they do not prove the existence of VP. Cerebrovascular disease, however, has been found to be the cause of parkinsonism in 2.5% to 3% of autopsied cases.^{1 ,56 - 57} In the absence of pathologic data it is not possible to determine the sensitivity, specificity, or positive or negative predictive value of our vascular score or patient characteristics. Since both cerebrovascular disease and PD are diseases of the elderly, some of our patients with VP may have had coincidental vascular disease and idiopathic PD. The role of age requires further clarification, particularly with respect to the MRI findings. Advancing age is correlated with the white matter changes common in our VP group. However, cerebrovascular risk factors are also important contributors to such changes.³⁷ Given the strong evidence of vascular disease required by our VP criteria, it is unlikely that age alone would account for the MRI changes seen.

In conclusion, VP should be suspected in patients presenting at more advanced age, and with predominantly lower body involvement and gait abnormalities rather than tremor. A history of stroke, heart disease, and the presence of hypertension and other risk factors for stroke supports a vascular origin of these symptoms. Although most patients respond poorly to therapy with levodopa, some benefit and this drug should be tried in all patients with disabling symptoms. Management of risk factors for stroke and use of antiplatelet drugs seem prudent practice, although whether these interventions alter the clinical course remains to be evaluated.

Accepted for publication June 24, 1998.

We thank Ken Schwartz, PA, for his invaluable assistance in designing the databases used, and in the statistical analysis of the data.

Reprints: Joseph Jankovic, MD, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030.