Vascular Parkinsonism

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VP, also known as arteriosclerotic parkinsonism, multi-infarct parkinsonism, and lower body parkinsonism, can result from lacunar infarctions, leukoaraiosis, and Binswanger's disease. In 1929, Critchley (2) described arteriosclerotic parkinsonism characterized by rigidity, pseudobulbar affect, dementia, incontinence, and short stepped gait in an elderly hypertensive individual with multiple ischemic insults in the basal ganglia. Zijlman et al. (3) in their report of clinico-pathological findings of VP showed the variability of clinical presentation of VP both clinically and pathologically. Based on the clinical evolution of symptoms in 17 patients in this clinico-pathological study, the following criteria for VP were proposed: parkinsonism in the presence of cerebrovascular disease, a relationship between the above two features, and (a) acute or delayed progressive onset with infarcts in or near areas that can increase basal ganglia output, or decrease the thalamocortical drive directly resulting in contralateral bradykinetic rigid syndrome termed Vpa, and (b) in the case of insiduous onset of parkinsonism with extensive subcortical white matter lesions, bilateral symptoms at onset, and the presence of early shuffling gait, or early cognitive dysfunction, termed Vpi (3). These patients with parkinsonism had atrophic gyri, ventricular dilatation, and major-artery atheroma on autopsy. There

From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan © Humana Press Inc., Totowa, NJ

was extensive small vessel disease in the globus pallidus, caudate, putamen, and thalamus in the parkinsonian brains, and nigral cell loss was present in four patients. Microscopic pathology included gliosis, perivascular myelin pallor, hyaline thickening of arteriolar walls, and enlargement of perivas-cular spaces, along with macroscopically visible infarcts in the basal ganglia in those patients with VP. In all the 17 patients the pathologically examined frontal, temporal, parietal, occipital, and striatal areas were equally affected by the small-vessel disease pathology (3). This study clearly demonstrates the pattern of pathology and variability of clinical findings in patients with VP. Clinical features are variable as shown in this study based on the onset of disease, resulting in a contralateral bradykinetic syndrome in the case of acute or delayed progressive onset, and a bilateral involvement in the case of insidious onset of VP. Three out of the 100 patients clinically diagnosed as PD had VP in the London Brain Bank study, showing that VP can very closely resemble PD (4). Thompson and Marsden described parkinsonian features in a series of patients with Binswanger disease (5). Binswanger's disease is a form of leukoencephalopathy that is mainly a result of hypoxic-ischemic lesions in the distal watershed periventricular areas, associated with aging, hyperviscocity, and increased fibrinogen levels, and has been reported to be associated with VP (5-7). Based on a review of published series, VP can be defined as a syndrome resulting in short stepped gait, rigidity, with or without dementia, predominant lower body involvement in the absence of tremor, and poor levodopa responsiveness. Some patients also exhibit incontinence, pseudobulbar affect, and freezing of gait (8-11).

VP can be clinically classified into three subgroups: (a) possible VP in patients who exhibit atypical parkinsonism and have a history of stroke and show vascular changes on their brain magnetic resonance imaging (MRI), (b) probable VP in patients with onset of parkinsonism within less than 1 mo after acute stroke supported by evidence of a multi-infarct state on brain MRI, and (c) definite VP, which is characterized clinically as possible or probable VP but at autopsy there is ischemic or hemorrhagic damage in the basal ganglia without any evidence of idiopathic PD, such the presence of Lewy bodies (11). There are several clinical presentations of stroke-related parkinsonism, including a syndrome indistinguishable from idiopathic PD, vascular PSP with clinical features similar to those in idiopathic PSP (12,13), lower body parkinsonism (14), and parkinsonian gait disorders (11,15-17).

As there were no previously established clinical criteria for VP, Winikates and Jankovic proposed a vascular rating scale for VP designed to establish diagnostic level of certainty (11,13). Parkin-sonism was defined as presence of at least two of the four cardinal signs of tremor at rest, bradykine-sia, rigidity, and loss of postural reflexes. The vascular rating scale has scores ranging from 0 to 6 based on pathological, historical, and neuroimaging evidence of vascular disease. Two points were given for pathologically or angiographically proven diffuse vascular disease, one point for pathological evidence of both vascular and neurodegenerative changes, one point for onset of symptoms within 1 mo of a clinical stroke, a history of two or more strokes, a history of two or more risk factors for stroke, and neuroimaging evidence of diffuse vascular disease or vascular disease in two or more vascular territories. When a vascular score of 2 or higher was used as a designation of VP such patients could be clearly differentiated from idiopathic PD (11,12). Zijlmans et al. (3) also proposed clinical criteria that include a differentiation between the unilateral and bilateral forms of VP.

Clinical features of patients with VP include older age at onset, male preponderance, higher frequency of dementia, and, as expected, vascular risk factors. About 25% of these patients may present with VP within a month after a stroke. Patients with VP typically present with gait difficulty and during the course have predominant lower body involvement, postural instability, history of falls, dementia, corticospinal findings, incontinence, pseudobulbar affect, and they are less likely to respond to levodopa (8,10,11). Patients with severe subcortical ischemia (as evidenced by MRI) tend to have more gait difficulties (4). In patients with lower body parkinsonism associated with VP, the upper body function is typically preserved. Some patients mainly have gait difficulties with and without freezing, mostly seen with multiple lacunar infarcts (11,12). Quantitative gait analysis in 12 patients with PD, 12 with VP, and 10 controls showed that patients with VP had relatively well-preserved armswing, with anterior rotation of the shoulders (17). Patients with VP were found to have more postural abnormalities on postural stability testing leading to balance problems on dynamic posturography testing (18). Patients with VP have less flexion posture of the elbow, hip, knee, and trunk than patients with idiopathic PD. Larger studies using specific gait instruments, such as the Gait and Balance Scale (GABS) (19), and other gait and balance analyses may help find other patterns of gait and balance abnormalities with high sensitivity and specificity for VP.

In addition to Binswanger's disease that has been associated with elevated fibrinogen levels, some VPs have been found to have high titers of anticardiolipin antibodies (ACLAs) (20). In a study of 44 individuals with VP, 9 of the 22 tested (40.9%) patients had positive ACLA. Further studies are needed to document the exact incidence of ACLAs in patients with VP. Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can sometimes present with parkinsonism. In the original descriptions patients had recurrent strokes, pseudobulbar palsy, and dementia. The abnormality on genetic linkage analysis was localized to chromosome 19q12, and the mutation in Notch-3 gene was subsequently identified (21). In autopsied brains, patients with CADASIL have changes in the vessel wall similar to those seen in polyarteritis nodosa, manifested by eosinophilic granularity or fibrinoid necrosis of the tunica media coupled with basophilic granular degeneration of the media (22).

Elevated homocysteine levels have been also associated with ischemic events resulting in VP, but this abnormality has been attributed to levodopa therapy (23,24). In one study, patients treated with levodopa had a significant increase in plasma homocysteine levels compared to the levodopa-naive patients, and patients with homocysteine levels in the higher quartile had increased risk of coronary artery disease (relative risk 1.75) (24). Although there is no evidence that stroke or coronary artery disease are any more frequent in PD patients than in individuals without PD, high homocysteine levels may increase the risk of dementia associated with PD.

Once VP is clinically suspected MRI scan of the brain must be performed to confirm the presences of subcortical ischemic changes on T1 and T2 images in the basal ganglia and white matter. As expected, in patients with VP the number and intensity of MRI lesions is greater (10,25). Although some authors have not been able to correlate asymmetric lesions with the side of symptoms in patients with VP and PD (16,26), Chang et al. (27) showed that most patients with VP had MRI correlates of ischemic changes. In their series of 11 patients they found common clinical features of akinesia, rigidity, shuffling gait, reduced armswing, hesitation while turning, very similar to PD, but these patients had more upright posture, more wide-based stance, and did not exhibit festination. They have identified three patterns of ischemia on computed tomography (CT) or MRI including frontal lobe, deep subcortical, and basal ganglia infarction associated with steady progression. They report that patients with specific basal ganglia lacunar infarcts had a better prognosis with resolution of PD symptoms, whereas those with frontal lobe infarction had a static course, and those with deep subcortical infarcts not specifically confined to the basal ganglia had a progressive course. Autopsy on one of their patients confirmed a multi-infarct state without any evidence of Lewy bodies (27).

Using functional imaging, such as 123I- p-CIT SPECT (single photon emission computed tomography) and TRODAT-1 scanning, may further enhance the diagnosis of VP (28,29). TRODAT-1 is a cocaine analog that can bind to the presynaptic dopamine transporter and has been found to be useful in differentiating VP from PD. A significant reduction of the uptake was more pronounced in the contralateral putamen of patients idiopathic PD than that in patients with VP (28). Proton MR spec-troscopy shows preservation of dopaminergic neurons in VP (30). Tohgi et al. (31) have shown narrowing of the width of SNc in patients who have both PD and vascular changes, but those with VP have normal width of SNc on the MRI brain. In a small study including 13 patients, EEG (electroencephelogram) slowing was less in those with VP compared to patients with PD (32), but this observation needs to be confirmed in a larger group of patients.

A small proportion (up to 50%) of patients with VP respond to levodopa, the first line of therapy in this population (5,14,16,33). Demikiran et al. (16) have also shown that 38% of patients with VP have a response to levodopa therapy. Depending on the identification of stroke risk factors patients should be started on antiplatelet therapy, or anticoagulation in those with atrial fibrillation and valvular heart disease with high risk of embolization. Occasionally, symptoms of VP may transiently improve with CSF (cerebrospinal fluid) drainage similar to that seen in Normal Pressure Hydrocephalus (NPH) (34). This improvement, however, is rarely sustained and is not predictive of response to CSF shunting.

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