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Review

Vascular parkinsonism: what makes it different?


Deepak Gupta,1 Abraham Kuruvilla2
1

Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada 2 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India Correspondence to Deepak Gupta, Division of Neurology, Department of Medicine, Walter C Mackenzie Health Sciences Center, 8440e112 Street, University of Alberta, Edmonton, Alberta T6G 2B7, Canada; docdeepakgupta@gmail.com Received 22 March 2011 Accepted 16 July 2011

ABSTRACT Vascular parkinsonism (VP) accounts for 2.5e5% of all cases of parkinsonism in various population based and clinical cohort studies. VP develops as a result of ischaemic cerebrovascular disease, so aetiologically it is classied as secondary parkinsonism. It has been variably referred to in the literature as arteriosclerotic parkinsonism, vascular pseudo-parkinsonism, and lower body parkinsonism. The most important consideration while making a diagnosis of VP should be to differentiate VP from Parkinsons disease (PD) because of prognostic and therapeutic implications. The salient clinical features in VP which differentiate it from PD are presentation with postural instability and falls rather than with upper limb rest tremor or bradykinesia; short shufing parkinsonian gait in VP is accompanied by a wider base of stance and variable stride length (parkinsonian-ataxic gait), absence of festination, frequent occurrence of pyramidal signs, and early subcortical dementia. In a patient where the clinical features are suggestive of VP the clinical diagnosis can be supported by demonstration of diffuse white matter lesions and/or strategic subcortical infarcts in the MRI of the brain. The therapeutic options in VP are limited to levodopa, and a poor or non-sustained response to levodopa is another differentiating feature between VP and PD.

INTRODUCTION
Vascular parkinsonism (VP) is a form of secondary parkinsonism resulting from ischaemic cerebrovascular disease. For a clinician, the most important aspect of VP should be its differentiation from Parkinsons disease (PD). The clinical features of VP are most helpful in making this distinction. The clinical diagnosis of VP is most often supported by radiological studies which have evolved over the last two decades from CT to MRI and dopamine transporter single photon emission CT scan (DATSPECT). A clinical criterion for diagnosis of VP has also been proposed.1 However, one aspect of VPdits pathophysiologydis still not completely understood. This article attempts to delineate the clinical and radiological features of VP and discusses the present evidence regarding its pathogenesis and treatment.

pre-CT era failed to demonstrate a consistent association between parkinsonism and arteriosclerosis. The validity of the concept of arteriosclerotic parkinsonism was questioned until CT and later MRI came into existence. With neuroimaging, discrete basal ganglionic and diffuse subcortical white matter lesions were identied in patients with parkinsonism who were clinically different from classical PD in more than one respect. Therefore, the fact that VP exists and is a distinct form of parkinsonism, both clinically and radiologically, came to be accepted more often. Critchley in 1981 renamed the condition arteriosclerotic pseudo-parkinsonism.3 Thompson and Marsden, in 1987, described 12 cases of Binswanger s disease with symmetrical hypodensities in the cerebral white matter on CT, parkinsonian signs and gait that were similar to those of the cases described by Critchley and quite different from the gait in PD.4 They termed these cases as having lower half parkinsonism. Around the same time, it was debated that Binswanger s disease was actually not a disease and that this eponymdwhich had been used until then to denote all patients with diffuse white matter hypodensities on CTdshould be replaced by the term leukoaraiosis.5 6 FitzGerald and Jankovic in 1989 coined the term lower body parkinsonism while clinically differentiating their cases of VP from PD and reemphasised the role of a vascular aetiology in VP.7 The rst clinical criteria for the diagnosis of VP based on a clinicopathological study was proposed by Zijlmans et al in 2004.1

EPIDEMIOLOGY
VP has been reported to account for 2.5e5% of the total cases of parkinsonism in various population based studies and clinic cohorts. The Rotterdam study was a prospective population based cohort study in which, of the total 132 subjects with parkinsonism, 5% had parkinsonism due to cerebrovascular disease.8 In their population based analysis of 5278 elderly subjects, the NEDICES (Neurological Disorders in Central Spain) study group found the prevalence rate of parkinsonism from all causes to be 2.2% (118 subjects).9 Of the 118 subjects, VP was diagnosed in 2.5% (three subjects). A joint analysis of ve community surveys of Europe, the EUROPARKINSON (European Community Concerted Action on the Epidemiology of Parkinsons disease) collaborative study, found VP to account for 3% of the total cases of parkinsonism.10 A diagnosis of VP was made in 3.9% (60/1528) of patients in the clinic based cohort study of Munhoz et al.11 Chang et al diagnosed VP in 11 (4.4%) of the 250 parkinsonian patients in their clinic cohort on the basis of radiological ndings and levodopa response.12
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HISTORICAL ASPECTS OF VP
VP was rst described as a distinct clinical entity by Critchley in 1929.2 Critchley referred to VP as arteriosclerotic parkinsonism. Although Critchley s monograph was very detailed in respect to the clinical aspects of VP, he did not provide a pathological correlation apart from opining that the disease was a result of vascular lesions in the brain and brainstem. Due to the lack of a well dened pathological correlate, subsequent workers in the
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PATHOPHYSIOLOGY
VP is the result of conventional vascular risk factors, particularly hypertension, leading to strategic infarcts of the subcortical grey matter nuclei, diffuse white matter ischaemic lesions (DWML), and least commonly large vessel infarcts.12e14 In a particular patient the aforementioned types of ischaemic lesions are most often mixed. The role of ischaemic cerebrovascular disease in the pathogenesis of VP has been shown in clinicoradiological7 12e18 and clinicopathological1 19 20 studies. In all these series, patients with VP have been shown to have had statistically more cerebral infarcts than neurologically normal subjects or patients with PD. For example, in one study a history of strokes was present in 43.5% patients with VP as compared to 2.9% of patients with PD.17 Taken the other way around, 11% of patients with stroke who were followed-up for a median of 3 years developed parkinsonism which was different clinically from the parkinsonism in PD.14 Parkinsonism occurred more often after lacunar than cortical infarcts and in the presence of coexisting WML.14 The pathogenesis of VP is not completely understood. Bilateral DWML cause parkinsonism because of damage to the net thalamocortical drive, which decreases the ultimate inuence of basal ganglia on higher centres of motor planning and execution.4 With regards to strategic infarcts there has been a considerable variation in the literature on their location. Strategic infarcts would be expected to produce clinical parkinsonism by disrupting the putamino-pallido-thalamic loop. Theoretically, infarcts of the substantia nigra (SN), striatum or the ventroanterior/ventrolateral (VA/VL) nuclei of the thalamus can decrease the net thalamocortical drive and cause parkinsonism. Although striatal, lenticular, thalamic, mesencephalic and frontal lobe infarcts have been reported to cause VP, all infarcts at these sites do not lead to VP since asymptomatic basal ganglia infarcts and white matter hyperintensities are a known occurrence. Lee et al found that in a cohort of 994 asymptomatic, 20- to 78-year-olds, silent infarcts were present on MRI in 5.84% of subjects.21 The most frequent sites were basal ganglia (46/121 silent infarcts), periventricular white matter (31/121), cerebral cortex, thalamus (15/121), pons, and cerebellum. Old age and hypertension were independent risk factors for these silent infarcts. Uehara et al performed brain MRIs on 219 adults, aged 33e83 years, without a history of stroke or transient ischaemic attacks and without any abnormality on neurological examination.22 Silent infarcts in the white matter and/or basal ganglia were detected in 88 (40.2%) of the 219 subjects. Age, hypertension, female gender, and extracranial atherosclerotic disease were independent predictors of these infarcts. Considering the above evidence, it seems probable that there are coexisting clinical and physiological factors at play in patients with basal ganglionic infarcts which preclude the appearance of parkinsonian features. For example, Peralta et al postulated that striatal infarcts could more commonly produce parkinsonism if they were selective enough to disrupt the putamino-pallidal outow only, but more frequently they damage the pallidum also causing a contralateral pallidotomy effect.23 A coexisting pyramidal tract lesion in patients with basal ganglia infarcts would mask bradykinesia and rigidity. Lastly, other factors such as the pattern of discharge of the nuclei of basal ganglia circuitry also play an important role in the pathophysiology of various movement disorders which may be true for VP.24 (synucleinopathies, tauopathies) as the diagnosis. The major pathological ndings in VP are related to small vessel ischaemic disease, lacunar infarcts, and occasionally large artery infarcts. The macroscopic ndings include varying degrees of cerebral atrophy and atherosclerosis of the cerebral arteries.1 20 Lacunar infarcts may be macroscopically visible or microscopic,19 and are more frequent in basal ganglia and thalamus compared to age matched non-parkinsonian subjects and patients with PD.1 20 Microscopic small vessel disease associated pathology, which includes gliosis, perivascular pallor, hyaline thickening of arteriolar walls, and enlargement of perivascular spaces, is also more frequent in VP than in age matched subjects with hypertension and other vascular risk factors.1 Although subtle overlap can occur, the pathological ndings in VP should not meet the diagnostic criteria of PD or other atypical parkinsonian disorders. The diagnosis of PD is based on a clear depletion of brain stem (nigral) pigmented neurons, fairly normal striatum with generalised and specic Lewy body (LB) distribution.25 It should be remembered that Lewy body can also be found in disorders other than PD.26 Comparison of VP and PD patients in the clinicopathological series of Yamanouchi and Nagura showed that the PD group had a greater loss of pigmented and non-pigmented neurons in the SN than the patients in the VP group.20 Rarely, SN neuron loss may be seen in VP as there is experimental evidence that slight to moderate loss of neurons in the ipsilateral SN can occur with massive unilateral infarction of the basal ganglia.27 The coexistence of ischaemic cerebrovascular disease and PD is also known. Whether PD is a risk factor for stroke, is protective, or has no effect against stroke is debated. Jellinger compared the frequency of cerebrovascular pathology in consecutive groups of 617 autopsy proven PD patients and 535 age matched control subjects.28 The PD group did not show an overall increased incidence of cerebrovascular pathology as compared to controls. The total number of infarcts or their location did not differ between the PD and the control groups. Although there are no pathological studies with head to head evaluation of VP and PD patients brains, existing literature does show a greater incidence and magnitude of cerebrovascular lesions in VP as compared to non-parkinsonian subjects or patients with PD. Therefore it would be correct to assume an association between VP and cerebrovascular disease.

CLINICAL FEATURES
VP presents clinically as an atypical parkinsonian disorder. Differentiating VP from PD at the bedside is an important aspect because on the basis of this the patient is prognosticated and subjected to various therapeutic options.

Onset and course


VP has been shown to have a later age of onset versus PD29 30 in some15 17 but not all series.7 13 16 In VP, age of onset can vary from 44e84 years, but most commonly the onset is in the eighth decade.7 13 15e17 A patient with VP is more likely to have a shorter duration of illness as compared to PD at their rst presentation.7 15 16 VP also has a more rapid evolution as compared to PD. Some patients with VP may not report past strokes. In those who have a past history of strokes, the duration from onset of stroke to onset of parkinsonism can vary considerably.1 12 Some clinical researchers have divided VP into two subgroups based on acute or insidious onset. Furthermore, acute onset cases have a chance of spontaneous improvement. However, the clinical criteria applied in these studies have not been uniform and the
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PATHOLOGY
Pathology is probably the gold standard for diagnosing VP, not because it shows the vascular lesions but because it can rule out PD and other atypical parkinsonian disorders
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clinical presentations, apart from mode of onset, have not been distinctive. Zijlmans et al subdivided 15 patients with VP into those with acute (n4) and those with insidious (n11) onset.13 Those with acute onset had infarcts in one or more of the deep grey matter nuclei (putamen, thalamus, pallidus, or caudate nucleus) and those with insidious onset had DWML. Only two of the 11 patients with insidious onset had infarcts in the deep grey matter. However, apart from the onset, the groups could not be differentiated. In a later different study,Zijlmans et al provided pathological evidence for this distinction.1 Among 17 patients with VP, they found that four patients who had acute (n3) or delayed (n1) progressive onset of parkinsonism after a hemiparetic stroke had lacunes in the thalamus, external segment of globus pallidus (GPe) and putamen with extension into the internal capsule and caudate. This was not an exclusive feature in those patients because seven of the 13 patients with insidious onset also had lacunes in the basal ganglia or thalamus. In another study, four of the 16 VP patients had acute onset but the radiological ndings in these were quite different from the patients of the above study.13 15 Two had basal ganglia infarcts, one had a brainstem infarct, and one had ischaemia in the basilar artery territory.15 Further clinical differentiation between the two groups in this study was not discussed. In the series of Chang et al,12 of the 11 patients with VP, ve had an onset immediately following a stroke. Three had basal ganglia lacunes, one had large frontal lobe infarct, and one had periventricular white matter lesions. The three patients with basal ganglia lacunes had spontaneous recovery, one with frontal lobe infarct had a non-progressive clinical course, and the patient with periventricular lesions had a progressive course. Four other patients with periventricular lesions had a progressive course. However, it is usually very difcult to distinguish between onset patterns that are acute or insidious. Overall, the majority of patients with VP present with insidious onset of bilateral symptoms and have a progressive course or less commonly stepwise worsening of their symptoms. Even patients with unilateral onset of disease generally progress to have bilateral features and become clinically indistinguishable from those with insidious onset of bilateral symptoms. This happens because the DWML become superimposed on the lacunar state. Rarely, patients with strictly unilateral parkinsonism due to well dened stroke may show spontaneous recovery.12 this advanced stage and render the patient unable to walk or even stand without support. Another factor contributing to the impaired mobility in advanced stages is truncal ataxia. These patients also have truncal and axial immobility. Sideways turning of the head is limited and patients turn their head, neck and shoulder en bloc to look sideways. The change of posture while lying in bed is also difcult and limited. An interesting feature in obvious PIGD, at least in the earlier stages, is that many patients can perform simple tasks with their legs, like imitating bicycling or walking movements, when seated or lying. However, these movements are also slow. The gait in VP resembles the gait in obstructive or communicating hydrocephalous including normal pressure hydrocephalous, frontal lobe infarcts, and frontal lobe tumours such as meningiomas and gliomas.4 31 The similarity of gait disturbance in these diseases occurs because of lamination dependent involvement of white matter bres in the frontal lobe. The bres concerning gait are involved to a greater extent because of being periventricular (deeper) in location. These bres are the basal ganglia-thalamic bres destined for the supplementary motor area and the bres originating from the cerebellum and destined for the leg area of the motor cortex.4 Abnormalities of the basal ganglia-thalamic-cortical loop have even been shown to explain gait disturbances in subjects with age related white matter changes.32 The relative sparing of the bres to the hand areas because of their more supercial location would explain the lesser involvement of upper limbs in VP.4

Upper limbs
The upper limbs in VP are less symptomatic in terms of parkinsonism throughout the disease course as compared to PIGD. This is in clinical contrast to PD, in which patients generally present with tremor, stiffness (rigidity) or slowness of the upper limbs. Thus VP is also called lower body or lower half parkinsonism.7 The Unied Parkinsons Disease Rating Scale (UPDRS) III scores are lower for upper limbs compared to lower limbs in VP. In VP, the upper limbs are bradykinetic but less than the lower limbs and less than in PD. Tremor is signicantly less common in VP than in PD. The classic 4e5 Hz pill-rolling type resting tremor of the hand and ngers, characteristic of PD, is typically absent in VP.14 Postural tremor is more common in VP or a non-rolling type of resting tremor may be observed. As the initial symptom, tremor was observed in only one of the 24 (4%) VP patients versus 14 of the 30 patients (47%) PD patients.20 In yet another series, rest tremor was present in only four of the 16 patients with VP but in 37 of the 50 patients with PD.15 A postural tremor was present in nine patients with VP and in 10 patients with PD.

Postural instability and gait difculty


The clinical hallmark of VP phenotype is early postural instability and gait difculty (PIGD). PIGD as the initial symptom is signicantly more common in VP than in PD. Gait disturbance was reported as the initial symptom in 90% of patients with VP as compared to 7% of patients with PD.7 The gait in VP is a parkinsonian-ataxic gait.4 31 The stance is wide based. The posture is upright at least in the earlier stages and a much lesser degree of exion is seen at the knees and hips than in PD. Steps are slow, short, with a tendency to shufe, particularly at the start (start hesitation) and while turning corners. Freezing of gait can be seen in VP, but festination (tendency to hasten) is absent.2 The arm swing is generally reduced but occasionally it is exaggerated. The gait in VP also has an element of ataxia with variable length of steps. In severe cases the patient is unable to initiate a step and the feet remained xed to the oor, the socalled magnetic foot response or magnetic gait. Attempts to take a step require support of nearby objects or persons with occasional excessive upper body movements. After the initiation of gait, shufing becomes even more pronounced. Postural instability and falls dominate the gait at
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Cranial nerves
The above symptoms in VP are intermixed with variable presence of dysphagia and dysarthria (pseudobulbar palsy).

Upper motor neuron signs


The parkinsonian features in VP have an undertone of upper motor neuron (UMN) or pyramidal signs. These manifest as spasticity, extensor plantar(s), brisk deep tendon reexes, and hemiparesis. In a clinicopathological study, 38% of the VP patients had hemiparesis and 63% had pyramidal tract signs. No hemiparesis or pyramidal tract signs were observed in patients with PD.20

Muscle tone in VP
The characters of hypertonia in VP can vary. Hypertonia can be most closely classied as rigidity although some patients may
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manifest spasticity. The rigidity is greater in the limbs than in the trunk, in the lower extremities than in the upper, and in the proximal parts of the limbs than in the distal.2 Cogwheeling, however, is quite rare in VP. with VP scored #23.8 on the Mini-Mental State Examination (MMSE) compared to 12% of patients with PD. The facial expression in VP is masked but not expressionless.2 The facial expression changes upon appropriate stimuli. In the early stages there is no delay in the initiation of the facial movement. In the later stages, due to involuntary emotional expression disorder (IEED; involuntary laughter or crying), there may be exaggerated or inappropriate facial expression (gure 1). Figure 1 exemplies the clinical and radiological features of a patient with VP who is under the authors follow up.

Non-motor symptoms
Apart from the motor symptoms detailed above, patients with VP also have non-motor symptoms (NMS). In the PRIAMO study (Parkinson disease NMS), NMS were evaluated in 83 VP patients.33 The three most commonly reported NMS were fatigue, psychiatric symptoms, and attention/memory impairment. Sleep disturbances, urinary and gastrointestinal symptoms and pain, in order, were the next most commonly reported NMS in more than half the patients. Urinary symptoms in VP include urgency, frequency, nocturia, and incontinence in the later stages.

BRAIN IMAGING MODALITIES IN VP


Imaging of the brain serves two purposes in a patient with VP. First, it rules out other causes of the parkinsonism, both degenerative (progressive supranuclear palsy) and secondary (tumours, hydrocephalous). Secondly, it should show the ischaemic lesions to support the clinical diagnosis. With respect to the imaging modality, the expected vascular lesions in VP are shown more clearly and in greater numbers in brain MRI than with CT. MRI/CT is supportive, but not conclusive, of the diagnosis of VP because there are no characteristic features of VP in CT/MRI. As shown in table 1, patients with VP show a greater number of infarcts and DWML as compared to both PD and age matched individuals. DWML can also be seen in non-parkinsonian patients with stroke, Alzheimer s disease34 35 and in dementia-free populations with a history of smoking, cardiovascular disease, hypertension or ageing.36

Cognition and other neuropsychiatric features in VP


Unlike in PD, cognitive decline can be present in VP at presentation or develops early in the disease course. The dementia in VP is subcortical, manifesting as a dysexecutive syndrome with impairment of attention, planning, judgement, goal directed behaviour, abstract thinking, verbal uency, and in the later stages apathy. Cortical functions are generally preserved unless coexisting cortical infarcts are there. The reduced attention span is primarily responsible for the memory impairment seen in VP. In the PRIAMO study, attention and memory impairment was reported by 73.5% of patients with VP after a mean disease duration of 4.463.4 years.32 In the same study, 29% of patients

Figure 1 Serial images of a patient with vascular parkinsonism. FLAIR axial (AeC) and T2 axial (D) MRI at the rst presentation with 4 year history of parkinsonian gait, 3 year history of falls and 2 year history of cognitive decline show conuent white matter hyperintensities in bilateral corona radiata (A); periventricular hyperintensities concentrated around the frontal and occipital horns of the lateral ventricles (B, C); gliosis of the left posterior putamen (C, white arrow); old infarct in the left cerebellar hemisphere (D, black arrow); non contrast CT head section (E) done before MRI also shows bilateral white matter hypodensities, most prominent in the periventricular regions but not as clearly as in MRI. Images FeH show new subcortical and brainstem infarcts on three successive occasions after the baseline evaluation and corresponding to the three episodes of acute deterioration in the patients gait and postural instability. (F) Diffusion weighted MRI sequence showing an acute infarct in the right corona radiata (black arrowhead); (G) non contrast CT head showing a left pontine infarct (black arrow) (H) non contrast CT head showing a left thalamic infarct (white arrow).
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Table 1 Brain imaging studies comparing the frequency and nature of ischaemic lesions in vascular parkinsonism, Parkinsons disease, and normal controls
Study and imaging used Paccini et al18 MRI Demirkiran et al15 MRI Subject groups compared and numbers (n) 102 patients with PD, 68 healthy controls 16 patients with VP, 50 patients with PD Normal versus abnormal scans PVH occurred in 37.2% of patients with PD and in 20.6% of controls In the VP group 100% of scans showed ischaemic lesions in the subcortical WM, BG or brainstem while in the PD group 70% of scans were normal 95.7% of patients with VP showed ischaemic lesions versus 22.3% of PD patients 100% of scans in the VP group were abnormal while 93% of PD patients had normal scans Abnormalities (by location) and major conclusions PVH more extensive in patients with PD PD patients with PVH had more severe disease and more PIGD Ischaemic lesions were bilateral in 87.5% of the patients with VP. In PD 60% were bilateral BG lesions in 37.5% of VP patients and in 8% of PD patients In VP the vascular disease was more common in multiple vascular territories, subcortical WM and BG WM lesions in 7% of PD patients and 88% of VP patients BG lesions in 7% of PD patients and 38% of VP patients

Winikates and Jankovic17 CT and MRI Rampello et al16 MRI

69 patients with VP, 175 patients with PD 32 patients with PD, 45 patients with VP

BG, basal ganglia; PD, Parkinsons disease; PIGD, postural instability and gait difculty; PVH, periventricular hyperintensities; VP, vascular parkinsonism; WM, white matter.

Dopamine transporter single photon emission CT scan: DATSPECT involves imaging the DATs located at the plasma membrane of presynaptic striatal dopaminergic terminals. DAT imaging can therefore assist in the differentiation of parkinsonism with and without presynaptic dopaminergic decit.37 38 DAT-SPECT is w100% sensitive in detecting presynaptic dopaminergic decit in PD.38 Two radiopharmaceuticals are available for DAT-SPECT: [123I]b-CIT and [123I]FP-CIT. Compared to controls, VP patients show a reduction of tracer uptake in the putamen.39 This is reected in the caudate/putamen radioactivity ratios which are signicantly higher in VP than in normal controls. DAT-SPECT based differentiation of VP and PD is based on the principle that PD is an asymmetric disease with asymmetry of degeneration of nigrostriatal dopaminergic projections to the motor striatum. VP, on the other hand, is a diffuse disease in the majority patients. The mean asymmetry index that compares right to left striatal radioisotope binding in most patients with VP therefore is normal and lower than in PD.40 The variation in this prototype nding is that some VP patients with an acute stroke or unilateral disease may show asymmetry in striatal tracer uptake.39 Due to this overlap and the w100% sensitivity of DAT-SPECT in detecting PD, PD can essentially be excluded if DAT-SPECT is normal.38 Transcranial colour coded sonography (TCCS) has been shown to differentiate PD from VP based on the presence of hyperechogenicity of SN in PD.41 TCCS has technical limitations (like absence of acoustic windows) and is a highly observer dependent technique.

bradykinetic rigid syndrome or shufing gait, within 1 year after a stroke; or (ii) an insidious onset of parkinsonism with extensive subcortical white matter lesions, bilateral symptoms at onset, and the presence of early shufing gait or early cognitive dysfunctiondthis criteria has not been validated in a larger number of patients.

DIFFERENTIAL DIAGNOSIS
1. PD: The differentiating features between PD and VP have already been dealt with in various sections of this article. 2. Frontal lobe tumours (meningiomas, gliomas), and obstructive and communicating hydrocephalous can have gait disturbances with overlapping clinical features with VP. 3. Normal pressure hydrocephalus (NPH): NPH is known by the classical clinical triad of gait and posture disturbances, cognitive decline, and urinary incontinence. These three manifestations need not be present in every case to diagnose NPH.42 43 It gets more difcult to differentiate NPH from VP because gait and posture disturbances are the most commonly reported symptoms in both NPH and VP, and the pattern of gait is also very similar in both disorders. The gait in NPH also resembles the frontal lobe gait with wide base, slow and short steps, shufing, and magnetic foot response.43 Freezing can be seen in up to 30% of NPH cases.44 The posture in NPH is upright or can be leaning forward mildly. Dementia and incontinence, on the other hand, are also part of the clinical spectrum of VP. However, there are a few subtle differences in the gait of these two disorders and there are some other signs which can help in differentiating them: the arm swing may be relatively preserved in NPH, the foot to oor clearance is notably reduced in NPH, and external cues are not helpful in improving gait in NPH. Bradykinesia affecting the upper extremities and parkinsonism have also been reported in NPH, the latter with a much lower frequency compared to VP. There are no pyramidal signs in NPH until or unless a stroke has occurred, unlike in VP where pyramidal signs go hand in hand with parkinsonism to complete the clinical picture. MRI of the brain is decisive. 4. Progressive supranuclear palsy (PSP): PSP is an atypical parkinsonian disorder where the hallmark signs are vertical supranuclear ophthalmoparesis (either moderate to severe upward or any downward gaze abnormalities), and prominent postural instability with falls (or tendency to falls) in the rst year of symptom onset.45 PSP patients who have not yet developed vertical gaze palsy but have falls or postural
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DIAGNOSTIC CRITERIA
Zijlmans et al proposed the rst clinical criterion for the diagnosis of VP based on clinicopathological evidence.1 The components of this criterion for the diagnosis of probable VP are: (1) parkinsonism: dened as bradykinesia and at least one of followingdrest tremor, muscular rigidity, or postural instability; (2) cerebrovascular disease, dened by evidence of relevant cerebrovascular disease by brain imaging (CT or MRI) or the presence of focal signs or symptoms that are consistent with stroke; (3) a relationship between the parkinsonism and cerebrovascular disease ascertained as: (i) an acute or delayed progressive onset with infarcts in or near areas that can increase the basal ganglia motor output (external segment of globus pallidus or SN pars compacta) or decrease the thalamocortical drive directly (VL nucleus of the thalamus, large frontal lobe infarct)dthe parkinsonism consists of a contralateral
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instability can be difcult to differentiate from VP as such patients can still be labelled as clinically probable PSP .45 Apart from early prominent PIGD, clinical features such as early cognitive decline, early pseudobulbar palsy (dysphagia and dysarthria), involuntary emotional expression disorder, symmetric parkinsonism, and pyramidal signs in PSP can create a clinical resemblance between VP and PSP. The clinical features which distinguish VP from PSP are as follows: supranuclear downgaze palsy is not a feature in VP; cranio-cervical dystonias occur in PSP (retrocollis, blepharospasm, eyelid opening apraxia, oromandibular); axial appendicular rigidity occurs in PSP; and there is a characteristic midbrain atrophy on MRI in PSP. Box 1 suggests a diagnostic algorithm for VP.

TREATMENT
The only accepted treatment for VP is levodopa. The levodopa response rates in VP vary from 20e40%.46 For all practical purposes the response to levodopa in VP will not be as encouraging as in PD, and some patients may not respond at all. However, a trial of levodopa should be given in all patients. A dose of up to 1000 mg/day should be given for at least 3 months before labelling the patient as a non-responder or poor responder. In good responders the duration of sustained response is typically less than in PD, with the drug becoming non-benecial after 1e2 years. The above response pattern occurs in VP because of the location of lesions in VP; the nigral neurons are preserved and the striatal cells or the basal ganglia circuitry are damaged in the majority, or the basal ganglia become de-efferented from the thalamocortical pathways. This is unlike in PD where the site of synthesis of dopamine, SN, is abnormal while the striatum and other parts of the basal ganglia are structurally intact. Within VP, patients with lesions (infarcts) in or near nigrostriatal pathway have a higher chance of responding to levodopa than those who have a greater white matter disease; this is because in the former the exogenously supplied dopamine can be taken up by the remaining nigral or striatal neurons and converted to dopamine to restore the dopaminergic drive to some extent in the remaining structurally intact basal gangliacortical circuitry.47 In those with a greater white matter disease, the basal ganglia are more effectively differented from the cortex. Patients with lesions in or near the basal ganglia may show a poor uptake of ligand in [123I]FP-CIT DAT-SPECT, and thus DAT-SPECT may guide the treatment in VP.40 Since ischaemic cerebrovascular disease has an aetiological role in VP, treatment should also be directed at secondary stroke prevention in an attempt to halt further disease progression, although understandably it would not reverse or give symptomatic relief to the existing clinical manifestations.48 Given the greater evidence for extensive small vessel disease in VP, management of conventional vascular risk factors such as diabetes, hypertension, dyslipidaemia, and smoking cessation would probably have the maximal impact in this approach to treatment. Although there is no evidence based data concerning the benet and use of antiplatelet agents in VP, particularly in patients who do not have a history of strokes, the use of aspirin, clopidogrel or aspirin/dipyridamole seems reasonable if the MRI shows extensive white matter disease or multiple lacunar infarcts.

Box 1 Suggested diagnostic algorithm for vascular parkinsonism Step I: Look for red ags in the clinical diagnosis of vascular parkinsonism (VP) < Early onset or presentation with postural instability and falls < Lesser symptoms in the upper limbs. UPDRS III scores are lower for upper limbs as compared to lower limbs < Absence of classic 4e5 Hz pill-rolling resting tremor of the hand and ngers < Presence of upper motor neuron signs as spasticity, extensor plantar(s), and hemiparesis < Lead pipe rigidity more appreciable than cogwheeling on examination < Early or prominent dysphagia, dysarthria or involuntary laughter or crying < Early onset of subcortical dementia < No downgaze palsy Step II: Obtain an MRI of the brain
< Look for features suggestive of VP (ischaemic lesions):

Diffuse supratentorial white matter hyperintensities on T2/ FLAIR sequences Multiple subcortical infarcts and lacunes in the deep grey matter nuclei Generalised atrophy with proportionate dilatation of the ventricles < Rule out hydrocephalous: Periventricular cerebrospinal uid ooze Ventricular dilatation out of proportion to cerebral atrophy (may be suggestive of normal pressure hydrocephalous) Obstructive hydrocephalous < Rule out frontal mass lesion < Rule out progressive supranuclear palsy: Midbrain atrophy Generally MRI (step II) would be able to support a clinical diagnosis of VP (step I). If clinical signs are not convincing, then to rule out the possibility of PD with white matter disease and/or subcortical infarcts, step III (DAT-SPECT imaging) should be taken.

Main messages
< Main differential diagnosis of vascular parkinsonism (VP) is

Parkinsons disease (PD).


< A patient with PD and ischaemic lesions on MRI is more

<

< <

Step III: DAT-SPECT imaging < Features suggestive of VP rather than Parkinsons disease: Symmetric reduction of striatal tracer uptake (normal or low mean asymmetry index) Strictly unilateral reduction of striatal tracer uptake Normal scan

<

commonly encountered in daily practice than a patient with VP. VP rather than PD should be suspected in a patient presenting with parkinsonian gait, postural instability and falls without many symptoms or rest tremor in the upper limbs. DAT-SPECT imaging may play a role in differentiating VP from PD when the red ags for VP are not apparent or convincing. Before labelling a patient with VP as a levodopa nonresponder, always try levodopa in an adequate dosage (at least up to 1000 mg/day) and for an adequate duration (at least for 3 months). The pathogenesis of VP is presently unclear.

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B. Falls are common C. Festination occurs in nearly 50% of the patients D. The gait has features of both parkinsonian gait and ataxic gait

Current research questions


< What is the magnitude of ischaemic lesions needed to cause

vascular parkinsonism? < Apart from the anatomic lesions, is any receptor dysfunction also present in vascular parkinsonism at the presynaptic or post-synaptic level? < Do antiplatelets and statins have a role in preventing the disease progression in vascular parkinsonism? < Pathological validation of the existing clinical criteria is required in a larger number of patients.

3. Which of the following statements about the pathogenesis of vascular parkinsonism is true?
A. There is an imprecise relation between the location and severity of cerebrovascular disease and development of vascular parkinsonism in a patient B. Lacunar infarcts of the basal ganglia always lead to contralateral parkinsonism C. Substantia nigra infarcts are the essential pathological correlate in vascular parkinsonism D. Vascular parkinsonism always has a clear temporal relation to the occurrence of cerebral infarcts

Key references
< Critchley <

<

< <

M. Arteriosclerotic parkinsonism. Brain 1929;52:23e83. Thompson PD, Marsden CD. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswangers disease. Mov Disord 1987;2:1e8. Zijlmans JC, Daniel SE, Hughes AJ, et al. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 2004;19:630e40. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol 2007;64:20e4. Thompson PD. Gait disorders. In: Bradley WG, Daroff RB, Fenichel GM, et al, eds. Neurology in clinical practice. 5th edn. Philadelphia, PA: Butterworth-Heinemann, 2008: 327e38.

4. Which of the following statements regarding the clinical features of vascular parkinsonism is false?
A. Non-motor symptoms are not part of the clinical spectrum of vascular parkinsonism B. The disease most commonly has an insidious onset C. Pseudobulbar features can occur in some patients D. Upper motor neurons are a frequent occurrence in vascular parkinsonism

5. Which of the following statements regarding atypical parkinsonian disorders is false?


A. B. C. D. Early onset of postural instability and gait disturbance Non-sustained response to levodopa Early onset of dementia may be a feature Excellent and sustained response to levodopa

Competing interests None.

Dopamine agonists should not be the rst line drugs in patients with VP because advanced age and cognitive and psychiatric issues in VP makes these patients more susceptible to their side effects. Deep brain stimulation is not an option for VP.

Contributors DG and AK were responsible for reviewing the literature, and writing and revising the manuscript. DG is the guarantor of the article. Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Zijlmans JC, Daniel SE, Hughes AJ, et al. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 2004;19:630e40. Critchley M. Arteriosclerotic parkinsonism. Brain 1929;52:23e83. Critchley M. Arteriosclerotic pseudo-parkinsonism. In: Rose FC, Capildeo R, eds. Research Progress in Parkinsons Disease. London, England: Pitman Books Ltd, 1981:40e2. Thompson PD, Marsden CD. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswangers disease. Mov Disord 1987;2:1e8. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44:21e3. OSullivan M. Leukoaraiosis. Pract Neurol 2008;8:26e38. FitzGerald PM, Jankovic J. Lower body parkinsonism: evidence for vascular etiology. Mov Disord 1989;4:249e60. de Lau LM, Giesbergen PC, de Rijk MC, et al. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 2004;63:1240e4. n J, Bermejo-Pareja F, Rodr guez J, et al. Prevalence of PD and other Benito-Leo types of parkinsonism in three elderly populations of central Spain. Mov Disord 2003;18:267e74. de Rijk MC, Tzourio C, Breteler MM, et al. Prevalence of parkinsonism and Parkinsons disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinsons disease. J Neurol Neurosurg Psychiatry 1997;62:10e15. Munhoz RP, Werneck LC, Teive HA. The differential diagnoses of parkinsonism: ndings from a cohort of 1528 patients and a 10 years comparison in tertiary movement disorders clinics. Clin Neurol Neurosurg 2010;112:431e5. Chang CM, Yu YL, Ng HK, et al. Vascular pseudoparkinsonism. Acta Neurol Scand 1992;86:588e92. Zijlmans JC, Thijssen HO, Vogels OJ, et al. MRI in patients with suspected vascular parkinsonism. Neurology 1995;45:2183e8. van Zagten M, Lodder J, Kessels F. Gait disorder and parkinsonian signs in patients with stroke related to small deep infarcts and white matter lesions. Mov Disord 1998;13:89e95.

CONCLUSIONS
VP does not have pathognomic radiological and pathological features and the diagnosis relies heavily on clinical features and demonstration of DWML and subcortical infarcts on MRI. Treatment options are limited to levodopa, the response to which is generally poor or non-sustained, and optimal management of conventional vascular risk factors such as diabetes, hypertension, dyslipidaemia, and smoking cessation. Despite our improved understanding of the radiological and pathological features of the disease over the last two decades, pathognomic radiological and pathological features of the disease are still not known.

SELF ASSESSMENT QUESTIONS (ANSWERS AFTER THE REFERENCES) 1. Which of the following statements regarding vascular parkinsonism is false?
A. B. C. D. It has its onset most commonly in the fth decade It is a secondary parkinsonism It presents clinically as atypical parkinsonism Some patients can have postural tremor

11. 12. 13. 14.

2. Which of the following statements regarding the gait in vascular parkinsonism is false?
A. Gait disturbances are a prominent and early feature in vascular parkinsonism
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Prevalence and risk factors of silent cerebral infarction in apparently normal adults. Hypertension 2000;36:73e7. Uehara T, Tabuchi M, Mori E. Risk factors for silent cerebral infarcts in subcortical white matter and basal ganglia. Stroke 1999;30:378e82. Peralta C, Werner P, Holl B, et al. Parkinsonism following striatal infarcts: incidence in a prospective stroke unit cohort. J Neural Transm 2004;111:1473e83. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol 2007;64:20e4. Hughes AJ, Daniel SE, Ben-Shlomo Y, et al. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125:861e70. Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinsons disease. J Neurol Neurosurg Psychiatry 1988;51:745e52. Forno LS. Reaction of the substantia nigra to massive basal ganglia infarction. Acta Neuropathol 1983;62:96e102. Jellinger KA. Prevalence of cerebrovascular lesions in Parkinsons disease. A postmortem study. Acta Neuropathol 2003;105:415e19. Jankovic J. Parkinsons disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368e76. Schrag A, Ben-Shlomo Y, Brown R, et al. Young-onset Parkinsons disease revisitedclinical features, natural history, and mortality. Mov Disord 1998;13:885e94. Thompson PD. Gait disorders. In: Bradley WG, Daroff RB, Fenichel GM, et al, eds. Neurology in Clinical Practice. 5th edn. Philadelphia, PA: Butterworth-Heinemann, 2008:327e38. Iseki K, Hanakawa T, Hashikawa K, et al. Gait disturbance associated with white matter changes: a gait analysis and blood ow study. Neuroimage 2010;49:1659e66. Colosimo C, Morgante L, Antonini A, et al. Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study. J Neurol 2010;257:5e14. Rosano C, Aizenstein HJ, Wu M, et al. 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[123I] FP-CIT SPECT study of vascular parkinsonism and Parkinsons disease. Mov Disord 2007;22:1278e85. Tsai CF, Wu RM, Huang YW, et al. Transcranial color-coded sonography helps differentiation between idiopathic Parkinsons disease and vascular parkinsonism. J Neurol 2007;254:501e7. Relkin N, Marmarou A, Klinge P, et al. Diagnosing idiopathic normal-pressure hydrocephalous. Neurosurgery 2005;57(3 Suppl):S4e16. Tsakanikas D, Relkin N. Normal pressure hydrocephalus. Semin Neurol 2007;27:58e65. Stolze H, Kuhtz-Buschbeck JP, Dru cke H. Comparative analysis of the gait disorder of normal pressure hydrocephalus and Parkinsons disease. J Neurol Neurosurg Psychiatry 2001;70:289e97. Litvan I. Progressive supranuclear palsy. In: Litvan I, ed. Atypical Parkinsonian Disorders: Clinical and Research Aspects. Totowa, NJ: Humana Press, 2005:287e308. Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord 2007;22:2141e8. 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ANSWERS
1. 2. 3. 4. 5. A C A A D

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Vascular parkinsonism: what makes it different?


Deepak Gupta and Abraham Kuruvilla Postgrad Med J 2011 87: 829-836

doi: 10.1136/postgradmedj-2011-130051

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