General Discussion

Parkinsonism is a distinct clinical syndrome defined by the United Kingdom Parkinsons Disease Brain Bank criteria [1-3] . The diagnosis of the presence of individual symptoms and of a complete parkinsonian syndrome is primarily made on clinical grounds. Bradykinesia has to be present in combination with tremor and/or rigidity and/or postural instability. Causes of the parkinsonian syndrome are numerous. The most frequent one is idiopathic Parkinsons disease. In an autopsy series of 700 patients with parkinsonism, 80.7 % had pathological anatomical findings compatible with idiopathic Parkinsons disease [4].
There is sufficient evidence in the literature to regard cerebovascular disease as an established cause of parkinsonism and parkinsonian symptoms: since Critchleys first description [5] of vascular parkinsonism (VP), this clinical concept has gained widespread acceptance. Most authors now agree on VP as a parkinsonian syndrome dominated by postural instability with shuffling gait and absence of tremor [6-15], occurring in 3-5% of patients with parkinsonism [16,17]. Affected patients have vascular risk factors, often hypertension, and/or suffered one or more strokes, usually of the lacunar type [6, 9-14, 16-19].
Cerebrovascular abnormalities reported as a cause of parkinsonism and parkinsonian symptoms can be divided into three groups: lacunar infarcts in basal ganglia and thalamus, lesions of suspected vascular origin in cerebral white matter (white matter lesions or leukoaraiosis [14,20]) and infarcts in the frontal brain region. Lacunar infarcts in strategic regions involving the extrapyramidal system can give rise to an acute parkinsonian syndrome clinically indistinguishable from idiopathic Parkinsons disease: locations include mesencephalon [21], substantia nigra [22], the striatum [23], basal ganglia [6,14,20,24,25].
In case of white matter lesions, patients suffer an insidious onset, where the relation of timing, location, and size of the lesions with the clinical syndrome is poorly understood [11, 17-19, 26]; clinically the gait disturbance predominates, resulting in lower body parkinsonism. Frontal brain infarction causing parkinsonian signs is only seldomly reported, and is also primarily related to disturbances of leg motor function [27-29]. Taken together, the exact spatial and temporal relation between the ischemic lesions in vascular parkinsonism remains unclear. To tackle this issue we decided to assses parkinsonian symptoms in a cohort of first-ever stroke patients.
In the previous chapters, we reported our findings in patients with parkinsonian symptoms after stroke. Already in the first two weeks after stroke, 4 % of patients developed a complete parkinsonian syndrome. This incidence concurs with previously mentioned reports on incidence of vascular parkinsonism [16]. We also found a relationship between these symptoms and white matter lesions (Chapter 1), as well as with asymptomatic infarcts in the supply area of the anterior choroidal artery (Chapter 3). Moreover, HMPAO SPECT showed abnormalities in perfusion of frontal brain regions in VP patients (Chapter 5).
The finding that parkinsonian symptoms relate to the presence of white matter lesions is of special interest. Already since the introduction of the terms subcortical arteriosclerotic encephalopathy or Binswangers disease [30] and, later on, leukoaraiosis and white matter lesions [12,31], debate has been raging wether or not this radiological finding must be considered as a separate disease entity [32]. Although white matter lesions are seen in normal healthy persons, the strong association we and others found between these lesions and VP, suggests that these are not solely a radiological phenomenon, but must be considered as a separate disease entity.
The exact mechanism that causes parkinsonian symptoms after stroke is still unknown. Based on what we and others have found, we can offer the following speculations. Several of the deep nuclei of the brain are involved in the regulation of automatic movements: substantia nigra, thalamus, globus pallidus, nucleus caudatus and subthalamic nucleus. All these nuclei are connected through white matter tracts and influence each other excitatorily or inhibitorily by means of different neurotransmitters. In the past, this system of connected nuclei was called the extrapyramidal system to discern it from the pyramidal system involved in voluntary movement control (figure 1 a-e General Introduction). Currently, it is thought that the circuitry connecting nuclei involved in automatic movement is more complex and primarily organized in parallel circuits [33]. Nevertheless, it is clear that both in the older concept of basal ganglia pathways and in the concept of parallel basal ganglia circuits, connecting white matter tracts are equally important as the nuclei themselves. So, lesions anywhere along connecting tracts and in the nuclei can disrupt the system and henceforth cause disturbances in automatic movement with parkinsonian symptoms.
Cerebrovascular disease (ischemia, haemorrhage and leukoaraiosis) can cause such lesions, involving the basal ganglia frontal cortex projections [12,25, 34-37]. This accords with the association we found with leukoaraiosis in VP patients , and more specifically with ischemia in the supply area of the anterior choroidal artery [38]. Leukoaraiosis can interfere with output from the thalamus to the motor cortex, mainly supplementary motor area, thus reducing thalamocortical drive [39].
The anterior choroidal artery arises from the internal carotid artery. It supplies the choroid plexus in the inferior horn of the lateral ventricle, but also provides perforators penetrating the anterior perforating substance to reach the internal capsule and occasionally thalamus, lateral geniculate body, cerebral peduncle and optic tract [40]. Of the internal capsule, mainly the genu and posterior limb are supplied by the anterior choroidal artery. These parts contain corticobulbar and corticospinal tracts as well as corticostriate fibers (posterior limb) but also thalamocortical fibers (genu). Ischemic lesions in the supply area of the anterior choroidal artery may thus influence cortical input to basal ganglia, but also output from thalamus to motor cortex.
As mentioned above, other studies relate parkinsonian symptoms to lacunar infarcts in external segment of globus pallidus, ventrolateral nucleus of the thalamus and substantia nigra resulting in reduced thalamocortical drive [18,39]. Frontal brain infarction is primarily related to disturbances of leg motor function as a result of involvement of leg motor area in the supply area of the anterior cerebral artery [27,29].
Apart from direct disruption of connecting pathways or lesions in nuclei as described above, cerebrovascular disease may damage the extrapyramidal system through more remote mechanisms. Following stroke, secondary degenerative changes in the ipsilateral substantia nigra are seen as a result of excessive excitatory influences caused by loss of inhibitoy GABA input (transneuronal degeneration) [23]. Other studies report loss of mainly D1 receptors or less expression of subunits of acetylcholine receptors in the case of ischemia-induced hypoxia or excitotoxicity [41,42]. Ischemia can down-regulate parkin protein with increased sensitivity of dopaminergic neurons to endoplasmatic reticulum dysfunction and cell injury as a consequence [43]. Another link between parkinsonism and ischemia is provided by research on adenosine A2A receptors: antagonists of these may relieve parkinsonian symptoms and protect against cerebral ischemia [44], and are perhaps interesting therapeutic agents in VP.
Chapter 4 describes our IBZM and FP-CIT SPECT data on VP patients. Normal findings in both investigations suggest that neither dopamine deficiency nor loss of dopamine receptors play a key role in pathophysiology of parkinsonian symptoms after stroke. This finding does not concur with other studies demonstrating loss of dopamine receptors as a result of ischemia. It theoretically contradicts the reported levodopa effects in VP patients [45], but it is also possible that FP-CIT SPECT is not a reliable predictor of clinical levodopa responsiveness [46]. Considering data from our study, but also from the literature, it is therefore justified in case of a clinical diagnosis of vascular parkinsonism to start a therapeutic trial with dopaminergic medication for a certain time period.
Finally, while speculating on the possible mechanisms underlying VP, one should not forget the burden to the patient: outcome after stroke is influenced by many factors: severity of neurological deficit, advanced age, cause of stroke, history of prior stroke and presence of concomitant disease as diabetes mellitus, cardiovascular disease, pulmonary disease and dementia [47]. In chapter 2 we found, in our cohort of 101 first-ever stroke patients, that the presence of parkinsonian symptoms in the acute phase after stroke negatively impacts prognosis, together with older age.

Concluding remarks.
Data presented in this thesis point out that parkinsonian symptoms are part of the extensive complex of symptoms that can result from acute stroke and negatively impact prognosis after 6 months. Lesions in connecting frontal white matter tracts are important in the pathophysiology of vascular parkinsonism, more than dopamine depletion or loss of dopamine receptors. The exact manner in which these lesions influence cerebral systems concerned with automatic movements is only in part known and has to be studied further. In particular, to further clarify the spatiotemporal relationship between the vascular lesion and the ensuing parkinsonism, a long-term cohort study on patients with cerebral small vessel disease must be undertaken.



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Chapter 6

Stroke and idiopathic Parkinsons disease: does a shortage of dopamine offer protection against stroke ?


Arthur Korten MD; Jan Lodder MD, PhD; Fred Vreeling MD, PhD; Anita Boreas MD, PhD; Lisette van Raak MD, PhD; Fons Kessels MD, MSc.


Movement Disorders 2001(16);119-123.



Abstract.

Background.
Data on the relationship between idiopathic Parkinson’s disease (IPD) and stroke are conflicting. In this study, we examined the frequency of IPD in stroke patients registered in the Maastricht Stroke Registry.
Methods and results.
With three different search strategies, we found among a total of 1516 stroke patients eight individuals with IPD. Based on IPD prevalence figures from a Dutch population-based study, we suspected to find approximately 30 IPD patients (relative risk 0.27; 95 % confidence interval 0.11 – 0.53).
Conclusions.
We speculate that dopamine deficiency may protect against ischemic brain damage, perhaps by reducing effects of excitotoxicity.



Introduction.

Data on the relationship between idiopathic Parkinson’s Disease (IPD) and stroke are conflicting. Stroke related mortality in IPD patients is 1,5 and 3,6 times higher in studies of Gorell et al. and Ben-Shlomo [1,2]. Iwasaki et al. found no difference in stroke related mortality between IPD patients and the general population [3].
Incidence of cerebrovascular disease as comobidity in IPD is increased to 27 % in one study [4] compared to controls, whereas in another study it is decreased [5].
Experimental data indicate that under ischemical conditions dopamine may act as a neurotoxic agent [6]. From these data one may hypothesize that shortage of dopamine may protect the brain from excitotoxic damage in case of vascular insufficiency or stroke. If so, this may imply a lower risk of stroke or less severe stroke in IPD patients. To verify or reject this idea would require a long term follow-up in a large number of IPD patients in comparison with controls, which would be a major and expensive endeavour. If IPD and stroke are inversely related, we would expect to find fewer IPD patients among a cohort of stroke patients than expected from population-based prevalence. In the present study, we made such comparison.



Methods.

Patients had been registered at the University Hospital of Maastricht in a prospective registry of all patients, regardless whether they were admitted to the hospital or visited the out-patient clinic, with a first-ever ischemic supratentorial stroke with symptoms lasting longer than 24 hours: the Maastricht Stroke Registry (MSR). The University Hospital is the only hospital in the Maastricht region with an adherent population of approximately 190.000 people. Routine investigations included standard blood tests, electrocardiogram, chest X-ray, CT scan of the brain, and ultra-sound carotid studies. Echocardiography, 24-hour ECG monitoring, and cerebral angiography were done in selected cases [7,8]. In the periods 1987-1992 and 1996-1998 of our registry, extensive information was available on comorbidity, previous history and medication use.
The MSR is a registration of baseline data for facilitation of further studies. Two separate studies especially provided data on medication use. As medication is not regularly stored in the database, we used the available data of these two studies, performed in two different periods since we required medication use as a screening parameter to identify IPD patients.
The completeness of data in the MSR was studied previously [9]. Incidence rates for stroke, first ever stroke and cerebral infarction were compared to data from the “Tilburg Epidemiological Study of Stroke 1978-1981” [10] and a population based study in France [11], concluding that up to 98 % of all patients was registered.
We used various ways to identify idiopathic Parkinson’s disease in our registered stroke patients. First, we screened all patients on a listed diagnosis of IPD in the stroke registry. Second, we screened the stroke data base on patients using antiparkinsonian medication. Finally, we compared the stroke data base with the data base of patients with Parkinson’s disease, to identify stroke patients with Parkinson’s disease who were not using antiparkinsonian medication and had not been recorded as such in the stroke registry.
For the purpose of this study, the following patient characteristics were listed : age at stroke, gender, year of diagnosis of IPD and of stroke, stroke symptoms, CT findings, comorbidity, vascular risk factors, Rankin score on admission and IPD symptoms.
Dutch IPD prevalence figures were available from the Rotterdam Study [12]. In this population-based cohort study, participants had been asked about a previous diagnosis of Parkinson’s disease and the use of anti parkinsonian medication. In addition, every patient had been examined neurologically for cardinal signs of parkinsonism. As the Rotterdam and Maastricht population composition are quite similar with respect to age, we assumed prevalence rates of IPD to be similar (Central Statistical Bureau, The Netherlands, 1999).

Definitions.
Lacunar stroke was defined as an acute symptomatic stroke syndrome with a CT lesion compatible with occlusion of a single perforating artery, i.e., a small, subcortical, sharply marginated hypodense lesion with a diameter smaller than 20 mm (small deep infarct), or in case of a specific lacunar syndrome (unilateral motor and/or sensory symptoms and signs that completely involve at least 2 of 3 body parts (face, arm and leg) without disturbance of consciousness or language, visual field defect or other signs of cortical dysfunction) when the CT scan showed no specific lesion.
Territorial stroke was defined (1) as an acute stroke syndrome with CT findings compatible with infarction involving the cortex, or (2) when no specific lesion was visible on CT, as clinically identified cortical syndrome consisting of unilateral motor and/or sensory symptoms and signs in combination with signs of cortical dysfunction with or without visual field defect, or as incomplete involvement of two body parts, or as isolated monoparesis, or as isolated cortical dysfunction (usually dysphasia).
White matter lesions (WML’s) were defined as focal or diffuse hypodensities in the periventricular or deep white matter, not involving the cortex, and with ill-defined margins to distinguish them from infarction [13,14,15].

Clinical diagnosis of Parkinson’s disease was made according to the UK Parkinson’s Disease Society Brain Bank (UKPDSBB) criteria. Key symptom in the diagnosis of parkinsonism is the presence of bradykinesia. Bradykinesia is defined as slowness of initiation of voluntary movements with progressive reduction in speed and amplitude of repetitive actions. Apart from bradykinesia, at least one of the following symptoms has to be present: muscular rigidity, 4-6 Herz resting tremor, or postural instability not caused by primary visual, vestibular, cerebellar or propioceptive dysfunction. For the clinical diagnosis of Parkinson’s disease UKPDSBB criteria give supportive positive criteria and exclusion criteria [16].



Results.

In the period 1987-1992, data on 816 first ever ischemic strokes had been collected and on 700 patients in the period from 1996 to 1998. Among these 1516 patients, we identified eight subjects with IPD; six were found in the combined search in our stroke database on IPD and use of antiparkinsonian medication. These 6 patients all used antiparkinsonian medication. Two patients were found after comparing our stroke data base with the IPD data base. Information on all patients is summarized in table 1. There were five men and three women. Age ranged from 57 to 83 years (median 73 years). Time between diagnosis of IPD and first ever stroke ranged from 6 months to 19 years (median 5 years). Three of the eight IPD patients were smokers. At the moment of stroke occurrence, one IPD patient was in Hoehn and Yahr stage I, two in stage II, three in III, and two in IV. On brain CT following stroke, two patients had a lacunar infarct, three had white matter lesions, two had a territorial infarct, whereas one patients had no ischemic lesion on CT. All patients used antiparkinsonian medication : levodopa (6), dopamine agonist (1), and amantadine in combination with selegeline (1). On admission, four patients of our series had a Rankin score between 0 and 3, whereas the remaining four patients had a score of 4 or 5. Among the 1516 patients in the stroke registry, 50 percent had a Rankin score on admission between 0 and 3, and 50 percent had a score of 4 or 5. Table 2 shows the frequency of IPD in different age groups of our stroke patients in comparison with the population-based Rotterdam cohort. On the basis of this study, we expected to find 30 patients in our population, whereas we found only 8 patients (relative risk 0.27; 95 % confidence interval 0.11 – 0.53).



Discussion.

To our knowledge, our study is the first on the prevalence of IPD in a prospectively registered stroke series. We observed that the prevalence of Parkinson’s disease was significantly lower in our patients than expected from general population prevalence estimates.
However, it has to be kept in mind that the number of IPD patients in our stroke series was small. Our study compares prevalence of IPD in a stroke population with that in a general population. Most other studies [1-5] were concerned with stroke related mortality and morbidity in IPD population. Therefore, it is not possible to compare these studies directly with our findings.
A low prevalence of IPD in a stroke population may be due to bias from an increased early death rate related to stroke. However, we looked for IPD diagnosis that had been made prior to a first-ever fatal or non-fatal stroke, which excludes such bias. Our findings concur with the idea that dopamine deficiency may protect against stroke. In experimental models, dopamine increases excitotoxic ischemic damage, whereas dopamine antagonists ameliorate such effect [6,17]. Whether an even small decreased stroke risk in IPD patients is due to amelioration of ischemia related excitotoxic effects, remains unclear; when we used the Rankin score as an indication of stroke severity, our eight IPD patients did not have less severe stroke than the non-IPD stroke patients. Based on our findings and experimental data , one may hypothesize that treatment with levodopa may increase the risk of stroke, stroke severity or both. Furthermore, levodopa may increase plasma homocysteïne levels and may thereby contribute to an increased stroke risk [18,19]. On the other hand, levodopa may lower blood pressure and thus decrease stroke risk [20,21].
Our findings may also relate to a differential effect of smoking. Clinical epidemiological studies suggest a protective effect on IPD occurrence by smoking [22]. There is experimental evidence that relates growth factor (fibroblast growth factor-2, and brain derived neurotrophic factor) upregulation in the striatum to nicotine stimulation [23]. Therefore, smoking may increase the risk of stroke while decreasing the risk of IPD. Any stroke risk in IPD patients could also be lower than generally expected, as fewer IPD patients smoke than those who ultimately suffer a stroke [22]. A meta-analysis showed that cigarette smoking doubled the risk of stroke [24]. Wether such increased stroke risk alone explains our findings of a four times decreased risk, is unclear. A lower stroke risk in IPD patients cannot be inferred from our findings, as this would require a large, prospective long-term follow-up study. However, our data concur with the idea that dopamine deficiency may protect against the occurrence of ischemic stroke, and against excitotoxic-ischemic brain damage.

(tables available from the author)



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24. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ 1989(298):789-794.

Chapter 5

Dopamine availability in vascular parkinsonism and idiopathic Parkinson’s disease: a comparison with [123I] FP-CIT and [123I] IBZM SPECT.


A.G.G.C. Korten MD; I.H.A. Al Younis MD; M.J.P.G. van Kroonenburgh MD,
PhD; W.E.J. Weber MD, PhD; F.W. Vreeling MD, PhD; F. Kessels MD, MSc;
J. Lodder MD, PhD.



Abstract.

Background.
Parkinsonian symptoms and the parkinsonian syndrome may have various causes with different therapeutic consequences. The diagnosis of a parkinsonian syndrome and idiopathic Parkinson’s disease is made on clinical grounds. We investigated if single photon emission computer tomography (SPECT) using different radioligands can differentiate idiopathic Parkinson’s disease from parkinsonism caused by cerebrovascular disease.
Methods.
We examined FP-CIT and IBZM SPECT findings in 5 patients with a history of stroke, predominantly a parkinsonian gait and a clinical diagnosis of vascular parkinsonism. Findings in these patients were compared to those in 5 patients with a clinical diagnosis of idiopathic Parkinson’s disease.
Results.
Median uptake ratio of FP-CIT in putamen of patients with vascular parkinsonism was 7.8 and in patients with idiopathic Parkinson’s disease (IPD) 4.2 (p<0.02). Median uptake ratio of IBZM was 3.6 in patients with vascular parkinsonism and 3.7 in patients with IPD.
Conclusions.
FP-CIT SPECT can help to differentiate vascular parkinsonism from IPD. Furthermore, our findings concur with the hypothesis that vascular parkinsonism is not caused by dopamine deficiency or degeneration of dopamine receptors in striatum. Lesions in connecting white matter tracts might be responsible.



Introduction.

Vascular parkinsonism (VP) is a clinical syndrome with predominantly parkinsonian gait disorder and less frequently tremor [1-11]. In 3 – 5 % of patients with parkinsonism, the syndrome can be attributed to vascular lesions [12,13]. Patients with VP have vascular risk factors, often hypertension, and/or suffered one or more strokes, usually of the lacunar type [2, 5-10, 12-15]. However, in clinical practice diagnosis may be difficult, as the great majority of patients with VP suffers an insidious onset, where the relation of timing, location, and size of the infarct with the clinical syndrome is unclear [7, 13-16]. As treatment strategies for VP patients are different from those for patients with idiopathic Parkinson’s disease (IPD) [7], a diagnostic test to distinguish the two would be helpful.
Recently, SPECT, to visualise dopamine availability in the striatum, has been used as such a test. Results have been conflicting: Gerschlager et al and Tzen et al, found relatively normal values compared with IPD patients [17,18], while others could not reliably discern VP from IPD [19,20]. Recently Plotkin reported both FP-CIT (123 I-FP-CIT (Iodine-123-N-w-Fluoropropyl-2b-Carbomethoxy-3b-(4-Iodophenyl)Tropane) and IBZM (123I-IBZM (Iodine-123-Iodobenzamide) SPECT abnormalities in 4 VP patients, suggesting that VP patients have abnormalities in both presymaptic and post-synaptic striatal dopamine receptors [21]. Conflicting results are partly caused by different methods to reach a clinical diagnosis of VP [2-11]. Recently, Zijlmans et al formulated rigorous clinical criteria for the diagnosis of VP [14]. Using these to select VP patients we compared FP-CIT and IBZM SPECT findings in VP patients with patients with idiopathic Parkinson’s disease.



Methods.

Patient selection.
Five patients with vascular parkinsonism clinically diagnosed according to recent criteria [14] entered the study. Patients predominantly had symptoms of the lower extremities and a parkinsonian gait: short stepping, starting and turning problems. All patients had one or more ischaemic lesions on CT or MRI scanning of the brain fitting the description of infarction or white matter lesions (leukoaraiosis) [10,22]. No patients had a previous history of IPD, multiple system atrophy, progressive supranuclear palsy or other obvious cause of parkinsonism. Motor function was assessed bilaterally using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III [23]. A higher score corresponds with more severe parkinsonian symptoms; maximum score on the UPDRS motor subscale is 56.
SPECT findings of VP patients were compared with those of 5 patients with IPD, previously examined as part of a screening protocol for surgery for IPD.

SPECT examination protocol.
Before SPECT examination, all patients were given thyroid protection agents and medication known to influence results of FP-CIT or IBZM SPECT was discontinued for a sufficiently long period. For SPECT studies of dopamine densities in the brain a dose of 185 MBq of 123I-IBZM (Amersham Cygne, Eindhoven, the Netherlands; Radionuclide purity >99.9% at time of calibration) was injected intravenously. Two hours later a SPECT study of the head was performed using a three headed gamma camera (MULTI-SPECT 3, Siemens Sonics, Hoffman Estate, Illinois, USA). Low energy high resolution collimator was used to construct the SPECT images. The three headed camera was rotated every 45 seconds for a total of 30 minutes using 128 x 128 matrix. The head of the patient was fixed using head and neck restful adjustment piece. We used an Alderson Phantom to correct and normalise the SPECT data [9]. Image reconstruction was done using a Butterworth filter with a cutoff frequency of 0.4-0.5 and order of 5. Chang’s attenuation correction of 0.12 per cm–1 was applied. On the reconstructed images, regions of interest (ROIs) were drawn semi automatically over the basal ganglia (Figures 1 a and b). The occipital cortex was used for background correction (non-specific binding). The results were shown in a form of ratio of activity over these two regions. At least two days later, 185 MBq of 123I-FP-CIT (Amersham Cygne, Eindhoven, the Netherlands: specific activity > 185 MBq/nmol, radiochemical purity of > 95%) was injected intravenously and 3 hours later SPECT study was conducted. The same software and acquisition procedure as for 123I-IBZM SPECT was used. A separation in the activity between the caudate nucleus and the putamen was then obtained semi automatically to mark the highest total activity over these regions.

Criteria used in the evaluation of the SPECT results: The normal ratio for 123I-IBZM SPECT corrected for age was 3.58 +/- 0.36 and for 123I-FP-CIT SPECT 7.76 +/-3.54 at the caudate nucleus/occipital cortex level and 8.25 +/- 3.70 for the putamen/occipital cortex ratio. These normal Alderson corrected ratios were obtained from studying twenty healthy volunteers (aged above forty years) at the Academic Medical Center of Amsterdam, the Netherlands.



Results.

From January to March 2001 five patients with vascular parkinsonism (4 males and 1 female, mean age 78, range 71 to 88, SD 6.3 years ) and five patients with IPD (4 males and 1 female, mean age 62, range 53 to 67, SD 5.3 years) were studied with 123I-IBZM SPECT and 123I-FP-CIT. Data on signs and symptoms, and additional investigations are listed in table 1. Striatum-occipital cortex activity ratio’s of FP-CIT and IBZM SPECT of patients with vascular parkinsonism and idiopathic Parkinson’s disease are listed in table 2. Table 3 provides mean ratio’s for both patient groups. Distribution of ratio’s of both groups was compared using the Mann-Whitney independent samples test. IBZM ratio striatum-occipital cortex on left and right side did not differ between patient groups (p>0.5). FP-CIT ratio caudate nucleus-occipital cortex on right side was significantly lower in patients with IPD (p<0.03). On the left side, this difference was also present, but not reaching statistical significance (p=0.076). FP-CIT ratio putamen-occipital cortex on left and right side was also significantly lower in patients with IPD (p<0.02). Figures 1 a and b show typical FP-CIT and IBZM SPECT findings in one patient with vascular parkinsonism.



Discussion.

In an effort to test the diagnostic accuracy of FP-CIT and IBZM SPECT in delineating VP from IPD, we scanned 5 VP and 5 IPD patients. FP-CIT SPECT showed a normal uptake ratio of the ligand in the striatum of VP patients, whereas in patients with IPD, the uptake ratio putamen-occipital cortex and caudate nucleus-occipital cortex was lowered compared to normal ratios (Academic Medical Center of Amsterdam) [25-27]. IBZM SPECT showed normal ligand uptake in the striatum in patients with vascular parkinsonism, as was also the case in the patients with IPD.
Our study, for the first time employing recently formulated clinical criteria for VP, accords with two previous ones suggesting that FP-CIT SPECT can delineate VP from IPD in patients with a parkinsonian syndrome and cerebrovascular disease [18,19]. This observation concurs with the idea that levodopa or dopamine agonists have no clinical effect in VP, since endogenous dopamine availability is presumably normal [28]. Lorberboym et al. did not find any correlation between FP-CIT SPECT results and levodopa responsiveness among VP patients [20]. However, eleven patients had significantly diminished binding suggesting nigrostriatal degeneration, while five of these had a good response to L-dopa. The investigators themselves suggested an underlying development of idiopathic Parkinson’s disease as a possible explanation [20]. Additionally, the dogma that VP patients do not respond to levodopa was recently challenged by Zijlmans et al who showed in a retrospective study that VP patients with lesions in the nigrostriatal pathways do respond to levodopa [29]. Taken together, these data suggest that FP-CIT SPECT may be used to discern patiens with VP from IPD, but that it does not predict a clinical levodopa response in these patients.
IBZM SPECT data in our VP patients were within normal range, pointing out that in our patients dopamine D2 receptor availability in the striatum was normal and not reduced as a result of stroke involving areas of the putamen. This contrasts to common findings in other parkinsonian syndromes, such as multiple system atrophy or Steele-Richardson-Olszewski syndrome [30,31]. IBZM SPECT may thus be of value to differentiate VP from other parkinsonism syndromes.
Combining the results of our FP-CIT and IBZM SPECT examinations in VP patients gives us new clues to the possible mechanisms causing parkinsonian symptoms after stroke. The striatal circuit projecting from caudate nucleus and putamen is the main circuit in the extrapyramidal motor system. Through the white matter of the corona radiata, these nuclei receive projections from the entire ipsilateral cerebral cortex and contralateral premotor, motor and somatosensory cortex. Caudate nucleus and putamen project to globus pallidus neurons and these, through ansa lenticularis, fasciculus lenticularis and fasciculus thalamicus, connect with the ventrolateral thalamic nucleus. From here, projections travel through the rostral part of the internal capsule back to the cerebral cortex, mainly area 6 and the supplementary motor area [32-34]. Normal findings in FP-CIT and IBZM SPECT suggest that dysfunction of this principal extrapyramidal motor circuit is not caused by loss of neurones in caudate nucleus, putamen or substantia nigra [35]. All our patients had white matter lesions on radiological examination of the brain. Possibly, lesions in white matter tracts serving projections between cerebral cortex and basal ganglia are the main cause of parkinsonian symptoms. A possible candidate area here is the frontal lobe, as we recently found that VP patients have local hyperperfusion in this location [36]. Future prospective cohort studies should be aimed at identifying critical areas in the white matter responsible for damaging the extrapyramidal system leading to vascular parkinsonism.

(figures and tables available from the author)



References.

1. Critchley M. Arteriosclerotic parkinsonism. Brain 1929; 52:23-83.

2. Chang CM, Yu YL, Ng HK, Leung SY, Fong KY. Vascular pseudoparkinsonism. Acta Neurol Scand 1992; 86(6):588-592.

3. Demirkiran M, Bozdemir H, Sarica Y. Vascular parkinsonism: a distinct, heterogeneous clinical entity. Acta Neurol Scand 2001; 104(2):63-67.

4. FitzGerald PM, Jankovic J. Lower body parkinsonism: evidence for vascular etiology. Mov Disord 1989; 4(3):249-260.

5. Jankovic J. Lower body (vascular) parkinsonism. Arch Neurol 1990; 47(7):728.

6. Peters S, Eising EG, Przuntek H, Muller T. Vascular Parkinsonism: a case report and review of the literature. J Clin Neurosci 2001; 8(3):268-271.

7. Sibon I, Fenelon G, Quinn NP, Tison F. Vascular parkinsonism. J Neurol 2004; 251(5):513-524.

8. Thompson PD, Marsden CD. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswanger's disease. Mov Disord 1987; 2(1):1-8.

9. Leong LK, O’Connor MK, Maraganore DM. Quantification of Iodine-123-b-CIT Dopamine Receptor Uptake in a Phantom Model. J of Nucl Med Tech 1999; 27:117-122.

10. Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts. Neurology 1984; 34:1516-1518.

11. 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(1):89-95.

12. Zijlmans JC, Poels PJ, Duysens J, van der Straaten J, Thien T, van't Hof MA, et al. Quantitative gait analysis in patients with vascular parkinsonism. Mov Disord 1996; 11(5):501-508.

13. Foltynie T, Barker R, Brayne C. Vascular parkinsonism: a review of the precision and frequency of the diagnosis. Neuroepidemiology 2002; 21(1):1-7.

14. Sibon I, Tison F. Vascular parkinsonism. Curr Opin Neurol 2004; 17(1):49-54.

15. Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 2004; 19(6):630-640.

16. Zijlmans JC, Thijssen HO, Vogels OJ, Kremer HP, Poels PJ, Schoonderwaldt HC, et al. MRI in patients with suspected vascular parkinsonism. Neurology 1995; 45(12):2183-2188.

17. Boon A, Lodder J, Heuts-van Raak L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke. Relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke 1994; 25(12):2384-2390.

18. Gerschlager W, Bencsits G, Pirker W, Bloem BR, Asenbaum S, Prayer D, et al. [123I]beta-CIT SPECT distinguishes vascular parkinsonism from Parkinson's disease. Mov Disord 2002; 17(3):518-523.

19. Tzen KY, Lu CS, Yen TC, Wey SP, Ting G. Differential diagnosis of Parkinson's disease and vascular parkinsonism by (99m)Tc-TRODAT-1. J Nucl Med 2001; 42(3):408-413.

20. Lorberboym M, Djaldetti R, Melamed E, Sadeh M, Lampl Y. 123I-FP-CIT SPECT imaging of dopamine transporters in patients with cerebrovascular disease and clinical diagnosis of vascular parkinsonism. J Nucl Med 2004; 45(10):1688-1693.

21. Vaamonde J, Ibanez R, Garcia AM, Poblete V. [Study of the pre and post-synaptic dopaminergic system by DaTSCAN/IBZM SPECT in the differential diagnosis of parkinsonism in 75 patients]. Neurologia 2004; 19(6):292-300.

22. Plotkin M, Amthauer H, Quill S, Marzinzik F, Klostermann F, Klaffke S, et al. Imaging of dopamine transporters and D2 receptors in vascular parkinsonism: a report of four cases. J Neural Transm 2005.

23. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987; 44:21-23.

24. Fahn S, Elton R, comittee MotUd. Unified Parkinson's disease rating scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent development in Parkinson's disease. Florham Park: McMillan Health Care Information; 1987. p. 153-163.

25. Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, et al. Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl Med 1998; 39(11):1879-1884.

26. Booij J, Hemelaar TG, Speelman JD, de Bruin K, Janssen AG, van Royen EA. One-day protocol for imaging of the nigrostriatal dopaminergic pathway in Parkinson's disease by [123I]FPCIT SPECT. J Nucl Med 1999; 40(5):753-761.

27. Booij J, Tissingh G, Winogrodzka A, Boer GJ, Stoof JC, Wolters EC, et al. Practical benefit of [123I]FP-CIT SPET in the demonstration of the dopaminergic deficit in Parkinson's disease. Eur J Nucl Med 1997; 24(1):68-71.

28. Yamanouchi H, Nagura H. Neurological signs and frontal white matter lesions in vascular parkinsonism. A clinicopathologic study. Stroke 1997; 28(5):965-969.

29. Zijlmans JC, Katzenschlager R, Daniel SE, Lees AJ. The L-dopa response in vascular parkinsonism. J Neurol Neurosurg Psychiatry 2004; 75(4):545-547.

30. Tissingh G, Booij J, Winogrodzka A, van Royen EA, Wolters EC. IBZM- and CIT-SPECT of the dopaminergic system in parkinsonism. J Neural Transm Suppl 1997; 50:31-37.

31. Schwarz J, Tatsch K, Arnold G, Ott M, Trenkwalder C, Kirsch CM, et al. 123I-iodobenzamide-SPECT in 83 patients with de novo parkinsonism. Neurology 1993; 43(12 Suppl 6):S17-20.

32. Alexander GE. Basal ganglia-thalamocortical circuits: their role in control of movements. J Clin Neurophysiol 1994; 11(4):420-431.

33. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13(7):266-271.

34. Nieuwenhuys R, Voogd J, van Huijzen C. The human central nervous system. A synopsis and atlas. Berlin: Springer Verlag; 1988.

35. Booij J, Tissingh G, Winogrodzka A, van Royen EA. Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism. Eur J Nucl Med 1999; 26(2):171-182.

36. Korten AGGC, Younis IHAA, Kroonenburgh MJPGv, Lodder J, Vreeling FW, Weber WEJ. Frontal lobe hyperperfusion in vascular parkinsonism patients. Submitted 2005.

Chapter 4

Frontal lobe hyperperfusion in vascular parkinsonism patients.


A.G.G.C. Korten MD; J. Lodder MD, PhD; I.H.A. Al Younis MD; M.J.P.G. van Kroonenburgh MD, PhD; F.W. Vreeling MD, PhD; W.E.J. Weber MD, PhD.



Abstract.

Background.
Vascular Parkinsonism (VP) is accepted as a parkinsonian syndrome dominated by postural instability with shuffling gait and absence of tremor, occurring in 3-5% of patients with parkinsonism. However, the precise spatiotemporal relation between the vascular lesions and the ensuing parkinsonism remains unclear. As CT and MRI imaging techniques do not allow the precise identification of the cerebral functions affected in VP, we decided to study cerebral perfusion in patients with parkinsonian symptoms after stroke.
Methods.
In seven patients fullfilling criteria for the diagnosis of VP , cerebral perfusion was evaluated with HMPAO SPECT and compared with seven patients with idiopathic Parkinson’s disease.
Results.
In all patients with vascular parkinsonism, there was statistically significant hyperperfusion in the right frontal brain area as compared to patients with idiopathic Parkinson’s disease.
Conclusions.
The finding of frontal lobe hyperperfusion supports the idea that altered function and changes in cerebral perfusion in the frontal brain regions play a role in the pathophysiology of parkinsonian signs after stroke.



Introduction.

Cerebrovascular disease as a cause of parkinsonism was first reported by Critchley in 1929 [1]. Since this first report, several studies have adressed the subject. Main symptom in patients with vascular parkinsonism (VP) is a disturbance of gait. Often there is no tremor and no or only minimal improvement of symptoms on antiparkinsonian medication [2-13]. Affected patients have vascular risk factors, often hypertension, and/or suffered one or more strokes, usually of the lacunar type [2, 5-10, 12-15]. However, the precise spatiotemporal relation between the vascular lesions and the ensuing Parkinsonism remains unclear. Patients with VP from a single stroke in a specific cerebral location are a great minority and published as case reports: locations include mesencephalon [16], substantia nigra [17], striatum [18], basal ganglia [19], anterior cerebral artery [20], cerebral peduncle [6,21], anterior choroidal artery [22,23]. The great majority of patients with VP suffers an insidious onset, where the relation of timing, location, and size of the infarct with the clinical syndrome is poorly understood [7, 13-15, 24]. Scanning patients with parkinsonism, several authors found an anatomical relation with ischemic lesions in the basal ganglia [2,19,25], as did Reider-Groswasser when examining a series of patients selected for basal ganglia lesions on CT [26]. In earlier studies we found frequent signs of parkinsonism in a consecutive series of acute first-ever stroke patients [27,28]. These were related to white matter lesions, and we found an association with the perfusion area of the anterior choroid artery [29]. However, the relation of clinical parkinsonian signs and ischemic lesions on CT and MRI remains indirect, indicating that these imaging techniques do not allow the precise identification of the cerebral functions affected in VP. In the present study, we examined cerebral perfusion in 7 VP patients diagnosed according to recent criteria [14], hypothesising that cerebral perfusion in the frontal subcortical areas of these patients is altered, influencing projections between basal ganglia and frontal cortex.



Methods.

Patient selection.
We studied seven patients with vascular parkinsonism, diagnosed according to recently formulated criteria [14]. The clinical diagnosis had been made on predominantly parkinsonian symptoms of the lower extremities: short stepping, starting hesitation and turning problems and problems of a parkinsonian gait. All patients had one or more ischemic lesions on CT and MRI scanning of the brain fitting the description of infarction, as well as white matter lesions (leukoaraiosis) [30,31]. No patient had a previous history of idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy or any other obvious cause of parkinsonism. Motor function and gait were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III. A higher score corresponds with more severe parkinsonian symptoms; maximum score on the UPDRS motor subscale is 56 [32]. Detailed information on the examined patients is listed in table 1. In all patients cerebral perfusion was evaluated with HMPAO SPECT imaging. SPECT findings in patients with vascular parkinsonism were compared with those in seven patients with a diagnosis of idiopathic Parkinson’s disease.

SPECT imaging protocol.
SPECT brain study was done in a quiet, half-dark room while the patient was left for 15 minutes and after the pulse rate had dropped below 100 beats per minute. 740 MBq of 99mTc-HMPAO (Ceretec, Amersham, England) was administered intravenously. On a large-field single-head gamma camera (Siemens Gammasonics, Hoffman Estate, IL, USA) a 128 x 128 matrix was used to image the head and the heart and 110 images of 1 second duration were obtained. 15 minutes later, brain SPECT was performed with triple-head gamma camera (Siemens Gammasonics, Hoffman Estate, IL, USA) using a matrix size of 128 x 128 and high-resolution collimators. 3 x 30 views were obtained. Images were reconstructed using Butterworth filter of the order 5 or 6 and a cut-off value of 0.35 – 0.40 of the Nyquist frequency. Chang’s attenuation correction was applied using attenuation coefficient of 0.12 cm-1. Transverse images of the brain were reconstructed parallel to the orbitomeatal line. Applying the brain perfusion index allowed hemispheric blood flow and regional cerebral blood flow to be calculated. The Siemens brain quantification program was used to determine mean blood flow. A side-to-side difference between regions of more than 10 % was taken as a significant sign of reduced luxury blood flow due to cerebrovascular insult.

Statistical parametric mapping analysis.
SPM (version 1999, SPM ’99) was used to determine the quantitative differences in the 99mTc-HMPAO images between patients with vascular parkinsonism and idiopathic Parkinson’s disease. Prior to statistical analysis, all of the images were spatially normalized using a standard template to remove the intersubject anatomical variability. Spatially normalized images were then smoothed to increase the signal-to-noise ratio and to account for the variations in subtle anatomical structures. The count of each voxel was normalized to the total count of the brain (proportional scaling in SPM ’99) to remove the differences in global cerebral blood flow (CBF) between individuals. After spatial and count normalization, significant differences in 99mTc-HMPAO SPECT between the two patient groups were estimated at every voxel using t-statistics. The voxels with a p value of less than 0.01 were considered to be significantly different. The t-values were then transformed into the standard Gaussian distribution (Z-score).



Results.

There were clear areas of hyperperfusion compatible with the neuroimaging diagnostic pictures in all patients with VP while there were no regional cerebral blood flow (rCBF) changes in patients with IPD on the 99mTc-HMPAO SPECT images by visual analysis. SPM ’99 analysis showed areas of increased rCBF in patients with VP compared to those of IPD (figure 1). 99mTc-HMPAO SPECT images displayed relatively higher radiopharmacon uptake mainly in the right frontal area in patients with VP (figure 1). By contrast, 99mTc-HMPAO SPECT images did not show lower uptake in the basal ganglia region or elsewhere in the brain in patients with VP compared to the uptake in IPD patients. Table 2 specifies brain areas of higher uptake.



Discussion.

Although case reports have identified specific vascular lesions leading to parkinsonian signs [6, 16-23, 33], studies on series of patients with VP only found indirect relations with basal ganglia lesions and white matter lesions in general [7, 13-15, 24,26,34], which may also be found in depression and dementia [35,36]. To our knowledge, our study is the first report on cerebral perfusion measured with 99m Tc-HMPAO SPECT in patients with vascular parkinsonism. We found a statistical significant hyperperfusion in the right frontal brain regions as compared to control values, reflecting an altered function in these frontal regions. This location accords with findings of other researchers, who implicated the frontal lobe in the emergence of parkinsonian signs in some patients [37-42]. The finding of hyperperfusion is unexpected. Based on the concept that metabolic demand and regional cerebral blood flow are coupled under physiological conditions, our findings suggest that in patients with vascular Parkinsonism these are un-coupled. All our seven VP patients had leukoaraiosis. Leukoaraiosis results from atherosclerosis of the medullary penetrators, and is most often located in the frontal brain areas, especially around the frontal ventricular horns [30,31,43]. The presence of leukoaraiosis is clinically associated with dementia and cognitive disturbances, problems of gait and urinary incontinence[44]. However, it is also reported in healthy individuals [43-48]. Claus et al, using SPECT, found no consistent relationship between severity of cerebral white matter lesions and cerebral blood flow [49]. Shyu et al found a reduction of cerebral blood flow in the frontal lobes in patients with mild to moderate vascular dementia and subcortical frontal leukoaraiosis [50]. Oppenheimer et al, with MR spectroscopy, also found a trend towards lower cerebral blood flow in white matter lesions [51].
Taken together, cerebral blood flow in white matter lesions of patients without parkinsonism seems to be decreased. This would imply that in our VP patients the frontal hyperperfusion must be linked with a dysfunction of the extrapyramidal system, as the sole presence of white matter lesions seems to lead to decreased blood flow.
To our knowledge, there are no previous prospective studies with technetium HMPAO SPECT or perfusion MRI in a series of patients with vascular parkinsonism. Ikeda et al. described one case of a patient with parkinsonism, basal ganglia lacunar infarcts, and periventricular high signal areas, in whom HMPAO SPECT showed diffuse cortical hypoperfusion [52]. In Parkinson’s disease, studies on regional cerebral blood flow have given conflicting results: on the one hand, basal ganglia dysfunction is associated with increased regional blood flow [53, 54], on the other hand increased cerebral blood flow is associated with increased motor function [55]. Sestini et al found that good clinical motor response with deep brain stimulation were associated with increased regional blood flow in the frontal areas [55]. Perhaps our results represent some kind of compensatory mechanism aimed at restoring the functional integrity of the extrapyramidal system. However intriguing, our first study on cerebral perfusion in a series of patients with vascular parkinsonism does need confirmation as the numbers of patients studied is small.

(tables and figures available from the author)



References.

1. Critchley M. Arteriosclerotic parkinsonism. Brain 1929; 52:23-83.

2. Chang CM, Yu YL, Ng HK, Leung SY, Fong KY. Vascular pseudoparkinsonism. Acta Neurol Scand 1992; 86(6):588-592.

3. Demirkiran M, Bozdemir H, Sarica Y. Vascular parkinsonism: a distinct, heterogeneous clinical entity. Acta Neurol Scand 2001; 104(2):63-67.

4. FitzGerald PM, Jankovic J. Lower body parkinsonism: evidence for vascular etiology. Mov Disord 1989; 4(3):249-260.

5. Jankovic J. Lower body (vascular) parkinsonism. Arch Neurol 1990; 47(7):728.

6. Peters S, Eising EG, Przuntek H, Muller T. Vascular Parkinsonism: a case report and review of the literature. J Clin Neurosci 2001; 8(3):268-271.

7. Sibon I, Fenelon G, Quinn NP, Tison F. Vascular parkinsonism. J Neurol 2004; 251(5):513-524.

8. Thompson PD, Marsden CD. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswanger's disease. Mov Disord 1987; 2(1):1-8.

9. Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts. Neurology 1984; 34:1516-1518.

10. 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(1):89-95.

11. Zijlmans JC, Poels PJ, Duysens J, van der Straaten J, Thien T, van't Hof MA, et al. Quantitative gait analysis in patients with vascular parkinsonism. Mov Disord 1996; 11(5):501-508.

12. Foltynie T, Barker R, Brayne C. Vascular parkinsonism: a review of the precision and frequency of the diagnosis. Neuroepidemiology 2002; 21(1):1-7.

13. Sibon I, Tison F. Vascular parkinsonism. Curr Opin Neurol 2004; 17(1):49-54.

14. Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 2004; 19(6):630-640.

15. Zijlmans JC, Thijssen HO, Vogels OJ, Kremer HP, Poels PJ, Schoonderwaldt HC, et al. MRI in patients with suspected vascular parkinsonism. Neurology 1995; 45(12):2183-2188.

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22. Sibon I, Guyot M, Allard M, Tison F. Parkinsonism following anterior choroidal artery stroke. Eur J Neurol 2004; 11(4):283-284.

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24. Boon A, Lodder J, Heuts-van Raak L, Kessels F. Silent brain infarcts in 755 consecutive patients with a first-ever supratentorial ischemic stroke. Relationship with index-stroke subtype, vascular risk factors, and mortality. Stroke 1994; 25(12):2384-2390.

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26. Reider-Groswasser I, Bornstein N, Korczyn A. Parkinsonism in patients with lacunar infarcts of the basal ganglia. Eur Neurol 1995; 35:46-49.

27. Korten AGGC, Lodder J, Vreeling FW, Boreas AMHP, Kessels AF, Weber WEJ. Extrapyramidal system dysfunction in 101 patients with acute first-ever stroke. Submitted 2005.

28. Korten AGGC, Weber WEJ, Kessels AHF, Boreas AMHP, Vreeling FW, Lodder J. Vascular parkinsonism: evolution of symptoms in a cohort of 101 first-ever stroke patients. Submitted 2005.

29. Korten AGGC, Weber WEJ, Vreeling FW, Boreas AMHP, Kessels AF, Lodder J. Neuroradiologic correlates of parkinsonian signs in 83 first-ever stroke patients. Submitted for publication 2005.

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Chapter 3

Neuroradiologic correlates of parkinsonian signs in 83
first-ever stroke patients.


Arthur G.G.C. Korten MD; Wim E.J. Weber MD, PhD; Fred W. Vreeling MD, PhD;
Anita M.H.P. Boreas MD, PhD; Alfons H.F. Kessels MD, MSc; Jan Lodder MD, PhD.



Abstract.

Background.
In vascular parkinsonism, the exact spatial and temporal relation between the ischemic lesion and the ensuing parkinsonism remains unclear. We recently found a high frequency of parkinsonian signs in a consecutive series of patients with a first-ever stroke. In this study we examine a possible relationship between location of cerebral ischaemia and parkinsonian signs.
Methods.
In a prospective series of 83 patients with ischemic stroke, presence of the four cardinal parkinsonian signs (bradykinesia, rigidity, tremor at rest and postural instability) and location of ischaemia on CT or MRI was examined in a standardized fashion.
Results.
A symptomatic lacunar infarct was present 26 patients, 36 had a territorial infarct and 37 one or more asymptomatic lacunar brain infarcts. 21 Patients had no symptomatic infarction on CT or MRI. Eleven patients had at least one of four cardinal parkinsonian signs.
We found no relation between involvement of specific cortical gyri in territorial infarcts and parkinsonian signs. There was no relation between location of the symptomatic lacunar infarcts and parkinsonian signs. However, one or more asymptomatic lacunar infarcts in the supply area of the anterior choroid artery related to the presence of rigidity.
Conclusion.
Asymptomatic lacunar infarcts in the supply area of the anterior choroidal artery are related to the presence of parkinsonian signs. We hypothesize that this lesion interferes with input from motor cortices to basal ganglia through tracts in the posterior part of the internal capsule.



Introduction.

Symptoms and signs resulting from stroke are numerous and various. Although it is well known that stroke can cause parkinsonian symptoms, this so called vascular parkinsonism (VP) receives relatively little attention as part of stroke symptomatology [1-13]. Reports in literature mention association of VP with hypertension and lacunar brain infarction [2,4, 5-10, 12-17]. The precise relation between the vascular lesions and the ensuing parkinsonism remains unclear. Case reports link the acute occurrence of VP to a single stroke located in mesencephalon [18], substantia nigra [19], the striatum [20], basal ganglia [21], the anterior cerebral artery territory [22], cerebral peduncle [6,23] and anterior choroidal artery territory [24,25]. In patients with an insidious onset of VP, the relation with type, location and size of ischaemic lesion is poorly understood [7, 13-15, 26]. Scanning patients with parkinsonism, several authors found an anatomical relation with ischemic lesions in the basal ganglia [2,21,27], as did Reider-Groswasser when examining a series of patients selected for basal ganglia lesions on CT [28].
In an earlier study we found that in a consecutive series of acute first-ever stroke patients, signs of parkinsonism are frequent and related to white matter lesions [29,30]. In the present study on 83 first-ever stroke patients, we explored a possible relationship between ischemic lesion site and the presence of parkinsonian signs: cortical versus deep lesions, as well as involvement of different cortical gyri in relation to parkinsonian signs.



Methods.

Patients admitted with acute stroke and symptoms lasting longer than 24 hours were examined on the presence of cardinal signs of parkinsonism: bradykinesia, rigidity, tremor at rest and postural instability. Routine stroke investigations included standard blood tests, electrocardiogram, chest X-ray, CT scan of the brain, and ultra-sound carotid studies [10,26]. Echocardiography, 24-hour ECG monitoring, MRI and cerebral angiography were done in selected cases. Patients with a previous history of idiopathic parkinson’s disease or any other neurodegenerative disorder with parkinsonism, repeated head injury, exposure to, exposure to1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) [31], those with definite encephalitis, and patients using neuroleptic medication or a cerebral tumour or hydrocephalus on CT scan were excluded. Patients with an intracranial haemorrhage, no abnormalities on CT or MRI during admission or those who did not have CT or MRI were also excluded.
The presence of bradykinesia was judged clinically. Grading was done according to the Unified Parkin­son’s Disease Rating Scale (UPDRS), item 31 [32]. Rigidity, tremor and postural stability were, if possible, scored on both body sides also according to the UPDRS [33]. Rigidity was judged by passively moving elbow, wrist and knee joints searching for the presence of a lead-pipe phenomenon. Is was distinguished from spasticity as only the latter is a velocity dependent sign. Presence of tremor was inspected in rest and action. Postural stability was examined by scoring the standing patients reaction to a sudden, strong posterior displacement produced by a pull on the shoulders [32].
Lesion site on CT or MRI was determined unaware of the presence of parkinsonian signs. In symptomatic territorial infarcts we listed the involvement of different gyri according to Bories method [34]. Symptomatic lacunar infarcts were localised according to the involved nuclei or white matter tracts (i.e. caudate nucleus or anterior part of the internal capsule). Asymptomatic lacunar infarcts were scored according to different penetrating arteries supply area, using Damasio’s templates [35], but for the supply area of the anterior choroidal artery, where we used the data by Hupperts and Lodder[36]. In patients who had both CT and MRI, ischaemia location was determined on MRI scan. Data on signs, symptoms, previous history and results on ancillary examinations of all patients had been registered prospectively in the Maastricht Stroke Registry (MSR) [10,26].

Definitions
Bradykinesia is defined as a slowness of initiation of voluntary movements with progressive reduction in the speed and amplitude of repetitive actions [37]. Patients were considered bradykinetic when UPDRS score on item 31 is 1 or more.
Rigidity is an increase in muscle tone during passive movement. Patients were considered rigid when UPDRS score on item 22 is 1 or more.
Tremor comprises involuntary oscillations of a body part produced by alternating or synchronous contractions of reciprocally innervated muscles[38]. According to the UPDRS, tremor at rest is present when the score on item 20 is 1 or more.
Loss of postural reflexes presents with impaired righting reflexes and problems of maintaining balance (UPDRS >=1).
A parkinsonian syndrome is the presence of bradykinesia and at least one of the following: rigidity, 4-6 Hz resting tremor or postural instability [32,37].
Lacunar stroke is defined as an acute symptomatic stroke syndrome with a CT lesion compatible with occlusion of a single perforating artery, i.e., a small, subcortical, sharply marginated hypodense lesion with a diameter smaller than 15 mm (small deep infarct), or in case of a specific lacunar syndrome (unilateral motor and/or sensory symptoms and signs that completely involve at least 2 of 3 body parts (face, arm and leg) without disturbance of consciousness or language, visual field defect or other signs of cortical dysfunction) when the CT scan showed no specific lesion.
Territorial stroke is defined (1) as an acute stroke syndrome with CT findings compatible with infarction involving the cortex, or (2) when no specific lesion was visible on CT, as a clinically identified cortical syndrome consisting of unilateral motor and/or sensory symptoms and signs in combination with signs of cortical dysfunction with or without visual field defect, or as incomplete involvement of two body parts, or as isolated monoparesis, or as isolated cortical dysfunction (usually dysphasia).
Asymptomatic (silent) brain infarct is defined as a low density area on CT or hyperintensity area on MRI compatible with infarction, but without a history of stroke, as taken from the patient’s history, from family, or any other accessible information. Also, the stroke symptoms at study entry had to be anatomically incompatible with this infarct.
Leukoaraiosis is defined as a CT finding consisting of focal or diffuse hypodensities in the periventricular or deep white matter, not involving the cortex, and with ill-defined margins to distinguish it from infarction [38].
Statistical analysis was performed with the Software Package for the Social Sciences version 8.0, SPSS inc. 1997, calculating odds ratio (OR) and 95 % confidence interval (CI) using logistic regression analysis. Rigidity and the presence of at least one of four parkinsonian symptoms were separately tested as dependent variables. Independent variables were : involved cortical gyri, asymptomatic lacunar infarcts in three different vascular supply areas and different localisations of symptomatic lacunar infarcts. Analysis was performed univariate to calculate crude odds ratios, and multivariate with age, sex, and leukoaraiosis as covariates to calculate adjusted odds ratios.



Results.

We examined 101 consecutive patients admitted to our hospital with an acute first-ever stroke on the presence of parkinsonian signs [29,30]. Seventeen patients with intracranial haemorrhage on acute CT examination and one patient who did not have CT or MRI were excluded from further analysis. Of the remaining 83 patients, 50 were male and 33 female. Mean age was 75 years (SD 11.9; range 28 to 99 years). Twenty-six patients had a symptomatic lacunar and 36 a territorial infarct. Twenty-one patients had no abnormalities on CT or MRI. Forty-six patients had at least one asymptomatic brain infarcts. Thirty-seven of these patients had one or more asymptomatic lacunar infarct. In 37 patients there was at least one asymptomatic lacunar infarct in the supply area of the lenticulostriate arteries, in 5 patients in the supply area of the thalamostriate arteries and in 7 patients in the supply area of the choroid anterior artery.
Rigidity and resting tremor could be scored in all 83 patients. Due to concomittant paresis, it was not possible te examine the other parkinsonian signs in all patients. Postural stability, the presence of a parkinsonian syndrome and bradykinesia alone could be evaluated in 38 patients. All four key parkinsonian symptoms could be examined in 37 of 83 patients. Bradykinesia was present in 6 patients, postural instability in 4 and rigidity in 26. Only 3 patients had a tremor at rest. Eleven patients had at least one of the four key parkinsonian symptoms.
Of 36 patients with a territorial infarct, thirteen had rigidity. Table 1 summarizes the involvement of different cortical gyri in these patients. Only two of 36 patients with a territorial infarct had a tremor at rest. In these two patients, the post-central and middle temporal gyrus were involved. Bradykinesia could be examined in 13 of 36 patients. Only one patient had a bradykinesia with involvement of post-central and precentral gyrus and cuneus. Postural stability was evaluated in 12 of 36 patients. Instability was present in only one patient with a cerebellar infarct. Examination of all four key symptoms of of parkinsonism was possible in 12 of 36 patients with a territorial infarct. Three patients had at least one of these four symptoms. Table 2 summarizes the involvement of different cortical gyri in these patients. Univariate logistic regression analysis did not show that the involvement of any gyrus was related to rigidity or the presence of at least one of four parkinsonian symptoms. In multivariate analysis with age, sex and leukoaraiosis as covariates, there was also no correlation between involvement of a specific gyrus and rigidity or the presence of at least one of four parkinsonian symptoms.
Symptomatic lacunar infarcts were located in caudate nucleus, medial and posterior parts of the posterior leg of the internal capsule, genu of the internal capsule, thalamus and posterior part of the corona radiata. None of these locations was related to rigidity or the presence of at least one of the four cardinal parkinsonian signs in logistic regression analysis with age, sex and leukoaraiosis as covariates. Of all 37 patients with one or more asymptomatic lacunar infarcts, 14 had rigidity (adjusted OR 2.2 (0.72-6.7), p=0.16). Eightteen of these 37 patients could be examined on all 4 parkinsonian signs. Six of these patients had at least one of the four signs (adjusted OR 3.3 (0.49-21.8), p=0.22). The presence of rigidity or at least one of four key parkinsonian symptoms in patients with asymptomatic lacunar brain infarcts in the three vascular territories is summarized in table 3. Multivariate logistic regression analysis showed that only the presence of at least one asymptomatic lacunar infarct in the territory of the anterior choroidal artery is related to rigidity (OR 7.6, p= 0.04, 95 % Confidence Interval 1.1 – 52.9).



Discussion.

In this study we report on location of ischemic brain lesions and their possible relationship with the presence of parkinsonian signs in a group of 83 consecutive patients admitted with an ischaemic first-ever stroke. In patients with a symptomatic territorial infarct, we found no relationship between the presence of parkinsonian signs and involvement of specific cortical gyri. In patients with a symptomatic lacunar infarct, lesion site also did not predict the presence of parkinsonian signs. Asymptomatic (silent) lacunar infarcts in general were not related to rigidity or the presence of at least one of four cardinal parkinsonian signs. When considering asymptomatic lacunar infarcts in different vascular territories however, infarcts in the supply area of the anterior choroidal artery related significantly and independently to the presence of rigidity.
We found no relationship between the involvement of any gyrus and parkinsonian signs. This accords with the current concept that VP results from a lacunar infarct in the basal ganglia or from diffuse white matter lesions with involvement of basal ganglia – frontal cortex projections [8,28, 40-43]. Scanning patients with parkinsonism, several authors found an anatomical relation with ischemic lesions in the basal ganglia [2,21,27], as did Reider-Groswasser when examining a series of patients selected for basal ganglia lesions on CT [28]. Alarcón et al. following up patients with movement disorders one year after a stroke, found basal ganglia infarcts in 6 patients with parkinsonian syndrome [44]. White matter lesions are caused by cerebral small vessel disease and are closely related to asymptomatic lacunar infarcts [45,46]. We found rigidity to be related to one or more asymptomatic lacunar infarcts in the supply area of the anterior choroidal artery. This area comprises, among others, the posterior leg of the internal capsule (fig 1) [36,47]. The posterior leg of the internal capsule contains fibers of the corticospinal tract, passing to brainstem and spinal cord, sensory thalamic projection fibers to the parietal lobe and pathways to and from the cerebellum [48,49].
The principal striatal circuit uses the anterior leg of the internal capsule for its output tracts to the cortex, mainly area 6 and the supplementary motor area, projecting from ipsilateral neocortex and bilateral from premotor, motor and somatosensory cortex. Lesions in the posterior part of the capsula interna probably cause dysfunction of the basal ganglia system as a result of a defective input from premotor, motor and somatosensory cortex. As regulation of muscle tone outside the context of coordination is not a function of cerebellar structures, it seems unlikely that the rigidity in our patients was caused by a lesion of cerebellar tracts alone [50].
Our study is somewhat limited by the relatively small number of patients, further reduced by separating different stroke types and vascular supply areas into different groups. Of the 21 patients without a symptomatic ischaemic lesion on CT or MRI, nine had rigidity and 5 had at least one of four parkinsonian signs. This may have obscured a relation of lesion type with parkinsonian signs. Further prospective studies on patients with lacunar infarcts and frequent follow-up are underway.

(tables and figures available from the author)



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Chapter 2

Vascular parkinsonism: evolution of symptoms in a cohort of 101 first-ever stroke patients.


Arthur G.G.C. Korten MD; Wim E.J. Weber MD, PhD; Alfonso H.F. Kessels MD, MSc; Anita M.H.P. Boreas MD, PhD; Fred W. Vreeling MD, PhD; Jan Lodder MD, PhD.



Abstract.

Background.
Parkinsonian signs can develop as a result of cerebrovascular disease. The prevalence and evolution of these signs after first-ever stroke, and their impact on functional outcome is unknown. In an earlier study we found a high prevalence of parkinsonian signs in first-ever stroke patients. We here present the 6-month follow-up of these patients, correlating the presence of parkinsonian signs with functional outcome and subtype of cerebral small vessel disease.
Methods.
One-hundred-and-one consecutive patients admitted in our hospital with a first-ever stroke were clinically examined for the presence of cardinal parkinsonian signs (bradykinesia, rigidity, resting tremor and postural instability) as well as parkinsonian gait and functional status 2 weeks and 6 months after stroke.
Results.
In total 101 patients were included. Two weeks after stroke, 40 patients had at least one of the four cardinal parkinsonian signs. After 6 months, 44 patients were examined of which 12 had at least 1 parkinsonian sign. The presence of at least one of four cardinal parkinsonian signs shortly after stroke predicted functional dependence or death at 6 months, independently of stroke type, but not age. White matter lesions were related to the presence of rigidity and a parkinsonian syndrome at 6 months as well as an independent predictor of progression of at least one of four parkinsonian signs.
Conclusions.
Parkinsonian symptoms frequently develop after stroke and these, together with age, negatively impact functional outcome. Leukoaraiosis or white matter lesions independently predict the presence and progression of parkinsonian symptoms. This observation is in support of the view that parkinsonian features in stroke patients are specially related to cerebral arteriolosclerosis.



Introduction.

Vascular parkinsonism (VP) is a parkinsonian syndrome with predominantly symptoms of the lower body half: postural instability and shuffling gait. Tremor is markedly absent, in contrast to idiopathic Parkinson’s disease [1-13]. Like patients with stroke in general, VP patients have vascular risk factors such as hypertension and previous stroke [2, 5-10, 12-15].
The exact mechanism by which cerebral lesions as a result of vascular disease can cause parkinsonism is not yet known. The great majority of patients with VP suffers an insidious onset, where the relation of timing, location, and size of the infarct with the clinical syndrome is poorly understood [7, 13-16]. A major reason for this is the fact that parkinsonian symptoms receive little attention in stroke patients: parkinsonian symptoms are not acknowledged in stroke syndrome diagnoses [17], thus obscuring prevalence and evolution of these symptoms. We recently found, in a consecutive series of 101 first-ever stroke patients, that 31 had rigidity, 3 patients resting tremor, 8 bradykinesia, 4 postural instability, and a parkinsonian syndrome was present in 4 patients [18,19]. In this study we found that these signs were related to lesions in the white matter or leukoaraiosis [20-23].
To our knowledge this was the first prevalence study of parkinsonian symptoms in a consecutive, unselected series of patients with a first-ever stroke. We now report on the evolution of these symptoms over six months in this patient cohort. This is important for two reasons. We found that the presence of parkinsonian symptoms is correlated with the functional status of the patients, so from a prognostic perspective one would want to know whether these symptoms worsen or dissolve over time. Secondly, follow-up would shed light on the validity of the hypothesis that there are two subtypes of lacunar infarcts: microatheromatosis and lipohyalinosis, the first associated with the presence of single, larger symptomatic lacunar infarcts, and the latter with hypertension, the presence of silent lacunar infarcts and white matter lesions, prognosis being more favorable in the first group [24-27]. If this hypothesis is correct, progression of parkinsonian signs would occur preferably in the patients with microatheromatosis-associated lacunar infarcts.



Methods.

Patients admitted to our hospital under the diagnosis of acute stroke with symptoms and signs lasting longer then 24 hours were examined for the presence of cardinal signs of parkinsonism: bradykinesia, rigidity, tremor and postural instability [19]. Also, in patients able to walk, gait was evaluated and scored as parkinsonian or not. Routine stroke investigations included standard blood tests, electrocardiogram, chest X-ray, CT scan of the brain, and ultra-sound carotid studies. Echocardiography, 24-hour ECG monitoring, MRI and cerebral angiography were done in selected cases [10,16]. Patients with a previous history of idiopathic parkinson’s disease or other neurodegenerative disorder with parkinsonism, repeated head injury, exposure to1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) [28], those with definite encephalitis or a cerebral tumour or hydrocephalus on CT scan, and patients taking neuroleptic medication were excluded.
As we found evaluation of gait of importance in as many patients as possible, but still aimed to study parkinsonian signs in the early stroke phase, first examination took place in the second week after stroke. Six months later, patients were re-examined. Again, presence of parkinsonian signs was examined and their severity graded.
The presence of bradykinesia was judged clinically. Grading was done according to the Unified Parkin­son’s Disease Rating Scale (UPDRS), item 31 [29]. Special attention was paid to bradykinesia in gait. Stride length and tempi in turning were measured in patients able to walk. Rigidity, tremor and postural stability were, if possible, scored according to the UPDRS [30]. Rigidity was judged by passively moving elbow, wrist and knee joints searching for the presence of a lead-pipe phenomenon. Presence of tremor was inspected in rest and action. Postural stability was examined by scoring the standing patients reaction to a sudden, strong posterior displacement produced by a pull on the shoulders. Progression of a parkinsonian sign was present when UPDRS scoring of one of these signs at six months was higher than scoring in the acute stroke phase. Table 1 provides information on UPDRS scoring.
Functional state was scored on admission, discharge from hospital and at six months using the modified Rankin scale [31]. Data on signs, symptoms, previous history and results on ancillary examinations of all patients were registered prospectively in the Maastricht Stroke Registry (MSR) [16]. Statistical analysis was performed with the Software Package for the Social Sciences version 8.0, SPSS inc. 1997, calculating odds ratio (OR) and 95 % confidence interval (CI) using logistic regression analysis.

Definitions.
Bradykinesia is defined as a slowness of initiation of voluntary movements with progressive reduction in the speed and amplitude of repetitive actions [32]. Patients were considered bradykinetic when UPDRS score on item 31 is 1 or more.
Rigidity is an increase in muscle tone during passive movement. Patients were considered rigid when UPDRS score on item 22 is 1 or more.
Tremor comprises involuntary oscillations of a body part produced by alternating or synchronous contractions of reciprocally innervated muscles [33]. According to the UPDRS, tremor at rest is present when the score on item 20 is 1 or more.
Loss of postural reflexes present with impaired righting reflexes and problems of maintaining balance (UPDRS item 30 >=1).
A parkinsonian gait is defined as bradykinesia in walking with shuffling or short stepping and turning in three or more tempi. Freezing during walking is also considered as a possible part of parkinsonian gait.
A parkinsonian syndrome is the presence of bradykinesia and at least one of the following: rigidity, 4-6 Hz resting tremor or postural instability [29,32].
Lacunar stroke is defined as an acute symptomatic stroke syndrome with a CT lesion compatible with occlusion of a single perforating artery, i.e., a small, subcortical, sharply marginated hypodense lesion with a diameter smaller than 15 mm (small deep infarct), or in case of a specific lacunar syndrome (unilateral motor and/or sensory symptoms and signs that completely involve at least 2 of 3 body parts (face, arm and leg) without disturbance of consciousness or language, visual field defect or other signs of cortical dysfunction) when the CT scan showed no specific lesion.
Territorial stroke is defined (1) as an acute stroke syndrome with CT findings compatible with infarction involving the cortex, or (2) when no specific lesion was visible on CT, as a clinically identified cortical syndrome consisting of unilateral motor and/or sensory symptoms and signs in combination with signs of cortical dysfunction with or without visual field defect, or as incomplete involvement of two body parts, or as isolated monoparesis, or as isolated cortical dysfunction (usually dysphasia).
Leukoaraiosis is defined as a CT finding consisting of focal or diffuse hypodensities in the periventricular or deep white matter, not involving the cortex, and with ill-defined margins to distinguish it from infarction [21].
Patients with a lacunar syndrome (LACI) present with a pure motor stroke, pure sensory stroke, sensory-motor stroke or atactic hemiparesis / dysarthria-clumsy hand syndrome.
A total anterior circulation infarct (TACI) syndrome was defined as the combination of higher cerebral dysfunction (e.g. dysphasia), homonymous visual field defect and ipsilateral motor and/or sensory deficit of at least two areas of the face, arm and leg.
In case of a partial anterior circulation infarct (PACI) syndrome, patients present with only two of the three components of the TACI syndrome.
A posterior circulation infarct (POCI) syndrome comprises of ipsilateral cranial nerve palsy with contralateral motor and/or sensory deficit, bilateral motor and/or sensory deficit, disorder of conjugate eye movement, cerebellar dysfunction without ipsilateral long-tract deficit or isolated homonymous visual field defect [17].
A “deep lesion” on CT was defined as a lacunar or striatocapsular infarct, or supratentorial deep haemorrhage.
A “deep lesion stroke” was defined on the basis of clinical and CT findings as lacunar, striatocapsular or haemorrhagic stroke.



Results.

There were 101 patients , 58 males and 43 females. Mean age was 75 years (SD 11.4; range 28 to 99 years). Twenty-three patients had a modified Rankin score on admission of 3 or less, 78 patients had a score of 4 or 5. Comorbidity is listed in table 2.
Symptoms and signs on admission were compatible with a TACI syndrome in 14 patients, a POCI syndrome in 13 patients and a PACI syndrome in 37 patients [17]. Thirty-four patients had a LACI syndrome. Stroke syndrome was not classified in 3 patients.
On CT or MRI 27 patients had a lacunar infarct, 30 a territorial infarct, and 5 a striatocapsular infarct. Leukoaraiosis was present in 33 patients. Asymptomatic lacunar infarcts were seen in 38 patients (38 %). Seventeen patients had an intracranial haemorrhage (ICH), 2 of which were cerebellar. CT or MRI showed no symptomatic lesion in 21 patients. Eight of these patients however, had leukoaraiosis and 10 had one or more asymptomatic lacunar infarcts. One patient had no CT or MRI. Combining clinical and CT or MRI findings, final stroke type was classified in all 101 patients: 33 had a lacunar stroke, 51 a territorial ischemic stroke and 17 had ICH. As only 44 patients of 101 were available for follow-up at six months (see under), table 3 shows the frequency of these symptoms in the acute phase in these 44 patients. Rigidity and resting tremor could be examined in all 101 patients. Due to concomitant severe paresis of left or right leg, postural stability, the presence of a parkinsonian syndrome and bradykinesia could only be evaluated in 45 patients and the presence of a parkinsonian gait in 53.
Six months after stroke 46 of the initial 101 patients had died (46 %) and 11 (11 %) refused further follow-up. So, 44 patients, 27 male and 17 female could be re-examined. Of these 44 patients, 16 initially had a lacunar and 21 a territorial infarct, and 7 an ICH. Asymptomatic lacunar infacts were present in 16 patients. 24 of 44 patients had a modified Rankin score of 4 or 5 six months after stroke, 14 a modified Rankin score of 3 or less. Eight patients had rigidity, three a parkinsonian syndrome and 12 at least one of four parkinsonian symptoms. Table 4 shows the frequency of other parkinsonian symptoms in the examined patients. Rigidity and resting tremor could be scored in all 44 patients. Postural stability and the presence of a parkinsonian syndrome could be examined in 33, bradykinesia in 35 patients. Gait was evaluated in 35 patients. Again, due to walking difficulty as a result of paresis, it was not possible to examine all patients on these signs.
In univariate analysis, the presence of rigidity, OR 5.2 (95 % CI 1.8-15.5), p=0.0029, at least one of four parkinsonian symptoms, OR 6.6 (95 % CI 2.2-19.6), p=0.0007, and gait disturbance (OR 3.6 (95 % CI 1.0-12.8), p=0.05) in the acute stroke phase were related to a functional dependence or death at six months (Rankin score 5 or 6). When corrected for final stroke type, this relationship persisted. When corrected for age and sex however, it was no longer present.
Seven of the patients examined at six months had leukoaraiosis on CT or MRI. Four of these patients had rigidity and two a parkinsonian syndrome. In univariate logistic regression analysis rigidity and a parkinsonian syndrome 6 months after stroke were related to leukoaraiosis. When corrected for age, sex and stroke subtype in multivariate logistic regression analysis, this relationship persisted: OR 10.6 (95 % CI 1.4-80.2), p=0.02 and OR 46 (95 % CI 2-1047), p=0.02 respectively. The presence of parkinsonian symptoms at six months after stroke was not related to deep lesion location on CT or a deep lesion stroke type (table 5).
Six of 44 patients at six months had progression of at least one of these symptoms. Three of these patients had leukoaraiosis. In multivariate analysis leukoaraiosis corrected for age, sex and stroke type predicted progression of at least one of four parkinsonian symptoms, OR 11.0 (95 % CI 1.2-99.0), p=0.03.



Discussion.

We recently found, in a consecutive series of 101 first-ever stroke patients, that 31 had rigidity, 3 patients resting tremor, 8 bradykinesia, 4 postural instability, and a parkinsonian syndrome was present in 4 patients [18,19]. In this study we found that these signs were related to lesions in the white matter or leukoaraiosis [20-23].
Our present, follow-up study on this patient cohort shows that 6 months after stroke a substantial part of stroke survivors still has parkinsonian signs: almost one third of the surviving 44 patients who could be tested on the presence of the four cardinal parkinsonian signs, had at least one such symptom. Independent of stroke type, rigidity or the presence of at least one of four parkinsonian signs in the acute stroke phase were related to worse functional outcome at six months. Results of multivariate analysis, however, showed that this relation can be explained partly by older age in the group of patients with parkinsonian signs. We found that the presence of these signs as well as their progression are independently related to the presence of white matter lesions, but not to deep lesion location or presence of asymptomatic lacunar brain infarcts. White matter lesions result from arteriolosclerosis of the medullary small vessels, with apart from age, hypertension as important risk factor [24]. Our observation suggests that stroke patients with white matter lesions may have a higher risk not only for developing cognitive decline but also parkinsonian features. Some patients may develop both, which, ultimately, may finalise into the so-called Binswanger’s disease with dementia, gait and balance disorders, pseudobulbar state or incontinence [15, 34-40].
As to the hypothesis of two distinct lacunar cerebral infact types [24-27], our results show no association between the microatheromatic type of cerebral small vessel disease and presence or progression of parkinsonian symptoms. This may be due to the relatively large number of patients who died within the six months follow-up. Most of these patients had larger infarctions, which may have led to bias towards underestimation of the relation between leukoaraiosis and parkinsonian symptoms, since 9 of these patients had concomittant leukoaraiosis. Eleven patients refused follow-up examination. Five of these had leukoaraiosis. If parkinsonian symptoms had also been present in these patients, this would again have led to underestimation of the relation between leukoaraiosis and parkinsonian symptoms.

Our study shows that parkinsonian symptoms frequently develop after stroke and that they, together with age, influence functional outcome. Leukoaraiosis or white matter lesions independently predict the presence and progression of parkinsonian symptoms. This observation is in support of the view that parkinsonian features in stroke patients are specially related to cerebral arteriolosclerosis.

(tables available from the author)



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Chapter 1

Extrapyramidal system dysfunction in 101 patients with acute first-ever stroke.


Arthur G.G.C. Korten MD; Jan Lodder MD, PhD; Fred W. Vreeling MD, PhD; Anita M.H.P. Boreas MD, PhD; Alfonso H.F. Kessels MD, MSc; Wim E.J. Weber MD, PhD.



Abstract.

Background.
Although the diagnosis of vascular parkinsonism, resulting from multiple strokes, is well established, the precise relation between the vascular lesions and the ensuing parkinsonism remains unclear. In particular, the prevalence of extrapyramidal tract dysfunction in acute, first ever stroke patients, is unknown.
Methods.
We prospectively investigated the presence of symptoms of extrapyramidal dysfunction, judged clinically according to UKPDSBB criteria in 101 consecutive patients with acute stroke.
Results.
Of 101 patients, 31 had rigidity, 3 patients resting tremor, 8 bradykinesia and 4 postural instability. A parkinsonian syndrome was present in 4 patients. Presence of rigidity was related to white matter lesions on CT or MRI and not to a deep lesion.
Conclusions.
Our results indicate that signs of parkinsonism and even complete parkinsonian syndromes are frequently present in acute first-ever stroke patients. These symptoms are related to white matter lesions resulting in damage to “extrapyramidal” connecting white matter tracts.



Introduction.

Since Critchleys first description [1] of vascular parkinsonism (VP), this clinical concept has gained widespread acceptance. Most authors now agree on VP as a parkinsonian syndrome dominated by postural instability with shuffling gait and absence of tremor [2-11], occurring in 3-5% of patients with parkinsonism [12,13]. Affected patients have vascular risk factors, often hypertension, and/or suffered one or more strokes, usually of the lacunar type [2, 5-10, 12-15]. The association of lacunar infarctions, as a result from small vessel disease, with VP is well established, both by imaging [4,8,9,15,16] and histopathological studies [14,17].
However, the precise relation between the vascular lesions and the ensuing Parkinsonism remains unclear. Patients with VP from a single stroke in a specific cerebral location are a great minority and are most often published as case reports: locations include mesencephalon [18], substantia nigra [19], the striatum [20], basal ganglia [21], the anterior cerebral artery [22], cerebral peduncle [6,23], anterior choroidal artery [24,25]. The great majority of patients with VP suffers an insidious onset, where the relation of timing, location, and size of the infarct with the clinical syndrome is poorly understood [7, 13-15, 26].
In particular, little is known about the prevalence of extrapyramidal tract dysfunction in acute, first-ever stroke patients. Parkinsonian symptoms have traditionally received little attention in the acute phase of stroke, and, in contrast to disturbances of muscle power and sensory modalities, are often not included in stroke syndrome diagnosis or stroke scales [2,27]. We hypothesized that, in acute stroke, signs and symptoms of parkinsonism are present and are related to leukoaraiosis, asymptomatic lacunar brain infarcts or deep location of the symptomatic lesion. To study this, we assessed extrapyramidal tract dysfunction in a consecutive series of 101 patients with an acute, first-ever stroke.



Methods.

Patients with acute stroke with symptoms lasting longer than 24 hours were examined in the second week after stroke for the presence of cardinal signs of parkinsonism: bradykinesia, rigidity, tremor and postural instability. Patients with a known history of idiopathic Parkinson’s disease or other neurodegenerative disorder with parkinsonism, repeated head injury, exposure to 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) [28], definite encephalitis, a cerebral tumour or a hydrocephalus on CT scan, or those using neuroleptic medication were excluded. The presence of bradykinesia was judged clinically. Grading was done according to the Unified Parkin­son’s Disease Rating Scale (UPDRS), item 31 [29]. Rigidity, tremor and postural stability were -if possible- also scored on both sides of the body according to the UPDRS, items 22, 20 and 30. Used UPDRS items and their scoring are shown in table 1. Rigidity was judged by passively moving elbow, wrist and knee joints searching for the presence of a lead-pipe phenomenon [30]. Presence of tremor was inspected in rest and action. Postural stability was examined by scoring the standing patients reaction to a sudden, strong posterior displacement produced by a pull on the shoulders. Data on signs, symptoms, previous history and results of ancillary examinations were registered prospectively in the Maastricht Stroke Registry (MSR) [26]. Statistical analysis (univariate and multivariate regression analysis) was performed with the “Software Package for the Social Sciences” (SPSS) version 8.0, SPSS inc. 1997.

Definitions.
Bradykinesia is defined as a slowness of initiation of voluntary movements with progressive reduction in the speed and amplitude of repetitive actions [31]. Patients are considered bradykinetic when UPDRS score on item 31 is 1 or more [29].
Rigidity is an increase in muscle tone during passive movement. Patients are considered rigid when UPDRS score on item 22 is 1 or more.
Tremor comprises involuntary oscillations of a body part produced by alternating or synchronous contractions of reciprocally innervated muscles. According to the UPDRS, tremor at rest is present when the score on item 20 is 1 or more.
Loss of postural reflexes presents with impaired righting reflexes and problems of maintaining balance (UPDRS >=1).
A parkinsonian syndrome is the presence of bradykinesia and at least one of the following: rigidity, 4-6 Hz resting tremor or postural instability [29,31].
Lacunar stroke and territorial stroke definitions were used as described elsewhere [10,27]. Leukoaraiosis is defined as a CT finding consisting of focal or diffuse hypodensities in the periventricular or deep white matter, not involving the cortex, and with ill-defined margins to distinguish it from infarction [32]. A “deep lesion” on CT or MRI was defined as a lacunar or striatocapsular infarct, or supratentorial deep haemorrhage. A “deep lesion stroke” was defined on the basis of clinical and CT or MRI findings as lacunar, striatocapsular or haemorrhagic stroke.



Results.

58 Males and 43 females were included in the study. Mean age was 75 years (SD 11.4; range 28 to 99 years). Information on comorbidity is listed in table 2. On CT or MRI 27 patients had a lacunar infarct, 30 a territorial infarct and five a striatocapsular infarct. Leukoaraiosis was present in 33 patients. Asymptomatic lacunar brain infarcts were seen in 38 patients. Seventeen patients had an intracranial haemorrhage (ICH), two of which were cerebellar. In 21 patients CT or MRI showed no symptomatic ischaemic lesions or haemorrhage. Eight of these patients however, had leukoaraiosis and 10 one or more asymptomatic lacunar brain infarcts. One patient had no CT or MRI on admission or during hospital stay. Combining clinical and radiology findings, final stroke type was classified in all 101 patients: 33 had a lacunar stroke, 51 a territorial ischaemic stroke (including 5 patients with a striatocapsular infarct) and 17 had intracerebral haemorrhage. Table 3 shows the frequency of parkinsonian symptoms related to final stroke type. Rigidity and resting tremor could be scored in all patients. Because of concomittant paresis, postural stability, the presence of a parkinsonian syndrome and bradykinesia could only be evaluated in 45 patients.
In univariate logistic regression analysis, bradykinesia, resting tremor, postural instability or parkinsonian syndrome were not related to leukoaraiosis, asymptomatic lacunar brain infarcts, deep lesion location on CT or MRI or a deep lesion stroke type (all p values >0.10).
Fifteen of 33 patients with leukoaraiosis had rigidity. Univariate analysis showed leukoaraiosis on CT to be related to rigidity (odds ratio (OR) 2.71, 95% Confidence Interval (CI) 1.12-6.56, p=0.03). Rigidity was not related to a deep lesion on CT or MRI (OR 0.76, 95% CI 0.33-1.80, p=0.54), asymptomatic lacunar brain infarcts (OR 1.60, 95% CI 0.63-4.08, p=0.32) or a deep lesion stoke type (OR 0.95, 95% CI 0.40-2.22, p=0.91).
Forty patients in total (40 %), and 17 (52 %) of the 33 with leukoaraiosis had at least one of four cardinal parkinsonian symptoms (bradykinesia, tremor at rest, rigidity and postural instability). In univariate analysis, the presence of one of four parkinsonian symptoms was related to leukoaraiosis (OR 3.84, 95% CI 1.22-12.07, p=0.02), but not to deep lesion location on CT or MRI (OR 0.90, 95% CI 0.35-2.31, p=0.82), asymptomatic lacunar brain infarcts (OR 1.40, 95% CI 0.50-3.93, p=0.52) or a deep lesion stroke (OR 0.70, 95% CI 0.27-1.81, p=0.46).
Results of multivariate analysis with final infarct types (lacunar and territorial) and deep lesion location or stroke type as covariates are shown in table 4.



Discussion.

We assessed, to our knowledge for the first time, the presence of parkinsonian signs in a consecutive series of patients with acute, first-ever stroke, in the second week after the onset of stroke. We found parkinsonian signs in 46 of 101 patients and a parkinsonian syndrome in 4 of 45 patients. Because of concomitant paresis we were not able to assess all parkinsonian signs in all patients, so this number is probably an underestimate. Alarcon and coworkers [33] found a lower prevalence 3.9% of patients, who within one year after an acute stroke, developed involuntary abnormal movements, probably because some patients have recovered within that year.
We found a relationship between the presence of leukoaraiosis and rigidity as well as the presence of one of four parkinsonian symptoms. This relationship remained when correcting for final stroke subtype and deep lesion location as covariate. As leukoaraiosis is often bilateral and located around the frontal horns, it is conceivable that projections from frontal cortex (for example supplementary motor area) to the basal ganglia and vice versa are damaged, resulting in parkinsonian motor symptoms [21]. However, leukoaraiosis did not stand out as an independent predictor of rigidity or presence of one of four parkinsonian symptoms on multivariate testing when using age and sex as covariate. Rigidity was not related to deep lesion location or asymptomatic lacunar brain infarcts, nor was any of the other parkinsonian signs. These findings suggest that damage to the deep nuclei by stroke is neither unique nor conditional for the occurrence of parkinsonian symptoms in acute stroke. Damage anywhere along the circuitry involved in the regulation of motor control may cause such symptoms. Lesion site rather than size may be of relevance in this respect, as one third of lacunar stroke patients had at least one symptom.
Most studies on VP focused on the identification of cerebrovascular lesions in patients presenting with parkinsonian signs or a parkinsonian syndrome [2-7, 10,13,15,17]. Most prominent symptom in these studies is a parkinsonian gait, explaining the use of the term “lower body parkinsonism” [4,5,8]. We found a parkinsonian syndrome in almost ten percent of our patients who could be examined on all symptoms. In a general population of 55 years and older this prevalence was almost two percent [34].
Our study has some limitations. Firstly, patient numbers are relatively small and some parkinsonian symptoms could not be investigated in all patients because of concomittant paresis. Secondly, spasticity is another important motor sign resulting from stroke, the presence of which may have interfered with diagnosis of rigidity. However, spasticity is a velocity dependent phenomenon, discerning it from rigidity, which is not velocity dependent. Thirdly, although our study aimed to be prospective and consecutive, including measurement of the eventual development of vascular parkinsonism over time, relatively more patients with a lesser degree of neurological deficit agreed to participate, which resulted in a slight overrepresentation of younger patients, and those with a lacunar stroke. This may have biased towards underdetection of parkinsonian symptoms [3].
Our study shows that acute stroke lesions in basal ganglia or connecting white matter tracts can result in signs of parkinsonism or a parkinsonian syndrome. Further study is needed to clarify wether the incidence of these symptoms increases over time and whether early parkinsonian signs independently predict eventual vascular parkinsonism, and stroke prognosis in general.

(tables available from the author)



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