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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1075-1079
 

Determinants of levodopa responsiveness in patients with vascular parkinsonism


Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

Date of Submission28-Jan-2022
Date of Decision22-Apr-2022
Date of Acceptance23-Apr-2022
Date of Web Publication21-Nov-2022

Correspondence Address:
Pramod Kumar Pal
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_100_22

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   Abstract 


Introduction: Vascular Parkinsonism (VaP) is characterized by symmetric, predominantly lower limb bradykinesia and rigidity and no significant improvement with levodopa. We aimed to describe the clinical and radiological features of patients with VaP and the factors that determine levodopa responsiveness. Methods: This is a retrospective chart review of patients with VaP. The study included 44 patients (36 men) with VaP. The diagnosis was based on Zijlman's criteria. Demographic and clinical details were recorded from the case files. MRI data were available for all the patients. However, the motor severity scores assessed in the OFF and ON states using the unified Parkinson's disease rating scale (UPDRS) part III were available for 17 patients only. Based on the Magnetic Resonance Imaging (MRI) finds, patients were categorized into isolated periventricular ischemic (PVI) changes, isolated basal ganglia (BG)/thalamic infarcts, and both combined. Results: The mean age at the diagnosis was 65.2 ± 7.4 years. Further, the age at the onset of symptoms was 61.8 ± 8.1 years and the total disease duration was 3.5 ± 2.5 years. Hypertension was the most common risk factor and was observed in 88.6% of patients. Symmetrical lower body parkinsonism was observed in 88.6%. The mean UPDRS part III OFF score was 33.76 ± 12.7 and ON score was 30 ± 13.98. PVI changes were the most common MRI abnormality detected. Patients with isolated BG/thalamic infarcts had better mini-mental status examination scores and better levodopa responsiveness compared to other groups. Conclusions: Hypertension was the most common risk factor seen in patients with VaP. Those with isolated BG/thalamus infarcts demonstrated better levodopa responsiveness.


Keywords: Basal ganglia, levodopa responsiveness, periventricular ischemic changes, vascular parkinsonism


How to cite this article:
Goyal S, Kamble N, Mukheem Mudabbir M A, Bhattacharya A, Yadav R, Pal PK. Determinants of levodopa responsiveness in patients with vascular parkinsonism. Ann Indian Acad Neurol 2022;25:1075-9

How to cite this URL:
Goyal S, Kamble N, Mukheem Mudabbir M A, Bhattacharya A, Yadav R, Pal PK. Determinants of levodopa responsiveness in patients with vascular parkinsonism. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1075-9. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1075/361549





   Introduction Top


Vascular parkinsonism (VaP) is an uncommon disorder and constitutes approximately 3% to 6% of all parkinsonian syndromes and predominantly involves the lower limbs.[1],[2] The clinical presentations are typically distinct from idiopathic Parkinson's disease (PD). It is sometimes difficult to diagnose with certainty on clinical grounds alone. It is usually characterized by bilateral symmetrical rigidity and bradykinesia predominantly involving the lower limbs, postural instability, shuffling of gait, falls, dementia, and corticospinal tract findings.[2] Neuropathology shows multiple subcortical ischemic lesions owing to small vessel disease in the striatum, globus pallidus, white matter, and, less often, substantia nigra, involving cortico-striato-pallidal (nigral), thalamo-frontal, and other loops, without evidence of Lewy bodies.[3] Cranial computed tomography and magnetic resonance imaging (MRI) are useful tests to evaluate vascular lesions. Major risk factors for VaP are the same as those for cerebrovascular disease, and their prevention and treatment are of utmost importance.[1],[4] Response to levodopa has been reported in upto 50% of VaP patients, particularly in those with lesions in or close to the nigrostriatal pathways, although only a few patients demonstrate long-term efficacy.[1],[5] In addition, the response and outcome to levodopa are variable.

There have been several debates and controversies regarding the concept of VaP that includes the definition of parkinsonism itself. Patients with pyramidal tract involvement can also have slowness and reduced amplitude of movements that do not qualify for bradykinesia.[6] The absence of any specific imaging abnormalities on imaging, poor neuropathological correlation, poor correlation between microangiopathic changes and white matter signal changes on imaging and parkinsonism, and presence of other entities (vascular pseudo parkinsonism, pseudo VaP, and pseudo vascular pseudo parkinsonism) make the syndromic diagnosis confusing making it difficult to identify true VaP.[6]

We aimed to describe the clinical and imaging profile of patients with VaP and determine the factors that influence the treatment responsiveness and associated cognitive impairment.


   Materials and Methods Top


The study is a retrospective chart review of 44 patients with VaP. All the patients fulfilled the diagnostic criteria laid by Zijlmans that include both clinical and radiological features.[7] The study was conducted in the Department of Neurology at the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, and was approved by the Institute Ethics Committee (IEC No. NIMHANS/IEC/2019-20). All the relevant demographic and clinical details including the clinical severity scores as assessed by the Unified Parkinson's disease rating scale (UPDRS) part III in the OFF and ON states were noted from the case files. In addition, mini-mental status examination (MMSE) scores, treatment details, and response to levodopa were also retrieved from the case records. Levodopa challenge was not done for the patients. The dose of levodopa and carbidopa (LDC) was increased gradually over a few weeks and UPDRS was reassessed at 3 months to look for levodopa responsiveness. “Levodopa responsiveness” was defined as at least 30% improvement in the UPDRS part III scores compared to baseline scores. The OFF and ON UPDRS part III scores were available for only 17 patients. The data were retrieved from the case files in a retrospective manner. Most of these patients were evaluated on an Out-Patient Department (OPD) basis and hence OFF and ON assessments were done on a limited number of patients.

Based on the MMSE score, patients were categorized into mild (20–24), moderate (13–20), and severe (below 12) cognitive impairment. MRIs of all the patients were reviewed and were categorized into three groups: isolated periventricular ischemic (PVI) changes, isolated basal ganglia (BG) and/or thalamic infarcts, and combined PVI and BG/thalamic infarcts.

Statistical analysis

Data were analyzed using the R software and were expressed as descriptive statistics, such as Mean ± SD for continuous variables and frequency and percentage for categorical variables. Data were assessed for normality using the Shapiro–Wilk test. Intergroup comparisons were performed by the t-test. Pearson's correlations were used to determine the association between the groups.


   Results Top


Demographic profile

There were 44 patients with VP (36 men and 8 women) with a mean (± SD) age at onset being 61.8 ± 8.1 years and a mean duration of symptoms being 3. 5 ± 2.5 years.

Hypertension was the most common risk factor and was observed in 39 patients (88.6%) with a mean duration of 9.9 years before the onset of symptoms. Other risk factors were diabetes mellitus in 19 (43.2%) patients, history of prior stroke in 12 (27.8%) patients, and coronary artery disease in 5 (11.4%) patients. One patient had undergone coronary artery bypass grafting (CABG) about 22 years before the onset of symptoms. A history of smoking was present in six patients (13.6%; an average of 15 pack-years). Eight patients (18.2%) had only one risk factor, 22 (50%) had two risk factors, eight (18.2%) had three risk factors, and six patients (13.6%) had four risk factors [Table 1].
Table 1: Demographic and clinical characteristics of patients with vascular parkinsonism

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Clinical profile

Bradykinesia was present in all the patients and was predominant in the lower limbs. It was also the most common presenting symptom and was seen in 27 patients (61.4%). Lower limb rigidity was present in 12 (27.7%) and upper limb tremors in five (11.4%) patients. Symmetrical bilateral lower limb involvement was observed in 39 patients (88.6%) and unilateral involvement in five (11.4%) patients. Pyramidal signs such as lower limb spasticity, brisk reflexes, and extensor plantar response were present in 18 (40.9%) patients. Among the frontal release signs, snout reflex was present in 35 (79.5%) patients, palmomental reflex in 29 (65.9%), glabellar tap in 25 (56.8%), brisk jaw reflex in 14 (31.8%), and applause sign in only one patient. MMSE scores were available in 36 patients out of which 22 patients had cognitive impairment (mild in 22.2% and moderate in 38.9%) and the mean score was 21.9 ± 5.2. UPDRS part III score (medication OFF and ON) was available for 17 patients. The mean (± SD) OFF score was 33.76 ± 12.7 and ON score was 30 ± 13.98 (p = 0.41). The mean levodopa equivalent daily dose (LEDD) for the entire group was 442.96 ± 155.37 mg.

Radiological findings

MRI of the brain was performed on all the patients. Isolated PVI changes without any BG/thalamic infarct were found in 23 (52.5%) patients. Combined PVI changes and basal ganglia (BG)/thalamic infarcts were found in 17 (38.6%) patients and isolated BG/thalamic infarcts were found in four patients (9.1%) [Figure 1], [Figure 2], [Figure 3] and [Table 2].
Figure 1: MRI images showing isolated periventricular ischemic changes. (1a and 1b) T2-Axial image and Axial-Flair image shows Faseka grade-3 white matter ischemic changes and diffuse atrophy. (1c) Axial-SWI image at the level of basal ganglia shows no evidence of any blooming, however, mineralization at bilateral globus pallid is seen. (1d). Axial-DWI at the level of basal ganglia shows no evidence of any infarcts

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Figure 2: MRI brain showing combined periventricular ischemic changes and basal ganglia infarcts. (2a and 2b) shows T2 Axial and Coronal images depicting bilateral asymmetric thalamic gliotic foci suggestive of chronic infarcts with Faseka grade 2 ischemic changes. (2c) Axial-Flair image shows Faseka grade 2 ischemic changes. (2d) Axial-SWI image shows bilateral deep and lobar microbleeds

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Figure 3: MRI brain showing isolated basal ganglia infarcts. (3a) Axial-T2WI shows bilateral asymmetrical thalamic gliotic foci suggestive of chronic infarcts. (3b) Axial-SWI image at the level of basal ganglia shows no evidence of any blooming however mineralization at bilateral lentiform nuclei is seen. (3c and 3d) Axial-T2WI and Flair show diffuse atrophy without any white matter ischemic changes

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Table 2: Clinico-radiological correlation of 44 patients with vascular parkinsonism

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Correlations

The levodopa responsiveness was found to correlate with the radiological features. All the patients received LDC for at least 3 months. The dose of LDC was gradually increased. Levodopa responsiveness was determined at the end of 3 months. Correlation was done between the clinical parameters (UPDRS part III scores and MMSE scores) and radiological findings.

In patients with isolated BG/thalamic infarct (n = 3), the improvement in UPDRS part III (ON) score was maximum (mean reduction of 6.0 points). However, the mean decrease in the other two groups was not significant (combined PVI and BG/thalamic infarct: 1.75 points; isolated PVI: 2.7; P = 0.06) [Table 3]. In addition, the LEDD was less in patients with BG/thalamic infarcts and combined pattern in comparison to PVI [Table 3].
Table 3: Mean UPDRS part III scores and LEDD in each radiological category

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The mean MMSE score for patients with isolated BG/thalamic infarct was 28 ± 0.8, for patients with combined PVI and BG/thalamic infarct was 22.9 ± 5.0, and for patients with isolated PVI was 20.4 ± 4.8 (p = 0.05).


   Discussion Top


The early description of VaP dates back to the early 19th century when Marie et al.[8] described a condition called “état lacunaire” in 1901. Many signs and symptoms of this condition resembled Parkinsonism. Critchley described the symptoms as rapidly progressive lower limb dominant manifesting as rigidity, short-stepped gait in an elderly hypertensive person, and usually absence of resting tremor.[9] Winikates and Jankovic categorized patients with parkinsonism with a vascular score of two or more on a vascular rating scale as having VaP.[10] However, many patients with PD and vascular risk factors were misdiagnosed as having VaP. Finally in 1996, “a criteria for the clinical diagnosis of probable VaP” was proposed by Zijlmans et al.,[7] which was subsequently modified in 2004, based on a postmortem examination study.

In a study done by Winikates et al.,[10] the average age of diagnosis was 71.3 years with slight male predominance (57.9%) and the mean duration of illness was 5.32 years. In contrast, our patients were younger (65.2 ± 7.4 years), predominantly male (81.8%), and had a comparatively shorter duration of symptoms (3.5 ± 2.5 years).

Prior history of stroke and acute stroke progressing to VaP has been documented by various studies.[11] Winikates J et al.[10] reported a history of stroke in 24.6% which is similar to our results. Hypertension is recognized as an important risk factor for VaP because of its original description and was confirmed in a recent epidemiological study.[12] In our study, hypertension was the most common risk factor.

Yamanouchi et al.[3] studied 24 patients with VaP and observed associated pyramidal signs in 62.5%, asymmetric rigidity of limbs in 29%, and action tremors in 12.5%. In a similar study by Winikates et al.,[10] the pyramidal signs were present in 27.5%, symmetric involvement in 50.7%, and tremors in 33%. The results of our study are also in close agreement with these previous reports.

Associated dementia has also been observed in upto 70% of VaP patients.[12],[13] In our study, we had patients with mild to moderate cognitive impairment. This could be due to the younger age and short duration of symptoms in our patients.

Bungo Okuda et al.[14] studied primitive reflexes in 55 patients with VaP and found that majority had snout reflex (78%), followed by exaggerated jaw reflex (33%) and palmomental reflex (5%). In our study, snout reflex (79.5%) and exaggerated jaw reflex (31.8%) were common primitive reflexes. In addition, we observed a higher incidence of palmomental reflex (65.9%) and Myerson's sign (56.8%). Periventricular white matter ischemic changes, BG infarcts, and cerebral atrophy have been described in various studies which are similar to our results.[13],[15]

Levodopa responsiveness has been observed in 12.5% to 29% of patients with VaP.[16],[17]

Zijlmans et al.[16] demonstrated that patients with macroscopic infarcts or lacunae caused by enlarged perivascular spaces in the basal ganglion or microscopic neuronal cell loss in the substantia nigra had a good or excellent response to levodopa. He studied the levodopa responsiveness in 17 pathologically confirmed VaP. The clinical features and levodopa responsiveness were retrieved from the case files. Excellent or good response was observed in 10 out of 12 patients who had macroscopic infarcts or lacunae caused by enlarged perivascular spaces in the BG or microscopic neuronal cell loss in the substantia nigra. Those patients who did not have any or moderate response had either infarcts in the putamen or no infarcts.[16] This is in accordance with our study where VaP patients with infarcts in BG had less LEDD when compared with those who had isolated PVI changes. The type of disease onset (acute or insidious), laterality, or the dominant motor symptoms or gait disturbance does not predict response to levodopa. Patients with VaP who have macroscopic infarcts or lesions in the nigrostriatal pathway or lacunar infarcts in the BG demonstrate a good response to levodopa. The possible explanation for levodopa responsiveness was given by Leduc et al., as the presence of a remaining pool of striatal dopaminergic nerve terminals in a dysfunctional nigrostriatal pathway that remains adequate to convert exogenous L-dopa into dopamine and thus restore the intrinsic dopaminergic drive.[17] In patients with poor response to levodopa despite the lesion in the nigrostriatal pathway may be due to dysfunctional thalamocortical drive. In a systematic review and metanalysis, it was shown that patients with VaP with the lesion in the nigrostriatal pathway are 15 times more likely to respond to levodopa.[18] This hypothesis was supported by a study by Vizcarra et al.,[6] wherein VaP patients with dopamine transporter deficiency as measured with SPECT had a good response to levodopa.

Levodopa responsiveness also depends on the lesion load. Patients with a higher lesion load respond poorly to levodopa.

We also correlated the MMSE scores with imaging findings and observed that patients with isolated BG/thalamic infarct had less cognitive impairment. To our knowledge, there are no studies that have correlated cognition with imaging in patients with VaP.

Our study had few limitations. This was a retrospective chart review and only 17 patients' UPDRS part III ON and OFF scores were available. A longitudinal study with a large cohort is required to confirm our results. In addition, the small sample size in our study is the study's limitation. However, our study provides a clinical description of patients with VaP and the factors that determine the clinical outcome.


   Conclusions Top


In conclusion, VaP should be considered in elderly patients presenting with lower limb predominant bradykinesia and rigidity with associated pyramidal tract signs on a background of multiple vascular risk factors. Cognitive impairment is mainly present in a subset of VaP patients having periventricular white matter changes rather than BG/thalamus involvement. Among all the primitive reflexes, the snout reflex is most commonly seen followed by the palmomental reflex, glabellar reflex, and exaggerated jaw reflex. Levodopa trial should be offered to all the patients irrespective of the site of infarctions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Okuda B, Kawabata K, Tachibana H, Kamogawa K, Okamoto K. Primitive reflexes distinguish vascular parkinsonism from Parkinson's disease. Clin Neurol Neurosurg 2008;110:562–5.  Back to cited text no. 14
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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