Clinical Spectrum of Non-motor Symptoms in Correlation with Quality of Life in Parkinson’s Disease and Atypical Parkinsonism: Evidence in Reaching Consensus

Abstract

Background

Non-motor symptoms (NMS) are frequently overlooked, yet they significantly contribute to the progression of Parkinson’s disease (PD) or atypical parkinsonism (AP), which include multiple system atrophy (MSA), progressive supranuclear palsy (PSP). Moreover, discrepancies exist in non-motor symptom scale (NMSS) scores for AP and PD, and no consensus has yet been reached.

Purpose

We evaluated and compared the NMS and their association with life quality in patients with AP and PD.

Methods

This cross-sectional observational report at a single-centre enrolling 204 patients (155 PD, 49 AP (27 MSA), and 22 PSP) from a tertiary care hospital’s movement disorder clinic. We used Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS)-III and modified Hoehn and Yahr (H&Y) to compute a motor score and disease severity, respectively. We assessed patients’ mental capabilities, such as cognitive impairment, through a Mini-Mental State Examination (MMSE). Meanwhile, the NMSS determined the NMSs. Quality of life (QoL) was estimated by PD Questionnaire-39 (PDQ-39).

Results

We observed insignificant differences between the PD and atypical parkinsonian syndrome (APS) groups based on disease duration and gender. Worsened motor disability and disease severity were observed in AP (PSP>MSA) (P < .001). The mean NMSS scores for PD, PSP and MSA were 23.7 ± 27.9, 47.6 ± 41.3 and 65.6 ± 35.5, respectively (P < .05). MSA had a comparatively high score for sexual, cardiovascular and urinary domains, while PSP scored higher for memory/attention domains. In contrast, PD group revealed significantly lower scores for perceptual and sexual domains.

Conclusion

Compared to PD, NMS was severe and highly prevalent among AP (MSA > PSP), which could be confirmed through the prevalence of sexual cardiovascular and urinary domains in MSA, while attention and mood/cognition, and sleep in PSP.

Introduction

Parkinson’s disease (PD), a complicated neurodegenerative disorder, is diagnosed primarily based on impaired motor activities, like muscle rigidity, akinesia, postural instability and rest tremors. However, diverse non-motor symptoms (NMS), like autonomic disabilities, psychiatric disorders, sensory disturbances and sleep disorders, also present in PD, are frequently overlooked yet contribute significantly to the PD progression and, therefore, the impaired quality of life (QoL). ¹ The mounting evidence reveals that NMS precedes motor symptoms and is a potential biomarker for PD patients.^{2, 3} Importantly, clinical studies suggest that depression, fatigue, olfactory dysfunction, rapid eye movement and sleep behaviour disorder might be considered significant markers of PD. ⁴

A recent systematic review of 5,760 PD patients reported a rapid olfactory dysfunction, causing anosmia in the early phase. ⁵ This implies a probable association between olfactory dysfunction and the progression of PD. However, there was a variable trend in anosmia, and only some patients developed anosmia, which warrants further longitudinal studies to corroborate olfactory dysfunction as a biomarker. In two contemporary studies, NMS is commonly reported with at least one NMS in nearly 100% of patients.^{6, 7} NMS frequently antecedent PD motor symptoms diagnosis by a decade or even longer, and they almost inevitably appear with disease progression, resulting in severe disability, contracted life expectancy and impaired QoL. Notably, NMSs might be the first clinical PD manifestation among 20% of patients. ⁸

NMS and QoL have an inverse correlation. ⁹ Routinely, many NMSs fail to be observed and may negatively impact the quality of care even though possible treatments are available for many NMSs. ¹⁰ The NMS in PD has been extensively investigated and documented in India and all over the globe.^{9, 11} Notwithstanding, very few studies described the atypical parkinsonian syndrome (APS), which may be more severe and disabling. Therefore, we aimed to profile NMS correlated with QoL in PD and AP.

Methods

Patient Selection

This study presents a cross-sectional, single-centre observational analysis involving 204 consecutive patients with PD, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) diagnosed by standard criteria from December 2019 to December 2021. All consecutive patients attending the movement disorders outpatient department and/or admitted to the neurology ward were enrolled after obtaining written informed consent.

In PD group, patients 18 years and above with clinically established PD were included as per the Movement Disorder Society (MDS) clinical diagnostic criteria, with the presence of parkinsonism in combination with two supportive criteria and absence of red flags and exclusion criteria. ¹² Diagnosis of probable MSA was done as per the second consensus criteria in sporadic patients 30 years and above, with progressive autonomic failure involving urinary incontinence or orthostatic hypotension with a reduction in blood pressure of at least 30/15 mm Hg within three minutes of standing and poorly levodopa-responsive parkinsonism or cerebellar syndrome. ¹³ The MDS criteria were followed to define the PSP group, which included all patients (aged 40 years and above) of probable PSP with Richardson’s syndrome, progressive gait freezing, predominant parkinsonism or frontal presentation. ¹⁴ Following a written informed consent, they were evaluated using a predesigned proforma. Thorough questioning regarding family history, history of stroke, head injury, encephalitis, drug or toxin exposure, jaundice or any other systemic illness was done and was recorded in the proforma. Subsequently, a detailed neurological examination was carried out. An magnetic resonance imaging (MRI) brain 1.5 T (to exclude vascular insult, structural cause and metal deposition) and slit lamp for KF ring were done in all the patients. A total of 204 patients (155 PD, 49 AP, 27 MSA, and 22 PSP) were finally enrolled.

The criteria of the exclusion for the study were as follows: age <18 years, infectious brain lesions, cerebrovascular disease, structural brain lesions, post-anoxic injury, post-encephalitic, post-trauma, delirium, drug-induced parkinsonism, toxicity, metabolic disorders, heredodegenerative parkinsonism patients, diabetes mellitus and the patients with insufficient information.

Study Parameters (Validated Scales Used)

Patient outcomes were determined by validated scales (Figure 1). Modified Hoehn and Yahr (H&Y) stage ¹⁵ assessed disease severity which was categorised into the following three groups: mild (1–2.5), moderate (3) and severe (4–5). Furthermore, the motor score was evaluated using Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS)-III. ¹⁶ Through Mini-Mental State Examination (MMSE), we assessed patients’ mental capabilities, such as cognitive impairments grouped into ≤24 and > 24. Based on the non-motor symptom scale (NMSS). ¹⁷ NMSs were graded as mild (1–20), moderate (21–40), severe (41–70), and very severe (>70). ¹⁸ PD Questionnaire-39 (PDQ-39) was used to determine QoL. ¹⁹

Figure 1. The Validated Scales Determining the Outcomes of Enrolled Patients. Created with BioRender.com.

Statistical Analyses

Mean, median and dispersion (standard deviation [SD]) were recorded for all data, while proportions and frequencies were used to determine categorical or qualitative variables. Measures of Kolmogorov–Smirnov tests of normality checked the quantitative data normality. Means/medians of different variables, including age, duration of therapy and sex, were compared using discrete categorical as n (%). The Mann–Whitney U test and t-test were used for skewed and normal data respectively. All two-sided statistical tests were analysed using IBM SPSS (version 23.0) at a P value <.05.

Results

Patient Cohort

We admitted and screened 250 patients of various aetiologies. Of those, due to exclusion criteria, 46 were excluded, and 204 enrolled (Figure 1). Baseline characteristics of enrolled subjects are depicted in Table 1. Patients of older age were significantly observed in PSP group compared to MSA and PD (P = .015). Mean disease duration and gender were almost equivalent among the groups. Two hundred patients (98%) had a minimum of one NMS.

Table 1. Baseline Characteristics of Patients.

Variables		PD	AP
		PD (n = 155)	MSA (n = 27)	PSP (n = 22)	P Value
Age, mean (SD)		55.6 (13.5)	55.2 (10.1)	64.4 (5.1)	.015
Gender, n (%)	F	53 (34.2)	7 (25.9)	9 (40.9)	.534
	M	102 (65.8)	20 (74.1)	13 (59.1)
LEDD, mean (SD)		592.5 (253.7)	525 (173.8)	403.2 (111.1)	.001
Disease duration mean (SD)		4.1 (3)	3.2 (1.7)	2.9 (1.8)	.101
Modified H & Y, mean (SD)		2.1 (0.8)	2.6 (0.8)	3.3 (0.6)	<.001
Modified H & Y, n (%)	Mild (1–2.5)	106 (68.4)	14 (51.9)	0 (0)	<.001
	Moderate (3)	39 (25.2)	9 (33.3)	16 (72.7)
	Severe (4.5)	10 (6.5)	4 (14.8)	6 (27.3)
MMSE, mean (SD)		26.9 (2.4)	27.7 (1.7)	20.9 (3.5)	<.001
MMSE, n (%)	≤24	17 (11)	1 (3.7)	18 (81.8)	<.001
	>24	138 (89)	26 (96.3)	4 (18.2)
NMSS score, n (%)	0 (0)	4 (2.6)	0 (0)	0 (0)	<.001
Mild	1–20	93 (60)	1 (3.7)	1 (4.5)
Moderate	21–40	28 (18.1)	7 (25.9)	12 (54.5)
Severe	41–70	22 (14.2)	8 (29.6)	6 (27.3)
Very severe	>70	8 (5.2)	11 (40.7)	3 (13.6)

Note: PD: Parkinson’s disease, AP: Atypical parkinsonism, MSA: Multiple system atrophy, PSP: Progressive supranuclear palsy, MMSE: Mini-Mental State Examination. LEDD: Levodopa equivalent daily dose.

In comparison to MSA and PD, a significantly lower MMSE score (<24) in the PSP group was observed (P < .001). No patients had mild grade PSP as per the modified H & Y scale (P < .001). We observed 98% of patients with at least one NMS and all enrolled PSP and MSA patients with at least one NMS (Table 1).

Frequencies on NMS

Falling asleep (87.7%), gastrointestinal tract (GIT; 72.3%) and miscellaneous (59.4%) were the highly frequent NMS observed among the PD group. The cardiovascular disorders (CVD_S) (100%), sexual (100%) and urinary (100%) were the most commonly observed NMS in MSA group. Further, attention and mood/cognition (100%) and sleep (95.5%) were the most prevalent NMS recorded in PSP patients (Table 2).

Table 2. NMS Frequency in PD and APS (MSA and PSP) Patients.

NMS	PD (Frequency %)	MSA (Frequency %)	PSP (Frequency %)
Sleep	87.7	96.3	95.5
Mood/Cognition	52.3	48.1	100
Hallucinations	16.8	66.7	31.8
Attention	33.5	70.4	100
GIT	72.3	88.9	90.9
Urinary	49.7	100	72.7
Sexual	41.9	100	77.3
CVDS	51	100	77.3
Miscellaneous	59.4	85.2	72.7

Note: NMS: Non-motor symptoms, PD: Parkinson’s disease, AP: Atypical parkinsonism, MSA: Multiple system atrophy, PSP: Progressive supranuclear palsy, GIT: Gastrointestinal tract, CVDs: Cardiovascular disorders.

NMSS Validation

As per maximum mean NMSS scores, the order of affected domains among PD subjects was sleep, GIT, miscellaneous, urinary and sexual issues with the values of 3.93 ± 3.2, 3.3 ± 3.3, 2.8 ± 3.9, 2 ± 2.3 and 1.3 ± 2, respectively. The minimally afflicted domain was perceptual issues (0.6 ± 1.5). However, in the MSA cohort, the impacted domain order was urinary (13.4 ± 2.8), sexual (12.5 ± 4.1), CVD_S (7.3 ± 5) and attention and memory (1.6 ± 1.6). Among PSP subjects, the impacted domain were sleep, mood and cognition, urinary, sexual and perceptual problems with scores of 8.3 ± 10.7, 8.2 ± 6.6, 9.91 ± 12.95, 6.91 ± 8.57 and 1 ± 1.6, respectively (Table 3).

Table 3. NMSS and Total PDQ-39 Score.

Variables	Diagnosis				P Value
	PD	MSA	PSP	Total	PD vs. MSA	PD vs. PSP	MSA vs. PSP
CVDs	1.4 ± 2	7.3 ± 5	2 ± 2.4	2.3 ± 3.3	.000**	.347	.000**
Sleep	3.9 ± 3.2	7 ± 4.3	8.3 ± 10.7	4.7 ± 4.9	.002**	.000**	.331
Mood/cognition	1.3 ± 1.5	1.6 ± 2.1	8.2 ± 6.6	2 ± 3.3	.485	.000**	.000**
Perceptual problem	0.6 ± 1.5	2.3 ± 2.6	1 ± 1.6	0.9 ± 1.8	.000**	.287	.008**
Attention and memory	1.3 ± 2.7	1.6 ± 1.6	5.5 ± 1.7	1.8 ± 2.8	.586	.000**	.000**
GIT	3.3 ± 3.3	4.9 ± 3.6	6.1 ± 4.3	3.8 ± 3.6	.033*	.001**	.216
Urinary	2 ± 2.3	13.4 ± 2.8	2.4 ± 1.7	3.5 ± 4.5	.000**	.462	.000**
Sexual	1.3 ± 2	12.5 ± 4.1	2.9 ± 1.7	2.9 ± 4.4	.000**	.002**	.000**
Miscellaneous	2.8 ± 3.9	6.4 ± 4.6	4 ± 3	3.4 ± 4.1	.000**	.180	.035*
Total NMSS score	23.7 ± 27.9	65.6 ± 35.5	47.6 ± 41.3	31.9 ± 34	.000**	.001**	.042*
Total UPDRS-III	35.2 ± 20.7	49.1 ± 12.8	58.2 ± 17	39.5 ± 21	.001**	.000**	.106
Total PDQ-39	60.8 ± 27.4	87.4 ± 38.5	77 ± 24.5	66.1 ± 30.3	.000**	.014*	.214

Note: NMSS: Non-motor symptom scale score, CVDs: Cardiovascular disorders. *p < 0.05; **p < 0.01.

Correlation Between NMSS, UPDRS, PDQ-39 and Modified H&Y

Our overall results indicated that the correlation between NMSS score and UPDRS motor score and PDQ-39, modified H & Y score and disease duration was significantly positive (P < .01) (Table 4).

Table 4. Correlation of NMS with Duration, H&Y Stage, UPDRS and PDQ 39 in the Study Population.

NMS Domain	Disease Duration	P Value	H & Y	P Value	Total UPDRS-III	P Value	Total PDQ 39	P Value
CVDS	0.238**	.001	0.434**	.000	0.381**	.000	0.427**	.000
Sleep	0.159*	.024	0.429**	.000	0.302**	.000	0.270**	.000
Mood/cog	0.038	.589	0.392**	.000	0.293**	.000	0.139*	.047
Perceptual issues	0.398**	.000	0.365**	.000	0.375**	.000	0.441**	.000
Attention	0.441**	.000	0.483**	.000	0.537**	.000	0.407**	.000
GIT	0.423**	.000	0.485**	.000	0.390**	.000	0.248**	.000
Urinary	0.120	.086	0.314**	.000	0.312**	.000	0.424**	.000
Sexual	0.019	.787	0.209**	.003	0.296**	.000	0.385**	.000
Miscellaneous	0.350**	.000	0.457**	.000	0.486**	.000	0.443**	.000
Total NMSS	0.395**	.000	0.547**	.000	0.557**	.000	0.484**	.000

Notes: **Significant Pearson Correlation at the 0.01 level (2-tailed).

*Significant Pearson Correlation at the 0.05 level (2-tailed).

Discussion

Very scarce literature on the NMS characteristics and their impact on health-associated QoL among AP patients is available. Therefore, we conducted this study of the NMS and its effects on the QoL between AP and PD patients. NMS was more prevalent and impaired in AP than in PD patients. The NMSS domain’s mean % score differed in the PD and the AP. Our results revealed high (97.4%) NMS prevalence in PD patients when compared to previous studies by Krishnan et al. ⁹ (100%), De Souza et al. ²⁰ (91.8%) and Ravan et al. ²¹ (100%). Further, as per the NMSS score, the majority of PD patients had mild NMS (60%), while only 5.2% of the population suffered severely. About maximum NMSS mean scores, we also found that the order of most critically afflicted areas was sleep (3.93 ± 3.2), GIT disturbance (3.3 ± 3.3) and perceptual issues (0.6 ± 1.5) among PD subjects. Sleep dysfunction is prominent in PD and represents a critical part of the disease, which might arise during various PD phases. This might be attributed to the disease itself, secondary to other NMS or a drug’s side effect, as indicated by previous studies.^{9, 22}

Our study also found GIT to be the second-ranked affected domain, which agrees with the previously reported study. ²³ Most previous reports have indicated a preponderance of sleep, memory, mood and urinary domain involvement.^{9, 22, 23} However, we found slight variations in different domains. In the PD cohort, all NMSS domains and total NMSS scores were significant and positively correlated with PDQ-39 score and disease duration, which are also consistent with other studies ²⁴ (Supplementary Table 1).

On the other hand, NMSS showed that most MSA patients had a very severe NMS (40.7%), while only 3.7% of the enrolled subjects had a mild burden, which is consistent with the previous study. ¹⁶ A high prevalence of NMS and a minimum of one NMS were observed in all enrolled subjects. As per maximum mean NMSS scores, the order of most critically affected domain was urinary (13.4 ± 2.8), sexual domain (12.5 ± 4.1), CVD_S (7.3 ± 5) and attention and memory (1.6 ± 1.6). These findings align with a prior study, ¹¹ which found almost 90% of urinary dysfunction in other studies.^{25, 26}

The involvement of the putamen, pontine micturition centre, sacral nucleus, substantia nigra, postganglionic cholinergic fibres and frontal cortical centre are the primary factors that contribute to the development of urinary dysfunction among MSA patients. ²⁷ The NMSS scores significantly correlate with PDQ-39 and UPDRS-III for all the AP. Thus, NMS are significant contributive factors to health-associated QoL in AP, which is in accord with previous studies^{7, 28} (Supplementary Table 2). As per maximum mean NMSS scores, the order of severely afflicted domain was sleep (8.3 ± 10.7), mood and cognition (8.2 ± 6.6), urinary (9.91 ± 12.95), sexual (6.91 ± 8.57) and perceptual problems (1 ± 1.6). In contrast, our previous study only assessed NMS of PD and their effect on the QoL in which disease type was akinetic rigid variant, tremor predominant type and mixed type in 29.3%, 36.9% and 33.6% respectively. ²⁹ Further, sleep and fatigue, subsequently after urinary tract manifestations, mood and cognition, cardiovascular indications and falls, GIT characteristics and sexual function were 83%, 63%, 51%, 43%, 38% and 33% respectively.

In this study, the population was distributed into PD and AP (MSA and PSP), where PSP patients revealed higher scores for NMSS, including attention/memory and mood/cognition domains. Executive dysfunction and slow processing confirm the presence of a deficiency in the ‘attention/memory’ domain among most PSP patients. Previous studies have reported that urinary symptoms are the third most common NMS domain among PSP patients. Notably, urological dysfunction has not been extensively studied in PRP patients, and very few studies elucidated the aetiologies of those factors such as age, detrusor sphincter dyssynergia, detrusor hyperactivity and forebrain dysfunction seem to be associated with these urinary disorders.

Comparative NMS Profiles Between PD and AP

Notably, the NMS is heterogeneous with diverse domains. Some of the NMS originate due to pathogenesis, while others are identified as side effects of treatment. Additionally, many of them may develop motor symptoms for a decade or even longer. These elements might demonstrate the variations and heterogeneity of our results. An Indian study in 2018 on 188 patients found the mean NMSS score of 37.1 ± 33.1-IPD, 80 ± 43.7-MSA and 70.7 ± 50.7-PSP and consummated that the NMS burden was worse in MSA, followed by PSP and PD. Notably, these diseases may be identified as prominent CVDs and sexual symptoms among MSA patients, while attention/memory manifestations among PSP subjects. ¹¹ In the year 2020, another study enrolling 219 patients (IPD-184, APS-35) found significantly frequent sleep disorders in idiopathic PD (IPD) patients (n = 92, 50%) compared to AP (n = 8, 22.86%, P = .0031). Previously, NMS was also significantly observed (P = 0.003) in AP patients (n = 32, 91.4%), compared to IPD patients (n = 122, 66.3%). ³⁰

A Swedish study on 185 patients (73-IPD, 53-SP (secondary parkinsonism) vs. 59 controls) reported that IPD and SP had more significant complications compared to the controls, with slight variations in the NMS expression among the groups. ³¹ In our study on 204 patients (155-PD, 22-PSP, 27-MSA), we reported mean NMSS scores of 23.7 ± 27.9-PD, 47.6 ± 41.3-PSP, 65.6 ± 35.5-MSA group and inferred that NMS burden was inferior in the order of MSA, PSP and PD, which is in agreement to a prior report. ¹¹ Our findings include several strengths, such as a considerable number of enrolled patients compared to other studies worldwide. Standard validated criteria are applied to diagnose all the patients and with excluded SP group by appropriate investigations. Our study has revealed noticeable differences compared to the existing sparse literature. As per the Polish study, ³⁰ though NMS are frequent in both IPD and AP, AP patients are more likely to present NMS with rare complaints of sleep disorders. However, another Swedish study ³¹ compared IPD and SP and demonstrated minor differences between them. However, symptoms like sleep, pain, reduced taste and bladder disturbances were more continual in the IPD group. Of note, though an abstract published by Kataria and Goyal. ¹¹ demonstrated similar parameters data in PD, PSP and MSA groups, we found certain comparative differences. They showed the mean order of NMSS scores for PD, PSP and MSA as 37.1 ± 33.1, 70.7 ± 50.7 and 80.0 ± 43.7, respectively. Despite revealing a similar pattern of mean NMSS scores for PD, PSP and MSA as 23.7 ± 27.9, 47.6 ± 41.3 and 65.6 ± 35.5, respectively, the lower mean NMSS scores observed in our study could possibly be attributed to our larger sample size. Further, we also found higher scores for the urinary domain in addition to the cardiovascular and sexual domain for the MSA group (not mentioned in the abstract of Kataria and Goyal. ¹¹ Furthermore, in addition to attention, the mood/cognition, the sleep domain was also impaired in the PSP group in our study. On the other hand, the PD group revealed sleep as maximally affected domain, while the lowest scores were observed for perceptual and sexual domains. However, the study by Kataria and Goyal reported the lowest score for the urinary domain.

Strengths and Limitations of the Study

The strength of this study includes a considerable number of enrolled patients compared to other previous reports. We also applied standard validated criteria to diagnose all the patients, which excluded the SP group, using appropriate investigations. This is a single-centre study with all the recruited participants from Northern India, which prohibits generalising our findings. Being a questionnaire-based analysis, a recall bias cannot be excluded. Moreover, the number of PD patients far outnumbered AP patients. PD patients mainly suffer from non-motor fluctuations, which could have affected the findings of NMS among the study group. Nevertheless, our study has delved into a crucial unmet need in Parkinsonism patients, which is often neglected. Therefore, future longitudinal cohort studies in a large and diverse population to assess the clinical course of NMS and fluctuations in both PD and AP would help better understand the pathophysiology and optimal utilisation of drug targets.

Conclusion

We found that NMS was highly prevalent and severe among AP (MSA > PSP) compared to PD. This could be corroborated by the prevalence of sexual cardiovascular and urinary domains in MSA, whereas attention and mood/cognition and sleep in PSP. However, extensive studies are required to validate our findings to reach a consensus.

Abbreviations

NMS: Non-motor symptoms; AP: Atypical Parkinsonism; MSA: Multiple system atrophy; PSP: Progressive supranuclear palsy; PD: Parkinson’s disease; NMSS: Non-motor symptom scale.

Authors Contribution

MT was involved in conceptualisation, formal analysis, investigation, methodology, software, visualisation and writing—original draft. AK helped in formal analysis, investigation, methodology, software, visualisation and writing—review and editing. AKJ contributed to data curation, formal analysis, investigation, validation and visualisation. VKS and AP helped in formal analysis, investigation, validation and visualisation. RNC and VNM was involved in formal analysis, investigation, validation and visualisation NKD and NRD helped in formal analysis, validation, visualisation, writing—review and editing. MS was involved in data curation, investigation and methodology. DJ helped in conceptualisation, formal analysis, methodology, project administration, supervision, validation and visualisation.

Authors’ Note

Madhusudan Tapdia and Anand Kumar contributed equally to the work.

Data Availability Statement

The data could be available upon reasonable request from the corresponding author.

Statement of Ethics

This study was approved by the Institutional Ethical Committee of the Faculty of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India (no. Dean/2020/EC/1924 and date of approval: 21^st, 2020). Prior to the initiation of the study, a written informed consent was obtained from the patient or guardian after explaining the conditions. A predesigned proforma was filled with detailed clinical and family history and a rigorous neurological examination.

ICMJE Statement

Provided online with the submission.