Neurological update: non-motor symptoms in atypical parkinsonian syndromes

Early cognitive dysfunction is one of the key clinical features of PSP, distinguishing it from other atypical parkinsonian syndromes, wherein patients may present symptomatically up to three years before diagnosis. [22]

One British study [23] explored whether scores from the Addenbrooke’s Cognitive Examination-revised (ACE-R) could be used to clinically differentiate between patients that presented with either PD (n = 86) or other atypical Parkinsonian syndromes (n = 30 PSP, n = 19 CBD). Total ACE-R scores and subscores for verbal fluency and visuospatial domains distinguished patients with PSP from those with PD. In particular, verbal fluency most strikingly distinguished those with PSP, supporting the hypothesis that executive cognitive dysfunction appears to be an early prominent feature among those with PSP.

In another series of papers [24, 25], researchers reported on the cognitive outcomes among 124 patients with frontotemporal lobar degeneration syndromes (35 PSP, 29 CBS, 33 primary progressive aphasia (PPA) and 27 behavioural variant-FTD (bvFTD)) as part of an epidemiological study encompassing assessments with ACE-R, mini-mental state examination (MMSE), Frontotemporal Dementia Rating Scale (FRS), PSP Rating Scale (PSPRS) and Frontal Assessment Battery (FAB). Apathy, considered by some to be closely linked to executive dysfunction, was found to be a prominent clinical feature among patients with PSP and a strong predictor of survival among this cohort. Furthermore, when carer-rated changes in terms of everyday skills, self-care, motivation, and impulsive-apathetic or challenging behaviours were correlated against neuroimaging parameters, they appeared to demonstrate disruption in ventral frontotemporal tracts. [26]

Speech impairments are prominent among patients with PSP, particularly those with the PSP-cortical subtypes [27]. A smaller clinicopathological case series (n = 4) [28] initially reported the association of prominent features of speech apraxia and PNFA in pathologically-proven PSP cases. A year later, this was confirmed in a larger clinicopathological case series [29] from the same research group involving over 100 cases of frontotemporal lobar dementia, CBD and PSP, in which 10% of those with PSP were found to have been clinically diagnosed with apraxia of speech and PNFA. In another large, multicentre clinicopathological case series [30], 30% of patients with a tauopathy (of whom, 55% of patients had either a diagnosis of CBD or PSP) presented with clinical features of progressive aphasia. In yet another study [31], investigating speech and language impairments among patients diagnosed with either speech apraxia or PNFA, 11 patients were found to have either CBD or PSP. Among those where speech apraxia was predominant, the most likely diagnosis was PSP, while CBD was more likely among those where aphasia was the main speech abnormality.

One study conducted in China [18] observed deficits in memory and attention among 96% of patients with PSP, which was markedly higher than a European multicentre study [19] reporting a prevalence of 76%. Another comparative study [32] considered 110 patients with PSP and 83 with MSA of similar disease durations, and demonstrated cognitive impairments were significantly more likely to occur among those with PSP compared to MSA (p = 0.03). In another European multicentre study [2], the prevalence of cognitive problems was compared in patients with either vascular parkinsonism (VP) (n = 83), MSA (n = 34), PSP (n = 30), DLB (n = 14) and CBD (n = 11), where it was found that 63% of patients with PSP had attentional/memory problems using NMSS. Another comparative study [15] matched 20 patients with PSP by age, education and global cognitive status to 20 with PD, 20 with MSA and 20 with PSP, and found that those with PSP were more impaired on cognitive tests assessing executive function than any other group. Using semi-structured interviews and the Quality of Life Assessment Schedule (QOLAS) interview questionnaires, one British study [12] reported 38% of 27 patients with PSP reported concentration difficulties, while 33% reported memory impairments.

In one European multicentre study [2] including 34 patients with MSA, 68% were found to have attentional/memory problems on NMSS. Meanwhile, another group [33] explored the prevalence of cognitive impairments in relation to postural hypotension among 10 MSA-P and 4 MSA-C patients and reported no significant differences in cognitive impairments between patients with or without postural hypotension.

In relation to cognitive impairments in CBD, there appears to be a wide range of clinical presentations which patients may develop throughout their clinical course. Using the ACE-R, several researchers have shown patients with CBD demonstrate a broad range of cognitive impairments that affect multiple domains [34‐38]. One Italian multicentre study [2] found that among 11 patients with a clinical syndrome of CBD, 70% reported attentional/memory problems.

A recent clinicopathological case series [39] considered the clinical course among 15 patients with a pathologically-confirmed diagnosis of CBD presenting with cognitive-predominant features (who had received a clinical diagnosis of either AD or FTD), and compared them to matched patients who were clinically diagnosed with CBS. At initial presentation, aphasia was found among 33% (5/15) with pathologically-confirmed CBD in this cases series, compared to 20% (3/20) in those clinical diagnosed with CBS (although the difference was not statistically significant) [39]. Meanwhile, apathy was far more common in those with pathologically-confirmed CBD (53%) compared to those who received a clinical diagnosis of CBS (16%) (p = 0.014) [39].

While executive dysfunction and memory problems are particularly common in CBD [34‐37, 40], they may not always help distinguish CBD from other neurodegenerative conditions [41]. However, there appears to be a growing understanding of how impairments in language processing, visuospatial dysfunction and social cognition may be a possible distinguishing feature among patients with CBD [35, 40]. Speech and language dysfunction in particular appears to be a common presenting feature among patients with CBD [42, 43], where it has been estimated to occur in up to a third of patients [44‐50], and encompass a wide range of clinical presentations including non-fluent aphasia [51], apraxia of speech [52] or agraphia [53]. In the large clinicopathological case series previously mentioned [29], 19% of patients with CBD were found to have clinical features of apraxia of speech and progressive non-fluent aphasia. In a Canadian case series [54] reporting on the evolution of several neurodegenerative conditions, a handful of cases that met the clinical diagnostic criteria for primary progressive aphasia were subsequently found to have CBD pathology at post-mortem.

Visual dysfunction appears to be another common problem among patients with CBD [37, 42, 45, 48, 51, 55, 56], and is included in the diagnostic criteria for the disease [51, 57, 58]. Although several studies [37, 45, 48] did not find any gross visual impairments on formal testing, one review [41] discussed how this might be due to confounding factors such as limb apraxia, motor deficits or co-existent executive dysfunction which could limit the ability to formally test visuospatial function.

Behaviour and personality changes have also been reported in the literature to occur commonly among patients with CBS [35, 40, 42, 59, 60], yet there appear to be few clinicopathological studies that comprehensively explore this aspect further. In one Mayo clinic study that was discussed [39], behavioural changes were reported to occur among 93% of a pathologically confirmed cohort of CBD who presented with cognitive impairment, compared to 19% in those with clinically diagnosed CBS (p < 0.001) [39].

Dementia defined as a progressive cognitive decline of sufficient magnitude to interfere with either normal social or occupational function, or with usual daily activity, is an essential criterion for diagnosing DLB. Fluctuating cognition is one of the core criteria in making the diagnosis [61], yet may not be exhibited by all patients as evidenced by one study reporting the phenomenon to occur in less than half of patients (44.5%) [62].

Mood [5] appears to have a significant correlation with the quality of life scores (based on PD-Q 39) in patients with PSP (ρ = 0.744, p = 0.002). Compared to healthy controls, all patients with PSP in one study from western China exhibited problems with mood/apathy, while 15% of patients with PSP also demonstrated hallucinatory or perceptual disturbances [18]. The frequency and severity of mood/apathy and attention/memory symptom domains on NMSS were significantly higher among patients with PSP compared to healthy controls (p < 0.05), while mood/apathy and attention/memory symptoms were also significantly higher in patients with PSP than those with PD (p < 0.05) [18]. In another European multi-centre study [19], problems with mood/apathy (as recorded on NMSS) were found among 88% of patients with PSP, while 36% had disturbances in perception/hallucinations. Patients with PSP were also significantly worse in terms of mood/apathy NMSS domain scores compared to patients with PD using comparative analyses (p = 0.0001) [19]. These findings were also mirrored in another comparative Italian multicentre study [2], where 67% of patients with PSP were found to have symptoms of apathy as reported on NMSS, while 73% had psychiatric problems. An apathetic neurobehavioral profile among patients with PSP has also been shown to predict a higher risk of disease-related mortality, further emphasising the need for better measurement tools to improve recognition and early intervention [63]. Another comparative study [15] demonstrated apathy and depression were more severe among patients with PSP compared to those who had PD, while apathy alone (without depression) was also more severe in PSP compared to MSA. Using QOLAS interview questionnaires, one study [12] found that among 27 patients with PSP, 54% reported symptoms of depression, 33% reported frustration, 29% anxiety, 21% sexual problems. A British longitudinal study [64] used several questionnaires, including the palliative care outcome scale (POS-S), to assess 15 patients with PSP and reported 13% of patients having hallucinations. An Italian study [16] which considered neuropsychiatric symptoms among outpatients with either PD (n = 155), PSP-Parkinson (PSP-P) (n = 11) and PSP-Richardson Syndrome (PSP-RS) (n = 14), used multivariate logistical regression analysis and found that early phonological verbal fluency deficits helped distinguish patients with PSP-RS, whilst apathy was more likely to support a diagnosis of PSP-P. A comparative study conducted in Germany [17] demonstrated that patients with PSP-RS (n = 14) showed more neuropsychological and neurobehavioral deficits than those with PSP-P (n = 9).

Among patients with MSA, mood and apathy symptoms were more common than other neuropsychiatric manifestations. One study [2] found that among 34 patients with MSA, 65% had symptoms of apathy, while 79% had psychiatric problems as reported on the NMSS. This finding was mirrored in another prospective study which also used the NMSS among 172 patients with MSA (n = 76 MSA-P, n = 96 MSA-C) [65], and found that 88% reported disturbances in mood/apathy (88% MSA-PC, 89% MSA-C), 74% reported depressive symptoms (76% MSA-P, 72% MSA-C) and 45% reported symptoms of anxiety (40% MSA-P, 50% MSA-C) [65]. Furthermore, 70% of patients with MSA had reported a loss of interest in surroundings (76% MSA-P, 66% MSA-C), while 67% reported a lack of motivation (70% MSA-P, 65% MSA-C). Hallucinatory symptoms and delusional thought disorders were scarcely reported among patients with MSA in this study (3.5% [3.9% MSA-P, 3.1% MSA-C] and 0.6% [1.3% MSA-P, 0% MSA-C] respectively) [65]. Similarly, among 17 patients with MSA included in one study [64], only 29% reported hallucinatory symptoms on the POS-S.

Among 11 patients with a clinical syndrome of CBD included in the Italian multicentre comparative study [2], 64% of patients were reported to have symptoms of apathy, while 55% had psychiatric problems using NMSS.

The prevalence of neuropsychiatric and behavioural symptoms in patients with DLB varied among published studies. In one large multicentre study [2], 86% of the 14 patients with DLB had symptoms of apathy as reported on NMSS, while 93% reported psychiatric problems. In another retrospective study conducted in Japan [66] the prevalence of prodromal NMS was surveyed using standardised questionnaires among 34 patients with DLB (n = 31 ‘probable’, n = 3 ‘confirmed’) presenting to a memory clinic who were matched by age, gender and MMSE scores to 30 control patients. 24% of patients with DLB had depressive symptoms, while 26% had apathy, 26% had anxiety symptoms, and 12% had a mood disturbance [66]. When the onset of NMS preceding cognitive impairments were explored among patients with DLB, 32% were found to have preceding symptoms of depression (mean duration − 4.5 ± 10.7 years). Certain NMS were actually found to be more common after the onset of cognitive impairments among patients with DLB; including symptoms of anxiety in 38% (0.3 ± 2.9 years); moodiness in 29% (0.8 ± 2.5 years) and a lack of motivation in 62% (2.4 ± 4.1 years) [66].

Sleep disturbances are particularly common among patients with PSP, where the prevalence reported in the literature ranges between 77–100% [2, 18, 19, 64]. In one study conducted in Western China [18], all patients with PSP demonstrated sleep/fatigue symptoms on NMSS, and the frequency and severity of sleep/fatigue symptom domains on NMSS were found to be significantly higher compared to that seen in healthy controls (p < 0.05). A similar finding was reported in another multi-centre European study [19], where most patients with PSP (92%) reported sleep/fatigue symptoms, with significantly worse sleep/fatigue NMSS domain scores compared to patients with PD using comparative analyses (p = 0.0007). Similarly, another European multicentre study [2] reported sleep disturbances among 77% of patients with PSP using NMSS, while another longitudinal study [64] identified that 73% of patients with PSP exhibited sleepiness, while 40% exhibited difficulty sleeping using standardised questionnaires and POS-S scores.

Among patients with MSA, the prevalence of sleep symptoms varied greatly in the published literature. Using POS-S scores, one longitudinal study [64] reported a prevalence of 82% for both excessive sleepiness symptoms and symptoms of difficulty sleeping. Meanwhile, two other studies [2, 65] used the NMSS to evaluate sleep symptoms: one study reported sleep disturbance in 68% of patients with MSA [2] while the other reported excess daytime sleepiness in 53% of patients with MSA(57% MSA-P, 50% MSA-C) [65].

One study [2] considered the prevalence of sleep symptoms among patients with a clinical syndrome of CBD, wherein the reported prevalence was 36% using NMSS.

Sleep disturbances were relatively common among patients with DLB, with a wide repertoire of sleep-related symptoms being identified. In general, sleep disturbances among patients with DLB were reported to be 79% in one European multicentre study [2] using NMSS, while another Japanese study [66] found sleep rhythm disturbances to occur in 62% of patients with DLB using a standardised survey of NMS. The latter group [66] also explored the prevalence of RBD features and found that 35% of DLB patients had abnormal limb movements during sleep, while 27% experienced nightmares. RBD is now included as a core criterion for the diagnosis of DLB [61] because it occurs frequently among autopsy-confirmed cases compared with non-DLB dementia cases (76% vs 4%) [68]. When the onset of NMS preceding cognitive impairments was explored among DLB patients, antecedent features of an anREM-sleep disorder were found to be common in DLB: crying or shouting in sleep preceded cognitive impairments in 77% of patients (mean duration − 4.9 ± 9.5 years); preceding abnormal limb movements sleep in 47% (− 3.9 ± 9.1 years); preceding nightmares in 38% (− 2.5 ± 8.0 years), and preceding sleep rhythm disturbances in 82% (− 0.5 ± 5.5 years) [66]. Sleep duration of less than 5 h per day or the presence of hypersomnolence have also been significantly associated with DLB amongst patients with various dementia syndromes [62].

Fatigue symptoms were particularly common among patients with PSP, wherein two studies [2, 64] both demonstrated a prevalence of 80% using either NMSS or POS-S scores respectively.

Among patients with MSA, fatigue symptoms were also frequently reported, with one longitudinal study [64] observing a prevalence as high as 88% using POS-S scoring. Two studies used the NMSS and observed the prevalence of fatigue at 82% [2] and 61% (62% MSA-P, 60% MSA-C) [65]. Another study [69] utilised the Fatigue Severity Scale (FSS) and found nearly a quarter of MSA patients reported fatigue symptoms using this tool.

One European multicentre study [2] reported fatigue symptoms in more than half of patients with a clinical syndrome of CBD as measured by the NMSS.

The same multicentre study [2] also reported the prevalence of fatigue symptoms using NMSS in more than 70% of patients with DLB.

Gastrointestinal symptoms, as reported on NMSS, were particularly common among patients with PSP, wherein three studies reported a prevalence between 80–86% [2, 18, 19]. One comparative study [18] found that the frequency and severity of gastrointestinal symptom domains on NMSS were significantly higher among patients with PSP compared to healthy controls (p < 0.05), while another [19] reported worse gastrointestinal NMSS domain scores among patients with PSP compared to those with PD using comparative analyses (p < 0.0001). Using the POS-S score and structured questionnaires, another study [64] also found that 60% of patients with PSP reported constipation symptoms, while only 7% reported nausea.

The prevalence of gastrointestinal symptoms among patients with MSA varied depending on the study and the type of assessment tools used. Two studies used the NMSS: one [2] reported gastrointestinal symptoms to occur in 82% of patients with MSA; while the other [65] observed difficulty swallowing occurring in 53% of patients with MSA (57% MSA-P, 50% MSA-C) and constipation in 55% (66% MSA-P, 46% MSA-C). Using standardised questionnaires and POS-S scoring, another study [64] reported nausea to occur in 41% of patients with MSA and constipation in 77%. Similarly, one comparative study [13] involving both patients with MSA-P and MSA-C (n = 95 and n = 48 respectively) observed a prevalence of constipation of 73% in all patients with MSA.

One comparative study [2] reported gastrointestinal symptoms to occur in 64% of patients with a clinical syndrome of CBD as reported on NMSS.

Among patients with DLB, one comparative study [2] reported gastrointestinal symptoms to occur in 86% of patients using NMSS. Using standardised surveys of non-motor PD symptoms, another study [66] found that 47% of patients with DLB had constipation while 53% experienced antecedent features of constipation prior to memory loss when the onset of NMS preceding cognitive impairments was explored (mean duration − 9.4 ± 16.9 years).

74% of patients with PSP in the study from western China [18] reported symptoms of urinary dysfunction on NMSS. Conversely, in another European multi-centre study [19], 92% of patients with PSP had symptoms of urinary dysfunction and had significantly worse urinary dysfunction NMSS domain scores compared to patients with PD using comparative analyses (p = 0.0001). Another study [2] also using the NMSS, found 53% of patients with PSP had urinary symptoms.

There is, not surprisingly, more work on urinary dysfunction symptoms in patients with MSA. One study [71] explored post-void residual (PVR) volumes and found that this was significantly higher among patients with MSA compared to those with PD or PSP. PVR volumes were also demonstrated to correlate strongly with symptoms of urinary dysfunction (e.g. incomplete micturition, weak urine stream, and nocturia), other autonomic features, NMS and activity of daily living scores among patients with MSA [71]. Perhaps unsurprisingly, the study also demonstrated a negative relationship between PVR and renal function [71]. Among studies using questionnaires, the prevalence of urinary dysfunction symptoms varied between 71–91% [64, 65] in patients with MSA. Another study from China [13] reported nocturia in 80% of patients with MSA, urinary urgency in 78%, and urinary incontinence in 70% using standardised questionnaires. Using the NMSS, one study [2] reported a prevalence of urinary symptoms of 91%.

There is very little research into urinary dysfunction among patients with a clinical syndrome of CBD. Only one study [2] considered urinary symptoms among patients with the condition and reported a prevalence of 55%.

Using the NMSS, one study [2] reported urinary dysfunction symptoms to occur in 79% of patients with DLB. Meanwhile, another study [66] utilised a standardised survey of NMS and only observed urinary incontinence symptoms among 26% of patients with DLB. Perhaps unsurprisingly, these symptoms were subsequently found to be more common (53%) among patients with DLB after the onset of cognitive impairments (2.4 ± 4.8 years) [66], since the impairment of cognition or dementia are risk factors for the development of urinary incontinence.

Two studies considered the prevalence of cardiovascular symptoms among patients with PSP, wherein one study [2] reported a prevalence of 13% for postural hypotensive symptoms using the NMSS. The other study [72] utilised standardised questionnaires to compare autonomic symptoms among patients with either PSP (n = 32), MSA (n = 38), PD (n = 26) or age-matched healthy controls (n = 27), along with five autonomic function tests (deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring). Other than pupillography, no other laboratory-based autonomic function tests distinguished one patient group from another, alone or in combination [72].

The prevalence of cardiovascular symptoms and orthostatic hypotension has varied greatly among published literature considering patients with MSA. Two studies [2, 65] utilised the NMSS and reported postural symptoms in 31–55% of patients with MSA, while one study [65] observed light-headedness symptoms to occur in 70% of patients (65% MSA-P, 74% MSA-C), while falls due to fainting occurred in 16% using NMSS (16% MSA-P, 16% MSA-C). Another study [33] considered both patients with MSA-P and MSA-C and found that 57% of patients had confirmatory evidence of postural hypotension, while 79% had orthostatic symptoms. Conversely, another study [13] only reported a prevalence of orthostatic hypotension among 30% of patients with MSA. One study [73] compared the prevalence of orthostatic hypotension among patients with either Parkinson’s disease (n = 1125) or atypical parkinsonian disorders (MSA n = 26, CBD n = 14, PSP n = 26), and found this to be most prevalent among patients with MSA (81%) compared to all other groups (PD 18%, DLB 31%, PSP 26%, CBD 7%).

One study [2] considered the prevalence of orthostatic postural symptoms among patients with a clinical syndrome of CBD and found that none of the patients reported these symptoms.

Using the NMSS, one study [2] demonstrated a prevalence of postural symptoms due to orthostatic hypotension of 21% among patients with DLB. This was similar to another study [66] which conducted a standardised survey of non-motor PD symptoms and reported a prevalence of orthostatic dizziness symptoms of 24% in patients with DLB. Orthostatic dizziness symptoms were also common after the onset of cognitive impairments, with 29% of patients exhibiting symptoms (mean duration 0.0 ± 2.1 years after the onset of cognitive impairment) [66]. The prevalence of cardiovascular symptoms among patients with PSP was 18% in a study from western China [18], and 50% in the European multi-centre study [19] using NMSS.

The prevalence of sexual dysfunction symptoms varied greatly among patients with PSP. Using the NMSS, one study [18] reported the prevalence of such symptoms to be as high as 93%, with the frequency and severity of sexual dysfunction symptom domains on the NMSS being scored significantly higher among those with PSP compared to PD (p < 0.05) or healthy controls (p < 0.05). Conversely, another European multi-centre study [19] found the prevalence of sexual dysfunction to only be present in 18% of patients with PSP using the NMSS, which was similar to a third study [12] which reported sexual dysfunction symptoms in 21% of patients with PSP using QOLAS.

One study [65] considered the prevalence of sexual dysfunction among patients with MSA in China using the NMSS, and reported a prevalence of 73% (70% MSA-P, 75% MSA-C). In another European study, genital hyposensitivity was reported by 56% of the women with MSA and 9% controls (p < 0.0001) [74].

Olfactory testing has previously shown merit in differentiating patients with PSP or idiopathic PD [75]. In one study [76], it was found that the olfactory scores of people with autopsy-confirmed PSP (mean UPSIT score 21.9 ± 9.4) were higher compared to those with PD (mean 13.8 ± 5.3), but lower than controls (mean 26.8 ± 6.8). Furthermore, patients who had a mixed PSP-PD pathology (mean 16.9 ± 4.5) had scores that reflected this where their score values were in between those observed with pure PSP or pure PD pathology.

Using the NMSS, one study [65] found anosmia or taste disturbances to occur in 23% of patients with MSA (MSA-P 28%, 20% MSA-C). Olfactory deficits are also thought to be less prominent in MSA than PD [77].

It is thought that odour identification deficits in CBD may be attributed to perceptual deficits [78] in the context of generalised executive dysfunction, as opposed to a pure olfactory loss as observed in cases of PD (where the primary pathology originates from olfactory structures such as the olfactory bulb) [79].

In one study [66], using standardised surveys of NMS it was found that 41% of patients with DLB had anosmia symptoms. When the onset of NMS preceding cognitive impairments was explored, antecedent features of anosmia preceded memory loss in 65% of patients on average 3 years before cognitive impairment [66].

Symptoms of pain among patients with PSP were considered by two studies: one study [2] observed such symptoms to occur in 40% of patients using NMSS, while the other [64] observed a prevalence of 60% using POS-S.

Pain symptoms are frequently reported in patients with MSA, where one study [2] reported a prevalence of 71% using the NMSS, while another [64] reported a prevalence of 88% using POS-S. However, a further study found that pain intensity as recorded on the visual analogue scale did not differ significantly in 136 patients with either PD or MSA [82].

One study [2] assessed pain symptoms in patients with a clinical syndrome of CBD and reported a prevalence of 36% using NMSS. In a pooled meta-analysis [80] of three studies involving 55 patients, the prevalence of pain symptoms was found to be slightly lower at 25%.

Half of the patients with DLB that were included in one study [2] reported pain symptoms using the NMSS. In a previous systematic review, the prevalence of such symptoms was found to range widely between 25–70% of cases [81].

One study [2] used the NMSS and reported skin disturbances (including seborrhoea and hyperhidrosis) in 17% of patients with PSP and respiratory symptoms (such as dyspnoea, cough or stridor) in 21%.

Skin disturbances (including seborrhoea and hyperhidrosis) were reported among 24% of patients with MSA using NMSS, while respiratory symptoms (such as dyspnoea, cough or stridor) were reported among 35% using NMSS [2]. Two additional studies explored the prevalence of excess saliva production among patients with MSA using NMSS: one study [65] reported a mean prevalence of 30% in patients with MSA-P and MSA-C (although found that this was more common among MSA-P patients [45% MSA-P, 17% MSA-C]), whilst the other study [13] observed a prevalence of 71% among patients with MSA. Stridor has been previously reported to occur among nearly two-thirds of patients with MSA [84]. Both obstructive sleep apnoea (OSA) and central sleep apnoea (CSA) may affect patients with MSA: in one French study involving 45 patients with MSA, 31% had OSA and 9% had CSA [85].

Among patients with a clinical syndrome of CBD, one study [2] used the NMSS and found skin disturbances (including seborrhoea and hyperhidrosis) to occur in 27% and respiratory symptoms (such as dyspnoea, cough or stridor) in 9%.

One study [2] found that the prevalence of skin disturbances (including seborrhoea and hyperhidrosis) and respiratory symptoms (such as dyspnoea, cough or stridor) among patients with DLB were both 29%. Hypersalivation symptoms were reported in 21% of DLB patients in one study [66], although this was more common (32% of patients) after the onset of cognitive impairments (0.5 ± 2.1 years). Meanwhile, the study also observed symptoms of increased sweating in 15% of patients, and when the onset of NMS preceding cognitive impairments was explored it was found that 29% had preceding increased sweating (mean duration − 6.5 ± 18.7 years) [66].

Compared to studies with PD, most studies of NMS in atypical parkinsonian syndromes are limited by their relatively small sample sizes (typically < 50 cases), and the heterogeneous case mix of confirmed and probable cases (wherein many cases in the included studies were not pathologically confirmed). For instance, among those with corticobasal syndrome, only half of the cases were accompanied by confirmatory histological findings for CBD [125]; whilst PSP, AD and TDP-43 pathology [126] may mimic the clinical syndrome. Many of the studies we included utilised standardised questionnaires (e.g. NMSS) which are validated for use in PD, but not atypical parkinsonian syndromes, limiting their generalisability or the accuracy of observed clinical findings, warranting the need for dedicated larger-scale studies with disease-specific validated questionnaires to confirm our results.