Abstract
Background and Objectives:
Although widely described in Parkinson’s disease (PD), peripheral neuropathy (PNP) is scarcely reported in progressive supranuclear palsy (PSP). We aimed to compare the frequency, clinical and electrophysiologic characteristics of PNP in PSP and PD patients.
Methods:
This cross-sectional study included 23 PSP and 93 PD patients. Demographic data, Movement Disorders Society-Unified Parkinson’s Disease Rating Scale-III (MDS-UPDRS-III), Hoehn–Yahr staging, Toronto Clinical Neuropathy Score, nerve conduction study (NCS), and sympathetic skin response (SSR) were recorded. Diagnosing isolated large fiber neuropathy required abnormal NCS. Isolated small fiber neuropathy required clinical findings of pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia with/without impaired SSR, along with normal NCS.
Results:
PNP was commoner in PSP than PD (65.2% vs. 50.5%, P = 0.21). While a comparable proportion in both groups had clinical neuropathy, NCS abnormalities predominated in PSP (65.2% vs. 39.8%, P = 0.03). All patients had distal symmetrical axonal polyneuropathy. A significantly higher proportion of PSP patients had large fiber involvement (65.21% vs. 39.78%, χ2 = 4.82; P = 0.03) and mixed fiber PNP (60.9% vs. 33.3%, P = 0.01). PSP patients with neuropathy had a significantly shorter disease duration [median (interquartile range {IQR} = 2 (2-3) years vs. 6 (3-9) years, P < 0.001], higher MDS-UPDRS-III score [median (IQR) = 47 (36–54) vs. 34 (28–49), P = 0.049], higher Hoehn–Yahr stage [median (IQR) = 4 (2–5) vs. 3 (1–5), P < 0.001], and shorter duration of levodopa use [median (IQR) = 2 (1-2) years vs. 3.5 (2-5) years, P = 0.006]. NCS parameters were comparable between PSP and PD patients with neuropathy. While PNP in PSP was not associated with any of the clinical variables, a longer disease duration was independently associated with PNP in PD.
Conclusions:
PNP affected two-thirds of PSP patients and was more prevalent than PD. Both groups had distal symmetrical axonal polyneuropathy, with mixed fiber PNP predominating in PSP. A longer disease duration in PD was associated with PNP.
Keywords: Progressive supranuclear palsy, Parkinson’s disease, peripheral neuropathy, nerve conduction study, levodopa
Introduction
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that is characterized by early axial involvement with recurrent falls, vertical supranuclear gaze palsy, cognitive decline, poor response to levodopa, and a relatively rapid progression.[1] While peripheral neuropathy (PNP) in Parkinson’s disease (PD) has been reported in up to 86% patients,[2,3,4,5,6,7,8,9,10] PSP was largely considered a central nervous system disorder, with no clear pathologic evidence of phosphorylated tau deposition in peripheral nerves.[11] However, recent studies have speculated a prion-like diffusion of phosphorylated tau from the spinal cord (intermediolateral column) to the cutaneous neurons via the paravertebral sympathetic ganglia, which thereby results in peripheral neuronal degeneration in PSP patients.[11,12,13] In fact, it has been contemplated that loss of large myelinated peripheral nerve fibers may reduce peripheral sensory input and contribute to an early postural instability in PSP.[11]
There is paucity of studies on the clinical characteristics of PNP in PSP.[11,14,15] While one study reported electrophysiologic features of PNP in 20% of 24 PSP patients,[15] a second study involving 27 PSP patients described sensory and autonomic symptoms in 60% and 100% patients, respectively.[11] A third study reported clinical and electrophysiologic features of PNP in two-thirds of their six PSP patients.[14] However, these studies either lacked detailed evaluation or were based on a small sample size.[14,15] Moreover, all three studies involved European population.[11,14,15]
PD and PSP differ in their pathophysiology, clinical manifestations, rate of disease progression, and response to anti-parkinsonian medications including levodopa.[16] Hence, we hypothesized that the frequency and characteristics of PNP may differ between these two entities. A couple of studies have assessed PNP in Indian PD patients, reporting a frequency of up to 31.8%,[5,17] but assessment in PSP patients is lacking. In this study, we aimed to assess the frequency of PNP along with its clinical and electrophysiologic characteristics in PSP patients and compare them with those in PD patients.
Methods
This cross-sectional study was conducted in a tertiary care teaching hospital in India. The study was approved by the Institutional Ethics Committee (AIIMS/IEC/20/500) and performed in accordance with the Declaration of Helsinki.
Inclusion and exclusion criteria
Consecutive PSP and PD patients aged ≥18 years and on stable dopaminergic therapy for at least 4 weeks, visiting the Movement Disorder Clinic between August 2020 and October 2022 were included in the study [Figure 1]. Included patients provided written informed consent. Patients who were pregnant, had cognitive impairment (defined as Montreal Cognitive Assessment score <24),[18] and had other common risk factors for PNP, such as diabetes, low serum vitamin B12 (<250 pg/L), and hypothyroidism, were excluded. A detailed clinical history along with general, neurologic, and other systemic examination, and relevant laboratory investigations were carried out to rule out neuropathy related to intake of drugs and native medications, systemic diseases, and other secondary factors. Movement Disorders Society criteria for PSP[19] and PD[20] were used for diagnosis. In addition to the clinical assessment of PSP and PD (NK), all patients underwent detailed clinical and electrophysiologic assessment for neuropathy (MK, AT).
Figure 1.
Flowchart for screening, inclusion, and exclusion of cases. LEDD: levodopa equivalent daily dose, MDS-UPDRS: Movement Disorders Society-Unified Parkinson’s Disease Rating Scale, MOCA: Montreal Cognitive Assessment, NCS: nerve conduction studies, PD: Parkinson’s disease, PSP: progressive supranuclear palsy
Assessment of PD and PSP
Demographic and clinical variables such as age of onset of PSP or PD, disease duration, Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)-III (motor) score in “off” state,[21] Hoehn and Yahr (H–Y) stage,[22] duration of dopaminergic treatment, and levodopa equivalent daily dose[23] were recorded.
Clinical assessment of PNP
Toronto Clinical Neuropathy Score (TCNS) was used to assess clinical neuropathy. TCNS comprises three parts – symptom scores, sensory test scores, and reflex scores. “Symptom scores” included foot pain, numbness, tingling, weakness, ataxia, and upper limb symptoms, with a score of 0 given for absence and 1 given for presence of each of these symptoms. Presence of symptoms, especially pain, numbness, tingling, and weakness, was scored only if they disturbed patients in both levodopa “off” and “on” states. “Sensory test scores” included responses to testing for pinprick, temperature, light touch, vibration, and position sense, with a score of 0 given for normal and 1 given for abnormal responses. “Reflex scores” included assessment of knee and ankle reflexes on each side, with a score of 0 given for normal reflex, 1 given for reduced reflex, and 2 given for absent reflex. The total score is 19, with a score of ≥6 favoring clinical neuropathy.[24]
Neurophysiologic assessment
Nerve conduction study
While motor nerve conduction study (NCS) and F-waves were evaluated in bilateral peroneal, tibial, median, and ulnar nerves, sensory NCS were assessed in bilateral median, ulnar, and sural nerves. The nerve conduction studies were conducted with standard techniques using Neuropack X1 EP/EMG/NCV, MEB-2300 (Nihon Kohden, Tokyo, Japan) and the values obtained were compared with normative values. Distal and proximal compound muscle action potential amplitude (base to peak), distal motor latency, and motor nerve conduction velocity (MNCV) were assessed. Sensory NCSs were performed antidromically, and averaging of at least eight responses was performed to improve the signal-to-noise ratio. The amplitude of the sensory nerve action potential was measured from baseline to the negative peak. NCS was done by the same technician with required expertise in the same laboratory and was supervised by a neurologist (MK). Limb temperature was maintained at around 32°C–34°C.
Sympathetic skin response
Sympathetic skin response (SSR) was recorded using four-channel Neuropack X1 EP/EMG/NCV, MEB-2300 (Nihon Kohden, Tokyo, Japan) according to the standard guidelines issued by the International Federation of Clinical Neurophysiology. Examination was done with the patient sitting comfortably in a chair in a luminous room with stable temperature. The recording (active) electrodes were placed at the palms of both hands, and the reference (neutral) electrodes at the dorsal surface of both hands. SSR was elicited by electrical stimulation of the right median nerve and simultaneously recorded from the palms of both hands. The electrical stimulus comprised a pulse of 0.1 ms duration and 10–20 mA intensity. Recording time was 1 sec/division, with a bandpass filter of 10–1000 Hz, and amplification ranged 200 V to 1 mV. Five electrical stimuli were initially applied at irregular time intervals at a frequency of approximately one stimulus per minute to avoid habituation. The response with the shortest latency and maximum amplitude was selected from all the recorded waveforms. SSR onset latencies and peak-to-peak amplitudes were also recorded.
Diagnostic criteria for PNP
Isolated large fiber neuropathy was diagnosed in the presence of abnormal NCS with or without clinical symptoms or signs suggestive of only large fiber involvement (tingling, numbness, sensory ataxia with/without reflex loss or weakness), while isolated small fiber neuropathy was diagnosed based upon the presence of clinical signs and/or symptoms suggestive of only small fiber impairment (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia) with or without impaired SSR along with normal NCS. Mixed fiber neuropathy was diagnosed in the presence of both large and small fiber involvement mentioned thereof.
Outcome
The primary outcome was the frequency of neuropathy in PSP and PD patients. Secondary outcomes included comparison of the clinical and electrophysiologic characteristics of neuropathy in PSP and PD patients.
Statistical analysis
Statistical Package for the Social Sciences version 28.0 for Mac was used to analyze the data. Normality of distribution was assessed with Shapiro–Wilk test. Parametric and nonparametric continuous variables were expressed as mean ± standard deviation and median (interquartile range [IQR]), respectively. Categorical variables were expressed as proportions or percentages. While independent t-test was used to analyze parametric continuous data, nonparametric data were compared using Mann–Whitney U test. Categorical variables were compared using Chi-square test or Fisher’s exact test. Variables with P < 0.1 on univariate analysis were considered for multivariate regression analysis to assess independent associations with the presence of neuropathy. A two-tailed P value of <0.05 was considered statistically significant.
Results
We assessed 154 consecutive patients with PSP or PD; of these patients, 24 had PSP and 130 had PD. Thiry-eight patients were excluded from them for several reasons [Figure 1]. Among the 116 included patients, 23 had PSP and 93 had PD. The PSP subtypes observed included PSP-Richardson syndrome (14, 60.9%), PSP-predominant parkinsonism (4, 17.4%), PSP-corticobasal syndrome (4, 17.4%), and PSP-progressive gait freezing (1, 4.3%).
Comparison of demographic and clinical variables in PSP versus PD patients
While the median (range) age at assessment was comparable between PSP and PD groups, PSP patients had a significantly higher age of disease onset compared to PD patients (mean ± standard deviation: 59.04 ± 10.02 vs. 54.12 ± 9.62; P = 0.03) [Table 1]. Compared to PD patients, the disease duration was significantly lower (P = 0.04) and MDS-UPDRS-III score (P < 0.01) and H–Y stage (P < 0.01) were significantly higher in PSP patients. The frequency of neuropathy was similar in PD and PSP patients (50.5% vs. 65.2%, P = 0.21) [Table 1]. The comparison of NCS parameters between PSP and PD patients is shown in Supplementary Table 1.
Table 1.
Comparison of demographic and clinical variables in patients with PSP and PD
| PSP (n=23) | PD (n=93) | P | Test value | df | |
|---|---|---|---|---|---|
| Age at assessment (years), mean (SD) | 62 (10.29) | 59.31 (9.69) | 0.24 | t: -1.18 | 114 |
| Age at onset of PD/PSP (years), mean (SD) | 59.04 (10.02) | 54.12 (9.62) | 0.03 | t: -2.18 | 114 |
| Male gender, n (%) | 14 (60.9) | 54 (58.1) | 0.81 | χ2: 0.06 | 1 |
| Duration of PD/PSPa, median (IQR) | 3 (2–3) | 4 (2–7) | 0.04 | U: 772 | - |
| Levodopa dose (mg)a, median (IQR) | 400 (400–600) | 400 (400–500) | 0.22 | U: 1235.50 | - |
| LEDD dose (mg)a, median (IQR) | 600 (400–700) | 450 (400–645) | 0.25 | U: 1231 | - |
| Duration of levodopa use (years)a, median (IQR) | 2 (2–3) | 2 (1–4.5) | 0.38 | U: 943.50 | - |
| MDS-UPDRS-III scorea, median (IQR) | 46 (35–53) | 33 (23–44) | <0.01 | U: 1541 | - |
| Hoehn–Yahr stagea, median (IQR) | 4 (3–4) | 2 (2–3) | <0.01 | U: 1820.50 | - |
| Peripheral neuropathy, n (%) | 15 (65.2) | 47 (50.5) | 0.21 | χ2: 1.59 | 1 |
aNonparametric distribution. df: degrees of freedom, IQR: interquartile range, LEDD: levodopa equivalent daily dose, MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, PD: Parkinson’s disease, PSP: progressive supranuclear palsy, SD: standard deviation
Supplementary Table 1.
Comparison of side-wise nerve conduction study parameters in patients with Progressive supranuclear palsy and Parkinson’s disease
| NCS characteristics | PSP (n=23) A | PD (n=93) B | P A vs B | Test value |
|---|---|---|---|---|
| Right median sensory DL (ms), median (IQR) | 3 (2.7-3.2) | 2.8 (2.5-3.1) | 0.07 | U=1329 |
| Right median SNAP (in μv), median (IQR) | 30.3 (20.4-43.7) | 28.3 (18.2-40) | 0.61 | U=1144 |
| Right median sensory CV (in m/s), median (IQR) | 50 (48.7-58.1) | 51.4 (46.3-58.1) | 0.55 | U=983 |
| Left median sensory DL (ms), median (IQR) | 2.9 (2.6-3.3) | 2.8 (2.5-3.2) | 0.15 | U=1279 |
| Left median SNAP (in μv), median (IQR) | 31.2 (17.5-43.7) | 30.5 (18.85-41.65) | 0.86 | U=1044 |
| Left median sensory CV (in m/s), median (IQR) | 53.6 (46.3-57.3) | 52.8 (46-59.1) | 0.79 | U=1107 |
| Right ulnar sensory DL (ms), median (IQR) | 2.7 (2.3-3) | 2.7 (2.35-2.9) | 0.81 | U=1104 |
| Right ulnar SNAP (in μv), median (IQR) | 28 (19.3-37) | 27.7 (20.55-40.4) | 0.67 | U=1007 |
| Right ulnar sensory CV (in m/s), median (IQR) | 50 (45.1-55.1) | 49.8 (43.9-56) | 0.81 | U=1105 |
| Left ulnar sensory DL (ms), median (IQR) | 2.7 (2.4-3.2) | 2.7 (2.4-2.9) | 0.34 | U=1206 |
| Left ulnar SNAP (in μv), median (IQR) | 33.5 (19.8-35.7) | 28 (20.45-39.35) | 0.81 | U=1105 |
| Left ulnar sensory CV (in m/s), median (IQR) | 51 (45-54.2) | 50.1 (45.05-56.5) | 0.89 | U=1050 |
| Right sural DL (ms), median (IQR) | 3.2 (0-3.6) | 3 (2.4-3.35) | 0.84 | U=1098 |
| Right sural SNAP (in μv), median (IQR) | 4.9 (0-8.5) | 7.7 (3.4-11.9) | 0.10 | U=868 |
| Right sural sensory CV (in m/s), median (IQR) | 37.6 (0-45.8) | 41.3 (34.2-46.3) | 0.32 | U=927 |
| Left sural DL (ms), median (IQR) | 3.3 (0-3.6) | 3.1 (2.35-3.4) | 0.79 | U=1107 |
| Left sural SNAP (in μv), median (IQR) | 6.5 (0-10.6) | 7.7 (3.4-12.8) | 0.14 | U=845 |
| Left sural sensory CV (in m/s), median (IQR) | 35.1 (0-44.4) | 41.5 (32.5-45.6) | 0.28 | U=918 |
| Right median DL (in ms), median (IQR) | 3.4 (2.7-3.8) | 3.4 (3-3.8) | 0.37 | U=940 |
| Left median DL (in ms), median (IQR) | 3.7 (3.2-4.1) | 3.5 (3.1-3.85) | 0.12 | U=1293 |
| Right median d-CMAP (in mv), median (IQR) | 7.6 (4.8-9.5) | 7.3 (6-8.9) | 0.81 | U=1035 |
| Left median d-CMAP (in mv), median (IQR) | 7.3 (5.1-9.3) | 7.6 (6.2-9) | 0.25 | U=902 |
| Right median motor CV (in m/s), median (IQR) | 49.5 (47.6-56.5) | 55.6 (52.4-60.2) | <0.01 | U=606 |
| Left median motor CV (in m/s), median (IQR) | 51.1 (46.8-53.8) | 55 (51.1-59.5) | <0.01 | U=612 |
| Right median F wave latency (in ms), median (IQR) | 27.9 (26.9-29.2) | 28 (26.45-29.5) | 0.64 | U=1001 |
| Left median F wave latency (in ms), median (IQR) | 28.2 (25.9-29.4) | 28.2 (26.7-29.2) | 0.86 | U=1096 |
| Right ulnar DL (in ms), median (IQR) | 2.7 (2.5-3) | 2.6 (2.3-3) | 0.65 | U=1134 |
| Left ulnar DL (in ms), median (IQR) | 3 (2.7-3.5) | 2.8 (2.5-3.3) | 0.24 | U=1239 |
| Right ulnar d-CMAP (in mv), median (IQR) | 6.1 (5.3-7.4) | 6.8 (5.5-8.6) | 0.06 | U=801 |
| Left ulnar d-CMAP (in mv), median (IQR) | 6 (4.9-7.3) | 7.3 (5.8-8.75) | 0.03 | U=745.5 |
| Right ulnar motor CV (in m/s), median (IQR) | 53.7 (49.1-57.1) | 57.1 (51.9-61.5) | 0.06 | U=794 |
| Left ulnar motor CV (in m/s), median (IQR) | 50.4 (47.3-56.5) | 56.8 (51.6-63.75) | <0.01 | U=608 |
| Right ulnar F wave latency (in ms), median (IQR) | 27.6 (27.3-29.3) | 27.6 (26.75-28.65) | 0.32 | U=1215 |
| Left ulnar F wave latency (in ms), median (IQR) | 28.1 (27.4-28.3) | 27.6 (25.6-28.5) | 0.12 | U=1292 |
| Right CPN DL (in ms), median (IQR) | 3.5 (2.9-4.9) | 3.9 (3.3 – 4.55) | 0.53 | U=980 |
| Left CPN DL (in ms), median (IQR) | 4 (2.6-5.1) | 3.8 (3.3-4.45) | 0.85 | U=1096 |
| Right CPN d-CMAP (in mv), median (IQR) | 3 (1.5-4.5) | 3.6 (2.4-4.9) | 0.05 | U=788 |
| Left CPN d-CMAP (in mv), median (IQR) | 2 (1.4-3.9) | 3.8 (2.35-4.9) | <0.01 | U=684 |
| Right CPN motor CV (in m/s), median (IQR) | 47.9 (40.7-54.1) | 50.4 (46.4-54.5) | 0.29 | U=919 |
| Left CPN motor CV (in m/s), median (IQR) | 45.7 (40.4-48) | 48.4 (45-54.1) | <0.01 | U=667 |
| Right peroneal F wave latency (in ms), median (IQR) | 45.7 (40.2-52.2) | 46.4 (43.6-50.5) | 0.71 | U=1017 |
| Left peroneal F wave latency (in ms), median (IQR) | 51.5 (41.2-54) | 47 (43.2-51.5) | 0.12 | U=1293 |
| Right tibial DL (in ms), median (IQR) | 3.8 (3.5-4.5) | 4.3 (3.6-4.8) | 0.23 | U=895 |
| Left tibial DL (in ms), median (IQR) | 3.9 (3.2-4.2) | 3.8 (3.3-4.45) | 0.62 | U=998 |
| Right Tibial d-CMAP (in mv), median (IQR) | 7.1 (3.6-8.2) | 7.4 (5.95-10.35) | 0.06 | U=801 |
| Left Tibial d-CMAP (in mv), median (IQR) | 6.2 (3.6-8.3) | 6.7 (5.35-8.4) | 0.34 | U=931 |
| Right Tibial motor CV (in m/s), median (IQR) | 45.4 (41.6-47) | 46 (42.75-50) | 0.13 | U=848 |
| Left Tibial motor CV (in m/s), median (IQR) | 43.6 (37.6-45.4) | 44.4 (41.75-48.55) | 0.11 | U=839 |
| Right tibial F wave latency (in ms), median (IQR) | 49.3 (44-54.4) | 48.8 (44.8-53.65) | 0.99 | U=1071 |
| Left tibial F wave latency (in ms), median (IQR) | 49.1 (43.1-54.5) | 49.3 (46.3-53) | 0.65 | U=1005 |
CPN: Common peroneal nerve, CV: Conduction velocity, d-CMAP: distal compound muscle action potential, DL: Distal latency, μv: microvolts, m/s: meter per second, ms: millisecond, mv: millivolts, PD: Parkinson’s disease, PSP: Progressive supranuclear palsy, SNAP: Sensory nerve action potential
Comparison of demographic and clinical variables in PSP and PD patients with neuropathy
PSP patients with neuropathy (PSP-PNP) had a significantly shorter disease duration [median (IQR) in PSP vs. PD = 2 (2–3) vs. 6 (3–9), P < 0.001], higher MDS-UPDRS-III [median (IQR) in PSP vs. PD = 47 (36–54) vs. 34 (28–49), P = 0.049], higher H–Y stage [median (IQR) in PSP vs. PD = 4 (2–5) vs. 3 (1–5), P < 0.001], and shorter duration of levodopa use [median (IQR) in PSP vs. PD = 2 (1–2) vs. 3.5 (2–5), P = 0.006], compared to PD patients with neuropathy (PD-PNP) [Table 2]. All our patients had distal symmetrical sensorimotor axonal polyneuropathy. None had pure motor axonal neuropathy or demyelinating neuropathy. While mixed fiber neuropathy was significantly more prevalent among PSP-PNP compared to PD-PNP patients (93.3% vs. 66%, P = 0.048), isolated small fiber polyneuropathy was seen only in the latter (21.3%). The median TCNS score was comparable. While all patients in the PSP-PNP group had abnormal NCS, it was seen in 37 (78.7%) patients in the PD-PNP group.
Table 2.
Comparison of demographic and clinical variables in PSP and PD patients with neuropathy
| Characteristics | PSP with neuropathy (n=15) A | PD with neuropathy (n=47) B | P (A vs. B) | Test value | df |
|---|---|---|---|---|---|
| Age at assessment, mean (SD) | 61.27 (11.58) | 60.96 (8.78) | 0.91 | t: -0.11 | 60 |
| Age at onset of PD/PSP, mean (SD) | 58.67 (11.39) | 53.98 (8.97) | 0.11 | t: -1.65 | 60 |
| Male gender, n (%) | 10 (66.7) | 26 (55.3) | 0.44 | χ2: 0.60 | 1 |
| Duration of PD/PSPa, median (IQR) | 2 (2–3) | 6 (3–9) | <0.01 | U: 116 | - |
| MDS-UPDRS-III scorea, median (IQR) | 47 (36–54) | 34 (28–49) | 0.049 | U: 472 | - |
| Hoehn–Yahr stagea, median (IQR) | 4 (2–5) | 3 (1–5) | <0.01 | U: 551 | - |
| Duration of PNP (in years)a, median (IQR) | 1 (1–2) | 1 (0–2) | 0.49 | U: 393 | - |
| Levodopa dose (mg)a, median (IQR) | 400 (400–600) | 400 (400–600) | 0.94 | U: 349 | - |
| LEDD dose (in mg)a, median (IQR) | 600 (400–600) | 500 (400–800) | 0.87 | U: 343 | - |
| Duration of levodopa use (in years)a, median (IQR) | 2 (1–2) | 3.5 (2–5) | <0.01 | U: 186 | - |
|
Neuropathy characteristics | |||||
| Clinical neuropathy (TCNS ≥6), n (%) | 10 (66.7) | 27 (57.4) | 0.53 | χ2: 0.40 | 1 |
| Abnormal NCS, n (%) | 15 (100) | 37 (78.7) | >0.99b | - | - |
| Abnormal SSR, n (%) | 3 (20) | 14 (29.8) | 0.53b | - | - |
| TCNS scorea, median (IQR) | 6 (4–12) | 6 (2–10) | 0.24 | U: 423 | - |
| Type of PNP | |||||
| Isolated large fiber neuropathy, n (%) | 1 (6.7) | 6 (12.8) | >0.99b | - | - |
| Isolated small fiber neuropathy, n (%) | 0 (0) | 10 (21.3) | >0.99b | - | - |
| Mixed fiber neuropathy, n (%) | 14 (93.3) | 31 (66) | 0.048b | - | - |
aNonparametric distribution. bFisher’s exact test. IQR: interquartile range, LEDD: levodopa equivalent daily dose, MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, NCS: nerve conduction study, PD: Parkinson’s disease, PNP: peripheral neuropathy, PSP: progressive supranuclear palsy, SD: standard deviation, SSR: sympathetic skin response, TCNS: Toronto Clinical Neuropathy Score
Overall, sensory and motor NCS parameters were comparable between PSP-PNP and PD-PNP patients. Although median MNCVs in bilateral median and left ulnar nerves were within normal limits in both PSP-PNP and PD-PNP groups, those in the PSP-PNP group were significantly lower as compared to PD-PNP patients [Supplementary Table 2].
Supplementary Table 2.
Comparison of side-wise nerve conduction study parameters in Progressive supranuclear palsy and Parkinson’s disease patients having neuropathy
| NCS characteristics | PSP-PNP (n=15) A | PD-PNP (n=47) B | P A vs B | Test value |
|---|---|---|---|---|
| Right median sensory DL (ms), median (IQR) | 3.1 (2.9-3.2) | 2.9 (2.6-3.1) | 0.16 | U=438 |
| Right median SNAP (in μv), median (IQR) | 22.8 (16.1-43.7) | 26.5 (13.3-39.5) | 0.57 | U=388 |
| Right median sensory CV (in m/s), median (IQR) | 48.9 (43.1-51.5) | 49.3 (45.7-58.1) | 0.69 | U=329 |
| Left median sensory DL (ms), median (IQR) | 2.9 (2.6-3.5) | 2.9 (2.5-3.2) | 0.36 | U=408 |
| Left median SNAP (in μv), median (IQR) | 24.9 (13.9-45.6) | 27.8 (13.6-36.8) | 0.62 | U=383 |
| Left median sensory CV (in m/s), median (IQR) | 53.4 (45.2-59.5) | 49.3 (43.4-56) | 0.32 | U=413 |
| Right ulnar sensory DL (ms), median (IQR) | 2.6 (2.3-2.9) | 2.6 (2.4-3.1) | 0.75 | U=334 |
| Right ulnar SNAP (in μv), median (IQR) | 24.4 (14.3-30.3) | 25 (16-38.6) | 0.77 | U=335 |
| Right ulnar sensory CV (in m/s), median (IQR) | 47.1 (44.7-55.1) | 47.1 (41.7-52.8) | 0.52 | U=392 |
| Left ulnar sensory DL (ms), median (IQR) | 2.6 (2.4-3.0) | 2.7 (2.5-2.9) | 0.75 | U=333 |
| Left ulnar SNAP (in μv), median (IQR) | 30.7 (19.5-33.7) | 26.3 (13-38.7) | 0.51 | U=393 |
| Left ulnar sensory CV (in m/s), median (IQR) | 50.4 (42-54.2) | 48.1 (40-54) | 0.62 | U=383 |
| Right sural DL (ms), median (IQR) | 2.9 (0-3.2) | 3 (0-3.3) | 0.72 | U=332 |
| Right sural SNAP (in μv), median (IQR) | 3.8 (0-4.9) | 4.1 (0-6.6) | 0.44 | U=314 |
| Right sural sensory CV (in m/s), median (IQR) | 32.2 (0-44) | 34.3 (0-41.3) | 0.98 | U=346 |
| Left sural DL (ms), median (IQR) | 2.6 (0-3.3) | 3 (0-3.2) | 0.93 | U=348 |
| Left sural SNAP (in μv), median (IQR) | 3 (0-6.5.5) | 3.4 (0-5.9) | 0.82 | U=322 |
| Left sural sensory CV (in m/s), median (IQR) | 32.4 (0-42.7) | 33.0 (0-41.5) | 0.75 | U=319 |
| Right median DL (in ms), median (IQR) | 3.5 (3.1-3.9) | 3.7 (3.2-3.8) | 0.54 | U=316 |
| Left median DL (in ms), median (IQR) | 3.7 (3.3-4.4) | 3.6 (3.2-4.1) | 0.37 | U=408 |
| Right median d-CMAP (in mv), median (IQR) | 7.5 (3.5-9.7) | 6.6 (5.1-8.5) | 0.81 | U=367 |
| Left median d-CMAP (in mv), median (IQR) | 7.7 (3.7-9.8) | 7.3 (6.2-8.7) | 0.66 | U=326 |
| Right median motor CV (in m/s), median (IQR) | 47.9 (45-51.3) | 54.1 (50.5-60.1) | <0.01 | U=170 |
| Left median motor CV (in m/s), median (IQR) | 47.6 (44.9-53.8) | 54.3 (49.5-61.1) | 0.048 | U=233 |
| Right median F wave latency (in ms), median (IQR) | 28.3 (27.9-30) | 28.5 (26.5-29.6) | 0.81 | U=368 |
| Left median F wave latency (in ms), median (IQR) | 29.2 (25.9-30.5) | 28.6 (26.7-29.5) | 0.54 | U=390 |
| Right ulnar DL (in ms), median (IQR) | 2.7 (2.3-3) | 2.6 (2.3-3) | 0.74 | U=373 |
| Left ulnar DL (in ms), median (IQR) | 3 (2.8-3.4) | 2.9 (2.4-3.3) | 0.43 | U=401 |
| Right ulnar d-CMAP (in mv), median (IQR) | 6.1 (5.5-7.4) | 6.5 (5.5-7.7) | 0.62 | U=322 |
| Left ulnar d-CMAP (in mv), median (IQR) | 6.6 (4.9-8.4) | 6.8 (6-8.7) | 0.27 | U=285 |
| Right ulnar motor CV (in m/s), median (IQR) | 52.2 (47.3-57.1) | 57.1 (51-61.1) | 0.10 | U=254 |
| Left ulnar motor CV (in m/s), median (IQR) | 49.5 (47.3-56.5) | 55.1 (50.4-64.1) | 0.04 | U=226 |
| Right ulnar F wave latency (in ms), median (IQR) | 28 (27.5-29.7) | 28 (27-29.1) | 0.18 | U=435 |
| Left ulnar F wave latency (in ms), median (IQR) | 28.1 (27.3-28.3) | 27.7 (25.4-29) | 0.69 | U=377 |
| Right CPN DL (in ms), median (IQR) | 3.8 (0-4.9) | 4 (3.3 – 4.9) | 0.43 | U=305 |
| Left CPN DL (in ms), median (IQR) | 4 (2.9-5.2) | 4.1 (3.4-4.6) | 0.61 | U=384 |
| Right CPN d-CMAP (in mv), median (IQR) | 1.6 (0-3.2) | 2.5 (1.3-4.1) | 0.28 | U=287 |
| Left CPN d-CMAP (in mv), median (IQR) | 1.5 (0.5-2.9) | 2.6 (1.3-4) | 0.09 | U=253 |
| Right CPN motor CV (in m/s), median (IQR) | 44.7 (0-52.6) | 50.7 (43.6-55.1) | 0.23 | U=279 |
| Left CPN motor CV (in m/s), median (IQR) | 43.7 (38.6-48) | 48.1 (41.9-54.7) | 0.06 | U=240 |
| Right peroneal F wave latency (in ms), median (IQR) | 45.7 (0-51.5) | 47.2 (42.2-52.3) | 0.31 | U=291 |
| Left peroneal F wave latency (in ms), median (IQR) | 51.3 (27.6-54) | 48 (42-52.2) | 0.47 | U=396 |
| Right tibial DL (in ms), median (IQR) | 3.8 (3.5-4.6) | 4.3 (3.2-4.8) | 0.65 | U=325 |
| Left tibial DL (in ms), median (IQR) | 3.9 (3.2-4.8) | 3.7 (3.0-4.6) | 0.59 | U=385 |
| Right Tibial d-CMAP (in mv), median (IQR) | 4.5 (1-7.9) | 6.5 (4-10.3) | 0.049 | U=233 |
| Left Tibial d-CMAP (in mv), median (IQR) | 5.8 (1.8-8.3) | 6.6 (4.7-9.3) | 0.28 | U=287 |
| Right Tibial motor CV (in m/s), median (IQR) | 45.1 (32.2-47) | 46 (41.8-47.8) | 0.27 | U=286 |
| Left Tibial motor CV (in m/s), median (IQR) | 43.6 (33-48.1) | 43.8 (37.6-46) | 0.69 | U=329 |
| Right tibial F wave latency (in ms), median (IQR) | 49.7 (0-53.9) | 51.7 (45-53.9) | 0.62 | U=323 |
| Left tibial F wave latency (in ms), median (IQR) | 50.4 (43.1-56.6) | 49.7 (46.4-56.1) | 0.61 | U=322 |
CPN: Common peroneal nerve, CV: Conduction velocity, d-CMAP: distal compound muscle action potential, DL: Distal latency, m/s: meter per second, ms: millisecond, PD-PNP: Parkinson’s disease patients with peripheral neuropathy, PSP-PNP: Progressive supranuclear palsy patients with peripheral neuropathy, SNAP: Sensory nerve action potential
Association between demographic and clinical variables and PNP in patients with PSP and PD
None of the demographic or clinical characteristics had an independent association with PNP in PSP patients. In the PD group, a longer disease duration, greater disease severity (using MDS-UPDRS-III score and H–Y staging), and duration of levodopa use appeared to be associated with PNP on univariate analysis, but only disease duration [median (IQR) in PD-PNP vs. PD-noPNP = 6 (3–9) vs. 3 (2–4); odds ratio = 1.72 (1.15–2.57); adjusted P = 0.008] was independently associated with PNP in PD patients [Table 3].
Table 3.
Association between demographic and clinical variables and PNP in patients with PSP and PD
| Characteristics | PSP-no PNP (n=8) | PSP-PNP (n=15) | P | OR (95% CI)a | Adjusted Pa | PD-no PNP (n=46) | PD-PNP (n=47) | P | OR (95% CI)a | Adjusted Pa |
|---|---|---|---|---|---|---|---|---|---|---|
| Age at assessment (years), median (IQR) | 60.50 (59.25–71) | 60 (50–69) | 0.51 | - | - | 57 (50.75–66) | 62 (55–67) | 0.06 | - | - |
| Age of onset of PD/PSP (years), median (IQR) | 57.50 (55.50–66.50) | 57 (48–67) | 0.68 | - | - | 53 (46.75–62.25) | 53 (48–60) | 0.94 | - | - |
| Male gender, n (%) | 4 (50) | 10 (66.7) | 0.44 | - | - | 28 (60.9) | 26 (55.3) | 0.59 | - | - |
| MDS-UPDRS-III, median (IQR) | 41 (32.75–51.50) | 47 (36–54) | 0.43 | - | - | 26.50 (20.75–42) | 34 (28–49) | 0.01 | 1.0 (0.96–1.05) | 0.87 |
| Hoehn–Yahr stage, median (IQR) | 3 (3–4) | 4 (3–4) | 0.55 | - | - | 2 (2–2) | 3 (2–3) | <0.01 | 2.25 (0.85–5.99) | 0.10 |
| Duration of PD/PSP (years), median (IQR) | 3 (3–4.75) | 2 (2–3) | 0.04 | 0.42 (0.16–1.12) | 0.085 | 3 (2–4) | 6 (3–9) | <0.01 | 1.72 (1.15–2.57) | <0.01 |
| Levodopa dose (mg), median (IQR) | 600 (400–750) | 400 (400–600) | 0.09 | 0.99 (0.98–1.00) | 0.10 | 400 (400–500) | 400 (400–600) | 0.77 | - | - |
| LEDD dose (mg), median (IQR) | 600 (450–800) | 600 (400–600) | 0.27 | - | - | 400 (400–600) | 500 (400–800) | 0.20 | - | - |
| Duration of levodopa use (years), median (IQR) | 2.50 (2–3.75) | 2 (1–2) | 0.13 | - | - | 2 (1–3) | 3.5 (2–5) | <0.01 | 0.67 (0.42–1.08) | 0.10 |
aUsing binomial logistic regression analysis. CI: confidence interval, IQR: interquartile range, LEDD: levodopa equivalent daily dose, MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, OR: odds ratio, PD: Parkinson’s disease, PNP: peripheral neuropathy, PSP: progressive supranuclear palsy
Discussion
In our study, PNP was seen in nearly two-thirds of PSP patients and half of the PD patients, similar to those reported in the previous literature.[3,4,11,14] All had distal symmetrical sensorimotor axonal polyneuropathy. Nearly all PSP-PNP patients had mixed fiber neuropathy, while isolated small fiber neuropathy was seen only in PD. A longer disease duration was associated with higher odds of developing PNP in PD patients.
Similar to the findings of previous studies, all our PSP-PNP and PD-PNP patients had distal symmetrical axonal polyneuropathy.[4,15,17] While a significantly higher proportion of PSP patients had mixed (large + small) fiber neuropathy compared to PD patients, isolated small fiber neuropathy was noted only in the latter. The reasons for such differential involvement of nerve fibers could be the following: (1) PSP has been shown to have more severe involvement of myelinated nerve fibers in neuropathologic studies.[11] Moreover, hyperphosphorylated tau has been observed in cutaneous Schwann cells.[25] In fact, tau protein has been reported to play an important role in mobility and phagocytosing ability of Schwann cells. Hence, tau pathology can not only impair neuronal function, but also damage Schwann cells (myelin sheath).[26] (2) There is a higher propensity of alpha-synuclein deposition in small nerve fibers in PD, where it has even been proposed as a possible biomarker.[27,28] Skin biopsy has demonstrated phosphorylated alpha-synuclein in small fiber nerves innervating autonomic structures.[29,30] In fact, skin biopsy has been shown to have the best diagnostic accuracy for detecting small fiber neuropathy, when compared to gastrointestinal tract, salivary glands, and olfactory epithelium.[29] On the contrary, no differences were observed with regard to the presence of phosphorylated tau in sympathetic ganglia between healthy and PSP subjects.[31] Neurofibrillary tangles (NFTs) were equally prevalent in the celiac, stellate, and sympathetic paravertebral ganglia of elderly individuals with or without tauopathies,[28,32] indicating normal aging as the primary factor related to the occurrence and frequency of NFTs in the sympathetic ganglia. PNP in PD has been linked with age, duration of levodopa intake,[33] motor severity, non-motor symptom burden, and longer disease duration in previous studies.[10] In our study, a longer disease duration in PD was associated with the development of PNP; however, none of the clinical variables had a significant association with PNP in PSP patients. While over one-third of PD patients on levodopa may develop PNP, the association of levodopa with PNP is still inconclusive.[4,34] In fact, duration of levodopa use may be associated with PNP in PD patients.[33] Although we found an association between duration of levodopa use and PNP in our PD cohort on univariate analysis, multivariate regression analysis revealed that only PD duration had a significant association with PNP. PNP in PD has also been linked to vitamin B12, B6, and B9 deficiency and increased serum methylmalonic acid and homocysteine levels.[4,35] Simultaneous intake of levodopa and dopa decarboxylase inhibitor (carbidopa) shifts levodopa metabolism toward catechol-O-methyltransferase, utilizing S-adenosylmethionine as the methyl group donor. This increases the formation of S-adenosylhomocysteine, thereby increasing the serum levels of homocysteine. Homocysteine can then either be transmethylated into methionine using vitamin B12 and folate as cofactors or trans-sulfurated to cystathionine using vitamin B6 as a cofactor. Moreover, carbidopa irreversibly deactivates pyridoxal phosphate, an active form of vitamin B6. In addition, gastroparesis, resulting from autonomic neuropathy in PD, may cause constipation leading to reduced absorption of levodopa and vitamins in food, further increasing the risk of PNP.[35] Thus, high homocysteine and low pyridoxine resulting from levodopa–carbidopa therapy along with reduced gastrointestinal absorption of vitamins in PD are likely to precipitate PNP. While vitamin B12 deficiency affects large fibers, lack of vitamin B6 can result in small fiber PNP.[35]
This study has several limitations. A single-center, cross-sectional design with a small sample size of PSP patients appears to be the primary limitation. Serum homocysteine and methylmalonic acid levels were not assessed. However, we excluded patients with diabetes, low serum vitamin B12, and hypothyroidism, which may contribute to the development of PNP. We did not screen for toxins or heavy metals in the present study. However, none of our patients provided history of consuming native Indian medications. Genetic factors, such as mutations in PRKN or methylenetetrahydrofolate reductase genes which increase susceptibility to develop PNP, were not assessed in the present study. We used SSR in upper limbs for assessing small fiber integrity. Although SSR is simpler and less invasive, it is less sensitive and specific for evaluating patients with autonomic symptoms, compared to Quantitative Sudomotor Axon Reflex Test and skin biopsy. Moreover, testing SSR in both hands and feet may have increased its sensitivity and diagnostic accuracy. A multicenter, prospective, longitudinal study involving a larger number of PSP patients may further enhance our understanding regarding peripheral nerve involvement in these patients.
Conclusion
We observed a higher frequency of PNP in PSP patients compared to PD patients (two-thirds of PSP patients were affected). PNP was distal symmetrical axonal polyneuropathy. Large and mixed fiber neuropathy was significantly more common in PSP, but isolated small fiber neuropathy was seen only in PD. While none of the clinical variables had a significant association with PNP in the PSP group, a longer disease duration in PD was independently associated with PNP.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
References
- 1.Armstrong MJ. Progressive supranuclear palsy: An Update. Curr Neurol Neurosci Rep. 2018;18:12. doi: 10.1007/s11910-018-0819-5. [DOI] [PubMed] [Google Scholar]
- 2.Rajabally YA, Martey J. Neuropathy in Parkinson disease: Prevalence and determinants. Neurology. 2011;77:1947–50. doi: 10.1212/WNL.0b013e31823a0ee4. [DOI] [PubMed] [Google Scholar]
- 3.Toth C, Breithaupt K, Ge S, Duan Y, Terris JM, Thiessen A, et al. Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease. Ann Neurol. 2010;68:28–36. doi: 10.1002/ana.22021. [DOI] [PubMed] [Google Scholar]
- 4.Zis P, Grünewald RA, Chaudhuri RK, Hadjivassiliou M. Peripheral neuropathy in idiopathic Parkinson’s disease: A systematic review. J Neurol Sci. 2017;378:204–9. doi: 10.1016/j.jns.2017.05.023. [DOI] [PubMed] [Google Scholar]
- 5.Mathukumalli N, Kandadai M, Shaik J, Kanikannan M, Borgohain R. Serum B12, homocysteine levels, and their effect on peripheral neuropathy in Parkinson’s disease: Indian cohort. Ann Indian Acad Neurol. 2020;23:48. doi: 10.4103/aian.AIAN_478_18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Merola A, Rosso M, Romagnolo A, Comi C, Fasano A, Zibetti M, et al. Peripheral neuropathy as marker of severe Parkinson’s disease phenotype. Mov Disord. 2017;32:1256–8. doi: 10.1002/mds.27025. [DOI] [PubMed] [Google Scholar]
- 7.Lee JJ, Baik JS. Peripheral neuropathy in de novo patients with Parkinson’s disease. Yonsei Med J. 2020;61:1050. doi: 10.3349/ymj.2020.61.12.1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Adewusi JK, Hadjivassiliou M, Vinagre-Aragón A, O’Connor KR, Khan A, Grünewald RA, et al. Sensory neuropathic symptoms in idiopathic Parkinson’s disease: Prevalence and impact on quality of life. Acta Neurol Belg. 2018;118:445–50. doi: 10.1007/s13760-018-0947-3. [DOI] [PubMed] [Google Scholar]
- 9.Müller T, Laar TV, Cornblath DR, Odin P, Klostermann F, Grandas FJ, et al. Peripheral neuropathy in Parkinson’s disease: Levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord. 2013;19:501–7. doi: 10.1016/j.parkreldis.2013.02.006. [DOI] [PubMed] [Google Scholar]
- 10.Kühn E, Averdunk P, Huckemann S, Müller K, Biesalski AS, Hof Zum Berge F, et al. Correlates of polyneuropathy in Parkinson’s disease. Ann Clin Transl Neurol. 2020;7:1898–907. doi: 10.1002/acn3.51182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dubbioso R, Provitera V, Vitale F, Stancanelli A, Borreca I, Caporaso G, et al. Cutaneous sensory and autonomic denervation in progressive supranuclear palsy. Neuropathology Appl Neurobio. 2021;47:653–63. doi: 10.1111/nan.12692. [DOI] [PubMed] [Google Scholar]
- 12.Vitaliani R, Scaravilli T, Egarter-Vigl E, Giometto B, Klein C, Scaravilli F, et al. The pathology of the spinal cord in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2002;61:268–74. doi: 10.1093/jnen/61.3.268. [DOI] [PubMed] [Google Scholar]
- 13.Iwasaki Y, Yoshida M, Hashizume Y, Hattori M, Aiba I, Sobue G. Widespread spinal cord involvement in progressive supranuclear palsy. Neuropathology. 2007;27:331–40. doi: 10.1111/j.1440-1789.2007.00787.x. [DOI] [PubMed] [Google Scholar]
- 14.Rohmann R, Kühn E, Scherbaum R, Hilker L, Kools S, Scholz L, et al. Prevalence and characteristics of polyneuropathy in atypical Parkinsonian syndromes: An explorative study. Brain Sci. 2021;11:879. doi: 10.3390/brainsci11070879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gawel M, Jamrozik Z, Szmidt-Salkowska E, Slawek J, Gawel D, Rowińska-Marcińska K, et al. Electrophysiological features of lower motor neuron involvement in progressive supranuclear palsy. J Neurol Sci. 2013;324:136–9. doi: 10.1016/j.jns.2012.10.023. [DOI] [PubMed] [Google Scholar]
- 16.Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson disease. CMAJ. 2016;188:1157–65. doi: 10.1503/cmaj.151179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ramachandran A, Jose J, Gafoor Va, Das S, Balaram N. Prevalence and risk factors of peripheral neuropathy in parkinson’s disease. Ann Indian Acad Neurol. 2022;25:1109. doi: 10.4103/aian.aian_669_22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Thomann AE, Berres M, Goettel N, Steiner LA, Monsch AU. Enhanced diagnostic accuracy for neurocognitive disorders: A revised cut-off approach for the montreal cognitive assessment. Alz Res Ther. 2020;12:39. doi: 10.1186/s13195-020-00603-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria: MDS clinical diagnostic criteria for PSP. Mov Disord. 2017;32:853–64. doi: 10.1002/mds.26987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease: MDS-PD clinical diagnostic criteria. Mov Disord. 2015;30:1591–601. doi: 10.1002/mds.26424. [DOI] [PubMed] [Google Scholar]
- 21.Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement disorder society-sponsored revision of the Unified Parkinson’s disease rating scale (MDS-UPDRS): Scale presentation and clinimetric testing results: MDS-UPDRS: Clinimetric assessment. Mov Disord. 2008;23:2129–70. doi: 10.1002/mds.22340. [DOI] [PubMed] [Google Scholar]
- 22.Hoehn MM, Yahr MD. Parkinsonism: Onset, progression and mortality. Neurology. 1967;17:427–42. doi: 10.1212/wnl.17.5.427. [DOI] [PubMed] [Google Scholar]
- 23.Schade S, Mollenhauer B, Trenkwalder C. Levodopa equivalent dose conversion factors: An updated proposal including opicapone and safinamide. Mov Disord Clin Pract. 2020;7:343–5. doi: 10.1002/mdc3.12921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bril V, Perkins BA. Validation of the Toronto clinical scoring system for diabetic polyneuropathy. Diabetes Care. 2002;25:2048–52. doi: 10.2337/diacare.25.11.2048. [DOI] [PubMed] [Google Scholar]
- 25.Rodríguez-Leyva I, Chi-Ahumada EG, Carrizales J, Rodríguez-Violante M, Velázquez-Osuna S, Medina-Mier V, et al. Parkinson disease and progressive supranuclear palsy: Protein expression in skin. Ann Clin Transl Neurol. 2016;3:191–9. doi: 10.1002/acn3.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yi S, Liu Q, Wang X, Qian T, Wang H, Zha G, et al. Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury. J Cell Sci. 2019;132:jcs222059. doi: 10.1242/jcs.222059. [DOI] [PubMed] [Google Scholar]
- 27.Nolano M, Provitera V, Stancanelli A, Saltalamacchia AM, Caporaso G, Lullo F, et al. Small fiber pathology parallels disease progression in Parkinson disease: A longitudinal study. Acta Neuropathol. 2018;136:501–3. doi: 10.1007/s00401-018-1876-1. [DOI] [PubMed] [Google Scholar]
- 28.Vacchi E, Kaelin-Lang A, Melli G. Tau and alpha synuclein synergistic effect in neurodegenerative diseases: When the periphery is the core. Int J Mol Sci. 2020;21:5030. doi: 10.3390/ijms21145030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Tsukita K, Sakamaki-Tsukita H, Tanaka K, Suenaga T, Takahashi R. Value of in vivo α-synuclein deposits in Parkinson’s disease: A systematic review and meta-analysis. Mov Disord. 2019;34:1452–63. doi: 10.1002/mds.27794. [DOI] [PubMed] [Google Scholar]
- 30.Donadio V, Doppler K, Incensi A, Kuzkina A, Janzen A, Mayer G, et al. Abnormal α-synuclein deposits in skin nerves: Intra- and inter-laboratory reproducibility. Euro J Neurol. 2019;26:1245–51. doi: 10.1111/ene.13939. [DOI] [PubMed] [Google Scholar]
- 31.Lionnet A, Wade MA, Corbillé AG, Prigent A, Paillusson S, Tasselli M, et al. Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy. Acta Neuropathol Commun. 2018;6:65. doi: 10.1186/s40478-018-0568-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Wakabayashi K, Furuta A, Takahashi H, Ikuta F. Occurrence of neurofibrillary tangles in the celiac ganglia. Acta Neuropathol. 1989;78:448. doi: 10.1007/BF00688183. [DOI] [PubMed] [Google Scholar]
- 33.Ceravolo R, Cossu G, Bandettini Di Poggio M, Santoro L, Barone P, Zibetti M, et al. Neuropathy and levodopa in Parkinson’s disease: Evidence from a multicenter study. Mov Disord. 2013;28:1391–7. doi: 10.1002/mds.25585. [DOI] [PubMed] [Google Scholar]
- 34.Romagnolo A, Merola A, Artusi CA, Rizzone MG, Zibetti M, Lopiano L. Levodopa-induced neuropathy: A systematic review. Mov Disord Clin Pract. 2019;6:96–103. doi: 10.1002/mdc3.12688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ganguly J, Tuesta Bernaola M, Jog M. Role of vitamins in advanced therapy for Parkinson’s disease: Decoding the paradox. Can J Neurol Sci. 2022;49:3–4. doi: 10.1017/cjn.2021.106. [DOI] [PubMed] [Google Scholar]