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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1109-1115
 

Prevalence and risk factors of peripheral neuropathy in parkinson's disease


Department of Neurology, Government Medical College, Kozhikode, Kerala, India

Date of Submission03-Aug-2022
Date of Decision29-Aug-2022
Date of Acceptance09-Sep-2022
Date of Web Publication3-Dec-2022

Correspondence Address:
James Jose
Department of Neurology, Government Medical College, Kozhikode, Kerala - 673 008
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_669_22

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   Abstract 


Introduction: A lesser studied aspect of Parkinson's disease (PD) is its associated peripheral sensory-motor neuropathy. Peripheral neuropathy is an intriguing aspect of PD, a problem not given sufficient attention and which if tackled properly could make a difference to the multifaceted sufferings of the PD patient. Studies regarding the prevalence of peripheral neuropathy and its risk factors in patients with PD are scarce from the Indian subcontinent. Methods: This prospective observational study was conducted in a tertiary care teaching hospital in South India. Patients diagnosed with idiopathic Parkinson's disease (IPD) were screened and enrolled. All the patients underwent detailed evaluation of symptoms, signs, and electrophysiology (Nerve conduction study, Sympathetic skin response), stimulated skin wrinkling with Eutectic Mixture of Local Anesthetics. Patients found to have large/small fiber neuropathy underwent additional tests to exclude other causes of neuropathy. Results: A total of 154 patients with IPD were enrolled in the study (mean age: 61.96 ± 9.15 years, mean duration of disease was 4.08 ± 3.16 years). The mean Hoehn and Yahr (H and Y) score was 2.3 ± 0.825 and the mean Unified Parkinsons Disease Rating Scale (UPDRS)-3 score in the ON state was 23.07 ± 11.14. The mean cumulative levodopa dose was 482.68 ± 651.76 (median: 292; range: 4728.57) grams. Peripheral neuropathy was found in 49 patients (31.8%), large fiber in 28 (18.2%) and small fiber in 47 (30.5%); an overlap of large and small fiber neuropathy was seen in 26 patients (16.9%). Around 34% of patients had serum homocysteine levels >20 mg/dl. In univariate analysis, duration of disease, levodopa cumulative dose, serum homocysteine level, H and Y score, UPDRS-3 ON score, Toronto Clinical Neuropathy Score (P < 0.001 for all), age at presentation, and rigidity predominant presentation (P = 0.02 for both) were associated with large fiber neuropathy. All of these variables were also associated with the presence of small fiber neuropathy (P = 0.004 for age at presentation and P < 0.001 for rest), except the type of PD presentation. However, in multivariate logistic regression analysis, only duration of disease, levodopa cumulative dose, and H and Y score were associated with the presence of large and small fiber neuropathy. Conclusions: In our cohort, majority of the patients were in early-stage PD and around one-fifth and one-third of patients suffer from large and small fiber polyneuropathy, respectively. Large and small fiber neuropathy in PD is mainly associated with duration of disease, levodopa cumulative dose, and H and Y score.


Keywords: Large fiber neuropathy, levodopa, neurodegenerative disease, Parkinson's disease, peripheral neuropathy, small fiber neuropathy


How to cite this article:
Ramachandran A, Jose J, Gafoor V A, Das S, Balaram N. Prevalence and risk factors of peripheral neuropathy in parkinson's disease. Ann Indian Acad Neurol 2022;25:1109-15

How to cite this URL:
Ramachandran A, Jose J, Gafoor V A, Das S, Balaram N. Prevalence and risk factors of peripheral neuropathy in parkinson's disease. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Feb 6];25:1109-15. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1109/361572





   Introduction Top


Parkinson's disease (PD) is one of the common neurodegenerative diseases of old age, debilitating the patients in several ways along its invariably progressive course. It has a prevalence of 1–2% in the global population aged over 65 years age and its prevalence increases with advancing age.[1] Peripheral neuropathy is an intriguing aspect of PD, a problem that has escaped sufficient attention. Sensory disturbances such as pain, paresthesia, burning, and itching sensations are as prevalent as 40–70% in patients with PD,[2] and central causes such as dystonia are commonly held responsible. The prevalence of large fiber neuropathy is 16.3% and that of small fiber neuropathy is as high as 56.9% in age >85 years.[3] Although autonomic involvement has been extensively described in PD and other forms of Parkinsonism (e.g., Multiple system atrophy, Lewy body disease), the presence of sensorimotor peripheral neuropathy has been only detailed in case reports and small case series until recently.

Proposed mechanisms of neuropathy in PD are both intrinsic and extrinsic. The extrinsic cause is hyper-homocysteinemia induced by levodopa therapy, which results from the conversion of methionine into homocysteine in the peripheral catechol-O-methyltransferase (COMT) pathway of levodopa metabolism.[4] The augmented incidence of neuropathy including acute severe neuropathy in patients treated with intestinal levodopa gel which can bypass first-pass metabolism and result in higher serum levels favors this.[5–8] The possibility of treatment with vitamin B12 to counter this mechanism is attractive. The intrinsic mechanism is the deposition of alpha-synuclein in peripheral axons, leading to degeneration and neuropathy. Studies have shown the presence of phosphorylated synuclein aggregates that block axonal transport and cause length-dependent peripheral neuropathy in idiopathic Parkinson's disease (IPD) patients as opposed to unphosphorylated synuclein in the control population.[9],[10] The pathologic synuclein was demonstrated in skin biopsy; thus, putting forth a cutaneous marker for IPD.

Studies regarding the prevalence of peripheral neuropathy and its risk factors in patients with PD are scarce from the Indian subcontinent. We aim to find the prevalence of large and small fiber peripheral neuropathy in patients with IPD and to find an association between the presence of neuropathy and the severity, duration of disease, and levodopa therapy.


   Material and Methods Top


This study was a prospective observational study conducted between January 2018 and December 2019 in a tertiary care teaching and referral hospital in South India. Ethical clearance was obtained from the Institute ethics committee (ref No. GMCKKD/RP2018/IEC/82). Written informed consent was obtained from the patients and/or their guardians.

Study population

Patients aged 40–80 years diagnosed with IPD according to the UK Brain Bank criteria,[11] presenting to our out patient clinic were assessed for eligibility and enrolled if willing. The primary objectives of the study were to assess the prevalence of large fiber and small fiber neuropathy in patients with IPD and to find its association with the duration, severity of the disease, dose, and duration of levodopa exposure. Patients with Parkinson's Plus syndromes and secondary Parkinsonism diagnosed clinically/radiologically and patients with a history of diabetes mellitus/exposure to drugs that cause peripheral neuropathy/known causes of peripheral neuropathy were excluded from the study. Patients with PD were classified into three subtypes: 1) Tremor dominant, 2) akinetic–rigid dominant and 3) mixed type based on the Unified Parkinsons Disease Rating Scale (UPDRS) motor scale. These subtypes were defined according to “the ratio of each patient's UPDRS 3 Tremor score (sum of Items 20 and 21 divided by 4) to his/her mean UPDRS akinetic/rigid score (sum of items 22–27 and 31 divided by 15).” A ratio of 1.0, 0.80 and between 0.80 and 1.0 suggest tremor dominant, akinetic–rigid dominant, and mixed subtypes, respectively.[12]

According to previous studies, the prevalence of large fiber neuropathy in IPD ranges from 6 to58%,[13],[14] and the prevalence of small fiber neuropathy in idiopathic PD varies from 30 to 60%.[9],[15] Expecting a prevalence of 45% in our study with keeping type 1 error at 5% and precision/absolute error at 8%, it was planned to enroll at least 154 patients.

Sampling strategy

All the consecutive patients who fulfilled the inclusion and exclusion criteria were enrolled in the study. Their duration of disease, the disease severity according to the Hoehn and Yahr (H and Y)[16] and UPDRS-3 scale in the ON state,[17] treatment details with special attention to the doses and duration of levodopa, treatment-related complications like dyskinesias or fluctuations in the symptoms were noted in a predesigned proforma.

Following this, all the included patients were asked about symptoms of peripheral neuropathy specifically numbness, tingling, pain, burning sensation, unsteadiness, and weakness. Detailed examination including fine touch by cotton wick, pinprick, temperature, vibration sense with 128 Hz tuning fork, joint position sense, and Romberg's test was done.

Neurophysiological assessment

All the patients were subjected to a nerve conduction study on the Nicolet machine to assess large fiber involvement and to stimulated skin wrinkling after EMLA (Eutectic Mixture of Local Anesthetics) (Lignocaine 2.5% + prilocaine 2.5% eutectic mixture) application and sympathetic skin response (SSR) for small fiber neuropathy. The nerve conduction study was performed on median, ulnar, common peroneal, tibial, and sural nerves. The following parameters were assessed: the distal motor latency, compound muscle action potential (CMAP), the mean, distal sensory latency measured to the negative peak, and sensory nerve action potential (SNAP) amplitude. Using standardized distances between electrode placements, conduction velocity was also assessed for both sensory and motor nerves. Patients with low (below 2 SD) SNAP amplitude were considered to have mild sensory neuropathy, with absent SNAP to have severe sensory neuropathy, and with low (below 2 SD) CMAP amplitude to have motor neuropathy. Absent SSR was taken as indicative of small fiber neuropathy. The Toronto Clinical Neuropathy Score (TCNS) was used to grade the severity of the neuropathy (minimum score: 0; maximum score: 19).[18] The TCNS has been preferred by various investigators in their clinical trials due to its easy use, patient acceptability, and its ability to classify the neuropathy severity and reflect clinical changes as the disease progresses.

This was corroborated with symptoms and signs of small fiber neuropathy, and with a stimulated skin wrinkling test which was performed by assessing the extent of wrinkles in the pulp of fingers after application of 1 ml of EMLA on the pulp of index, middle, and ring fingers of a hand. Wrinkles were graded after 30 min according to the visual scale by Ping et al.[19] The wrinkling was graded as “absent (grade 0), just perceptible wrinkling, with the fingertip not completely smooth (grade 1), two or fewer lines of superficial wrinkling on the fingertip (grade 2), three or more lines of deep wrinkling on the fingertip (grade 3), and wrinkling completely distorts the pulp of the fingertip (grade 4).” The wrinkling grades for the tested digits were averaged and a total score of 9 or less was taken as abnormal. Skin wrinkling is attributed to postganglionic sympathetic mediated vasoconstriction; hence, the absence of wrinkling is indicative of small fiber dysfunction.[20]

Biochemical assessment

Any patient found to have neuropathy according to the above-mentioned criteria underwent oral glucose tolerance test, HbA1c, serum vitamin B12 level, erythrocyte sedimentation rate, serum protein electrophoresis, HBsAg, anti-hepatitis C virus antibodies, serum cryoglobulin, chest X-ray, ultrasound abdomen and pelvis to exclude secondary causes of neuropathy. Serum homocysteine levels were done in all the included patients. The patients for whom the above causes were excluded were considered to have neuropathy associated with idiopathic PD, and the prevalence of neuropathy in patients with idiopathic PD was estimated. Further, it was attempted to find an association between the prevalence of neuropathy and the duration, severity of the disease, and levodopa exposure.

Statistical analysis

Statistical Package for Social Sciences version 29 software was used for data analysis. Categorical variables were expressed as frequency. Continuous variables were expressed as mean and standard deviation or median with an interquartile range. To assess whether the difference between the two variables was statistically significant, Chi-square or Fisher's exact test were used for categorical variables and the student's t-test was used for continuous variables. For non-parametric variables, the Mann–Whitney U test and the Kruskal–Wallis test were used as tests of statistical significance. A P value of <0.05 was considered statistically significant. Spearman's correlation coefficient was used to check the correlation between different study variables. The variables which were found to have a significant association with the prevalence of neuropathy in univariate analysis were subjected to multivariate logistic regression analysis.


   Results Top


During the study period, a total of 186 patients with PD were screened and a total of 154 patients with IPD were enrolled in the study (32 excluded: Parkinson plus syndrome-8, history of diabetes mellitus-22, Hepatitis C positive-2) (mean age: 61.96 ± 9.15 years, range: 39–80 years, 109 males, 71%). The mean duration of disease was 4.08 ± 3.16 years and 46%, 41%, and 23% of patients had disease duration <2, 2–5, and >5 years, respectively. The vast majority of patients had tremor dominant PD (n = 142, 92.2%), and the rest had rigidity dominant PD (n = 12; 7.8%) [Table 1].
Table 1: Association of various variables and neuropathy

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Disease severity was quantified using H and Y score and UPDRS-3 score in the ON state. The mean H and Y score was 2.3 ± 0.825 and the mean UPDRS-3 score in the ON state was 23.07 ± 11.14. Trihexyphenidyl (n = 154), levodopa/carbidopa (n = 148), rasagiline (n = 47), pramipexole (n = 34), amantadine (n = 26), and ropinirole (n = 17) were the various medications used for parkinsonism in our patient cohort. Entacapone was used only in one patient. All the levodopa naïve patients in our study had a duration of illness < 1 year, and none of them had neuropathy. Among the exposed group, 69 (46.6%) had a cumulative dose of <250 grams; 40 (27%) had 250–500 grams, and 39 (26.3%) had >500 grams of levodopa exposure. The mean cumulative levodopa dose was 482.68 ± 651.76 (median: 292; range: 4728.57) grams.

The occurrence of peripheral neuropathy in our cohort was found in 49 patients (31.8%). Large fiber neuropathy was seen in 28 (18.2%) patients and small fiber neuropathy was found in 47 (30.5%) patients; an overlap of large and small fiber neuropathy was seen in 26 patients (16.9%) [Figure 1]. The mean TCNS score was 3.67 ± 24.71 (median: 2, range: 0–17). Among the patients with large fiber neuropathy, 15 had mild axonal sensory neuropathy, 8 had severe axonal sensory neuropathy, and 5 had sensory-motor axonal neuropathy. The parameters considered to measure small fiber neuropathy in our study were SSR and stimulated skin wrinkling after EMLA cream application, and we found the prevalence of small fiber neuropathy to be 30.5%. SSR abnormality was found in 38.9% and skin wrinkling abnormality in 28.5%.
Figure 1: Prevalence of peripheral neuropathy

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Among the patients with large fiber neuropathy, 15 (53%) had mild axonal sensory neuropathy, 8 (29%) had severe axonal sensory neuropathy, and 5 (18%) had sensory-motor axonal neuropathy. The prevalence of different clinical symptoms and signs in our patient cohort have been described in [Table 2] and [Table 3], respectively. Pain (n = 84, 54.5%), numbness (n = 71, 46.1%), burning sensation (n = 64, 41.6%), and tingling/pins and needles sensation (n = 60, 38.9%) were the predominant clinical symptoms, whereas temperature impairment (n = 48, 31.2%), pinprick impairment (n = 47, 30.5%), light touch impairment (n = 29, 18.8%), and vibration impairment (n = 29, 18.8%) were the predominant clinical signs.
Table 2: Prevalence of symptoms of neuropathy in our PD cohort

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Table 3: Prevalence of signs of neuropathy in our PD cohort

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The mean homocysteine level in our patients was 20.33 ± 11.25 mg/dl and 34% of patients had serum homocysteine levels >20 mg/dl. In univariate analysis, duration of disease (in years), levodopa cumulative dose, serum homocysteine level, H and Y score, UPDRS-3 ON score, TCNS score (P < 0.001 for all), age at presentation, and rigidity predominant presentation (P = 0.02 for both) were associated with large fiber neuropathy. All of these variables were also associated with the presence of small fiber neuropathy (P = 0.004 for age at presentation and P < 0.001 for rest), except the type of PD presentation. However, in multivariate logistic regression analysis, only duration of disease, levodopa cumulative dose, and H and Y score were associated with the presence of large and small fiber neuropathy. Moreover, there was a significant positive correlation between levodopa cumulative dose and serum homocysteine level (Spearman's Rho: 0.73) (P < 0.01) [Figure 2].
Figure 2: Spearman's correlation between serum homocysteine and levodopa cumulative dose (Rho: 0.73) (P < 0.01)

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   Discussion Top


Our study showed around one-fifth and one-third of IPD patients suffer from large and small fiber polyneuropathy, respectively. The mean duration of illness in our study was around 4 years; with only 13% of patients having disease duration longer than 5 years when motor complications could be expected. Thus, the findings of this study predominantly project on the early-stage PD population. Our cohort showed a male predilection, which is in concordance with the previous epidemiological studies in PD patients which have shown the incidence of PD to be 1.5 to 2 times more in males compared to females. A proposed mechanism is the increased level of physiological striatal dopamine in women that is estrogen-mediated and thus a lesser occurrence and a later age of occurrence of the disease in women.[21]

We found axonal polyneuropathy in a significant subset of patients and there were no cases of demyelinating neuropathy in our study. Previously in the study by Toth et al.,[22] the prevalence of peripheral neuropathy was 69% and they found a significant association between fasting homocysteine/methylmalonic acid (MMA) levels and the presence of neuropathy. Another study by the same group[23] comparing PD patients and the control population found the prevalence of peripheral neuropathy in the PD group to be 55% and in the control group to be 9%. They found that neuropathy in PD is associated with levodopa cumulative dose, homocysteine/MMA level, older age, and higher UPDRS score like our study. The higher prevalence of peripheral neuropathy found in their study was probably due to a cohort of longer duration (about 9 years) and the severity of PD. Another study by Ceravolo et al.[24] found the prevalence of neuropathy to be 19.4% in the group with long exposure to levodopa (>3 years), and 6.8% in the short exposure group. In their study, the predominant type of neuropathy obtained was axonal sensory neuropathy. The findings in our study are in close concordance with the results of this study.

We found skin wrinkling to better correlate with the symptoms and signs of small fiber neuropathy than SSR. Some cases with only SSR abnormality were not included as having small fiber neuropathy, as SSR tends to overestimate the presence of small fibre neuropathy. The study by Schestatsky et al.[25] found similar results. In their study, abnormal SSR latency/amplitude was found in 77.1% of the PD group and SSR was absent in 32.7%. But SSR did not correlate with dysautonomic symptoms/orthostatic hypotension/R-R interval variability in their study. The study by Braune et al.[26] found abnormal latency/amplitude of SSR in 48% of PD patients, with a significant inter-side difference of SSR according to the side affected by PD. They found an association with disease duration and severity; however, they did not find an association between SSR abnormality and the clinical type of PD or medication use.

The use of stimulated skin wrinkling as a measure of small fiber neuropathy has been validated in various studies. A study by Djaldetti et al.[27] on 18 patients (and 9 controls) with hemi-Parkinsonism found significantly a smaller number of fingertip wrinkles on the less affected side after 30 min of hand immersion in warm water. Araujo et al.[14] found that 50% of PD and 37.5% of Parkinsonism patients had abnormal skin wrinkling tests, and 34.2% of PD and 23.5% of Parkinsonism patients had large fiber neuropathy. This suggests that small and large fiber neuropathies are not only prevalent in the Parkinsonism syndromes but also have a predilection for the affection of IPD more than the other Parkinsonism syndromes (excluding MSA which has a higher incidence of autonomic neuropathy).

Levodopa exposure had a significant association with both large fiber and small fiber neuropathy, but this interpretation requires caution. Whether the effect is due to longer disease duration/higher severity or due to ingestion of levodopa at higher doses as the disease progresses is unclear. The study by Toth et al.[23] that reported a 55% incidence of neuropathy based on electrophysiology was challenged by Nolano et al.[28] who studied the epidermal nerve fiber density, the density of Meissner's corpuscles, and electrophysiological evidence of neuropathy. In the study by Nolano et al.,[28] a decrease in Meissner's corpuscle density (receptors that carry large fiber sensation) was found in patients of PD as disease severity increased even without exposure to levodopa. Thus, the contribution of levodopa per se to the incidence of neuropathy (separate from the disease pathology itself affecting the peripheral nerves) remains unsettled. Various other studies have also studied the relation of levodopa to neuropathy in PD and come up with conflicting results. A study by Rajabally et al.[29] compared the prevalence of neuropathy in 33 levodopa naïve and 36 levodopa exposed patients with PD. Though they found an association of neuropathy with cumulative levodopa exposure, they concluded that the influence of levodopa was only contributory, and was surpassed by older age and reduced folate levels. Reports which suggested that the route of delivery of levodopa also influences neuropathy (higher in intestinal gel vs. oral tablet) are also found in the literature, all of which found a significant association between these two parameters.[5],[6],[8],[30]

The causative role of levodopa in hyper-homocysteinemia is well explained by the biochemical reaction of COMT that uses up S-adenosyl methionine and creates S-adenosyl homocysteine.[22] All the studies of levodopa and neuropathy have also found a positive correlation between hyper-homocysteinemia and neuropathy. In our study also, levodopa cumulative dose is found to have a positive association with serum homocysteine level; and both are associated with the presence of small as well as large fiber neuropathy. A recent study from India by Mathukumalli et al.[31] found a 9% prevalence of peripheral neuropathy in PD patients. In this study, the prevalence of hyper-homocysteinemia and vitamin B12 deficiency was less compared to the Western population. This is the study with a population ethnically closest to our group. All the patients with peripheral neuropathy had axonal neuropathy, with all having sensory and four having additional motor involvement. Small fiber neuropathy was not specifically studied in that study. Despite a longer mean disease duration and higher levodopa exposure, their prevalence of neuropathy was half of that found in our group. The worse baseline characteristics in our group in comparison were the UPDRS ON score (23.07 vs. 15.99) and slightly older mean age (61.9 vs. 57.6). The contribution of these factors to the causation of large fiber neuropathy might explain the contradiction.

The use of COMT inhibitors to downregulate the synthesis of homocysteine via the COMT metabolism of levodopa has gained interest. Grofik et al.[32] in their study on 180 PD patients separately assessed three groups of patients with PD on levodopa, on levodopa + entacapone, and controls. They found a prevalence of 29.5% large fiber neuropathy. The occurrence of neuropathy and hyper-homocysteinemia were significantly lower in the group taking entacapone. This could not be assessed in our study as only 1 patient was on entacapone.

There are some limitations to our study. It was a cross-sectional study assessing the prevalence of neuropathy and its relation to levodopa exposure. A prospective study with determination of improvement of the neuropathy after supplementation of vitamin B12 would have been more powerful. Serum homocysteine level was not assessed in all patients due to cost factors, loss of follow-up, etc., Exclusion of other causes of neuropathy by more extensive evaluation could have further increased the certainty of findings in our study.


   Conclusion Top


In our cohort, the majority of the patients were in early-stage PD, and around one-fifth and one-third of patients suffer from large and small fiber polyneuropathy respectively. Large and small fiber neuropathy in PD are mainly associated with duration of disease, levodopa cumulative dose, and H and Y score.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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    Abstract
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