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ORIGINAL RESEARCH
Is Median Nerve Enlargement at the Wrist Associated With Tremor in Parkinson Disease? Seung Nam Yang, MD, PhD, Hyo Jeong Kang, MD, Joon Shik Yoon, MD, PhD, Sun Jae Won, MD, Woo-Keun Seo, MD, PhD, Seong Beom Koh, MD, PhD
Article includes CME test
Objectives—Tremor is one of the cardinal features of Parkinson disease (PD) and may cause cumulative trauma-related injury to nerves of the hands. The aim of this study was to assess the electrodiagnostic and sonographic features of patients with PD and to assess the effect of tremor in PD on the median nerve. Methods—We studied 31 hands of healthy control participants (n = 16; mean age ± SD, 60.25 ± 14.67 years) and 81 hands of patients with PD (n = 42; 64.95 ± 11.13 years). Motor symptoms were measured by the Unified Parkinson’s Disease Rating Scale III. Median nerve conduction studies and sonographic cross-sectional area measurements were performed in all participants. Results—The median nerve cross-sectional area in patients with PD (10.71 ± 2.79 mm2) was significantly larger than that in the control group (7.40 ± 1.05 mm2; P < .05). However, there was no significant difference in median nerve electrodiagnostic findings between the PD and control groups. The median nerve cross-sectional area was associated with the severity of the tremor but not with the Unified Parkinson’s Disease Rating Scale motor score.
Received January 6, 2014, from the Department of Physical Medicine and Rehabilitation, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea (S.N.Y., H.J.K., J.S.Y.); Department of Physical Medicine and Rehabilitation, Yeouido St Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea (S.J.W.); and Department of Neurology, Korea University College of Medicine, Seoul, Korea (W.-K.S., S.B.K.). Revision requested January 22, 2014. Revised manuscript accepted for publication April 2, 2014. Address correspondence to Seong Beom Koh, MD, PhD, Department of Neurology, or Joon Shik Yoon, MD, PhD, Department of Physical Medicine and Rehabilitation, Korea University College of Medicine, 80 Guro-gu, Gurodong, Seoul, Korea. E-mail: [email protected], rehab46@ korea.ac.kr Abbreviations
PD, Parkinson disease; PDQ, Parkinson’s Disease Questionnaire; UPDRS, Unified Parkinson’s Disease Rating Scale doi:10.7863/ultra.33.12.2079
Conclusions—Tremor in PD is associated with median nerve enlargement but not with impairment of median nerve conduction. Key Words—median nerve; musculoskeletal ultrasound; Parkinson disease; sonography; tremor
P
arkinson disease (PD) is a progressive movement disorder that may result in musculoskeletal problems and deformity.1–3 Musculoskeletal problems in PD are mainly related to parkinsonian rigidity, akinesia, dystonia, and postural abnormalities.1 Muscle cramps, tightness, frozen shoulder, arthritis, finger deformities, and spinal deformities commonly accompany PD.1,4–6 Tremor is one of the cardinal manifestations of PD, and repetitive hand movements may cause cumulative trauma-related injury and hand pain.7 High-resolution sonography has been used to assess nerve disorders. The most common and reproducible finding of entrapment neuropathy is nerve enlargement just proximal to the site of entrapment. Although the cause of nerve enlargement is not well understood, axoplasmic damming as well as inflammatory and vascular components are thought to contribute to nerve disorders.8,9
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One previous study described sonographic findings of the median nerve and the prevalence of carpal tunnel syndrome in PD.10 In that study, carpal tunnel syndrome was more prevalent in patients with PD compared to a control group, and patients with PD had a higher crosssectional area of the median nerve at the wrist, but there was no statistically significant difference between patients with PD and controls. The authors suggested that tremor might be a risk factor for development of carpal tunnel syndrome in PD; however, the correlation between the degree of tremor and median nerve enlargement at the wrist was not investigated. The aim of this study was to compare the median nerve enlargement at the wrist between patients with PD and control participants and to verify the correlation between the degree of tremor and median nerve enlargement at the wrist.
Bradykinesia and Hopokinesia” items. All participating patients were asked to complete the Parkinson’s Disease Questionnaire (PDQ-39)13 to assess impairment of their health-related quality of life. For subjective evaluation of hand symptoms, patients completed the Boston Questionnaire,14 which contains 11 items assessing symptom severity and 8 items regarding functional status.15 Electrodiagnostic Examinations Median motor and sensory nerve conduction studies using the antidromic technique were performed in the supine position on patients with PD and controls with surface electrodes according to standard protocols. The hand temperature of the participants was maintained at 32°C or warmer. A carpal tunnel syndrome diagnosis was made according to American Association of Electrodiagnostic Medicine criteria.16
Materials and Methods Participants A total of 82 hands from 41 consecutive patients with PD and 31 hands from 16 control volunteers were prospectively enrolled from the Department of Neurology of the Korea University Guro Hospital from January 2008 to February 2010. All patients met the clinical diagnostic criteria for PD, as described by the UK Parkinson’s Disease Society Brain Bank. Patients who had a history of carpal tunnel syndrome before the onset of parkinsonian motor signs were excluded. Neither patients nor controls had any diseases that can cause peripheral neuropathy, such as diabetes, amyloidosis, chronic renal failure, and alcoholism. All participants gave written informed consent to participate in this study. This protocol was approved by the regional Institutional Review Board of the Korea University Guro Hospital. Clinical Evaluation Patients underwent a neurologic examination and a clinical assessment. The modified Hoehn and Yahr stage11 was determined, and the degree of disease severity was quantified by Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores12 in the “on state” (ie, when the tremor was active) by a single movement disorder specialist. On the basis of the UPDRS motor scores, the severity of tremor was scored from 0 to 28 by the “Tremor at Rest” and “Action or Postural Tremor of Hands” items. The severity of rigidity was scored from 0 to 20 by the “Rigidity” item. Bradykinesia was scored from 0 to 40 by the “Finger Taps,” “Hand Movements,” “Rapid Alternating Movements of Hands,” “Leg Agility,” “Arising From Chair,” and “Body
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Sonographic Examinations Sonographic examinations were performed by a boardcertified physiatrist with 10 years of experience in sonography. The examinations were performed without information about the clinical findings or electrodiagnostic results. An HDI 3500 ultrasound device (Philips Healthcare, Bothell, WA) with a 7–12-MHz linear array transducer was used for this study. Each participant was placed in the supine position with the elbow and wrist fully extended. The transducer was first used to obtain a transverse view of the median nerve at the distal wrist crease. The cross-sectional area of the median nerve was calculated by a direct method using a continuous boundary trace just within the echogenic boundary of the nerve. An effort was made to minimize additional pressure from the probe on the nerve. Statistical Analyses All statistical analyses were performed with SAS version 9.2 software (SAS Institute Inc, Cary, NC). Group differences in age, sex, and body mass index were evaluated by a t test and χ2 test. Continuous variables were tested for normality by the Shapiro-Wilk test. Logarithmic transformations were applied to the amplitude of the median compound muscle action potential, latency of the median sensory nerve action potential, and median nerve crosssectional area as needed to ensure normal distributions of these variables. To analyze the results, a general linear model was used. The compound motor action potential and sensory nerve action potential latency, amplitude of median nerve conduction, and cross-sectional area of the median nerve were compared between patients with PD and controls. Correlations between motor examinations
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as assessed by the UPDRS, latencies and amplitudes of the compound motor action potential and sensory nerve action potential, and cross-sectional area of the median nerves in patients were evaluated after adjustment for age, sex, body mass index, and hand side. P < .05 was considered statistically significant.
Results General Characteristics A total of 82 hands from 41 patients with PD (14 male and 27 female) and 31 hands from 16 control participants (5 male and 11 female) were enrolled in this study. The mean ages ± SDs of patients with PD and controls were 64.95 ± 11.13 and 60.25 ± 14.67 years, respectively. By modified Hoehn and Yahr staging, 12 patients were classified as stage 1 to 1.5; 6 were stage 2; 10 were stage 2.5; 11 were stage 3; and 2 were stage 4. The mean levodopa equivalent dose at the patient evaluations was 228.66 ± 274.96 mg/d (Table 1). Electrodiagnostic and Sonographic Findings The latencies and amplitudes of median nerves in patients with PD and controls revealed no statistically significant differences (P > .05). There were 6 hands in 5 of the 42 patients in the PD group and none in the control group that met the diagnostic criteria of carpal tunnel syndrome by the nerve conduction studies. The prevalence of carpal tunnel syndrome was not significantly different between patients with PD and controls (P > .05). On sonography,
Table 1. General Characteristics of Patients With PD and Controls Characteristic Age, y Male/female, n Body mass index, kg/m2 Duration of PD, mo Hoehn and Yahr stage, n 1–1.5 2 2.5 3 4 UPDRS motor examination (108) Severity of tremor (28) Severity of rigidity (20) Severity of bradykinesia (40) PDQ-39 (100)
PD
Control
64.95 ± 11.13 14/27 24.81 ± 3.33 38.66 ± 40.47
60.25 ± 14.67 5/11 23.33 ± 3.11
12 6 10 11 2 22.18 ± 17.11 1.75 ± 2.11 8.68 ± 7.31 7.68 ± 6.65 16.37 ± 12.43
Data are presented as mean ± SD where applicable. Numbers in parentheses are maximum scores.
the median nerve cross-sectional area of patients with PD (10.71 ± 2.79 mm2) was statistically significantly larger than that of the controls (7.40 ± 1.05 mm2; P < .05; Table 2). Correlation Between the Degree of Tremor and Sonographic Findings There was no significant correlation between total UPDRS motor scores and the median nerve cross-sectional area in patients with PD (P > .05); however, the severity of tremor was significantly correlated with the median nerve crosssectional area in patients with PD (P < .05). The severity of rigidity and bradykinesia had no significant correlation with the median nerve cross-sectional area (P > .05). There was no significant correlation between total UPDRS motor, tremor, rigidity, and bradykinesia severity scores and nerve conduction study results (P > .05). No significant correlation existed between the symptoms of carpal tunnel syndrome evaluated by the Boston Questionnaire and the median nerve cross-sectional area. There was no correlation between the PDQ-39 score and the median nerve cross-sectional area or nerve conduction study results (Table 3).
Discussion Table 2. Median Nerve Parameters in PD and Control Groups Parameter Median nerve CMAP Latency, ms Amplitude, mV Median nerve SNAP Latency, ms Amplitude, μV Median nerve CSA, mm2
PD
Control
P
3.60 ± 0.09 8.51 ± 0.31
3.54 ± 0.15 8.72 ± 0.65
.8637 .5938
3.28 ± 0.41 35.34 ± 1.63 10.71 ± 2.79
3.33 ± 0.08 40.78 ± 6.11 7.40 ± 1.05
.6995 .7123 .002
Data are presented as mean ± SD. P values represent overall differences across the groups by a general linear model. CMAP indicates compound motor action potential; CSA, cross-sectional area; and SNAP, sensory nerve action potential.
Table 3. Correlation of Motor Examination by the UPDRS and Median Nerve Cross-sectional Area in Patients With PD Parameter Total UPDRS motor score Severity of tremor Severity of rigidity Severity of bradykinesia Boston Questionnaire PDQ-39
P .7604 .0341 .8504 .8643 .5427 .6613
P values represent correlation with the median nerve cross-sectional area by a general linear model.
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Yang et al—Median Nerve Enlargement in Parkinson Disease
We investigated the median nerve cross-sectional area at the wrist in patients with PD and healthy control participants. The median nerve cross-sectional area in patients with PD was significantly larger than that in the control group. Tremor in PD was correlated with median nerve enlargement but not with slowing of median nerve conduction. In a study by Yucel et al,10 tremor in patients with PD appeared to be the primary contributing factor for carpal tunnel syndrome; however, they did not prove any correlation between carpal tunnel syndrome and the degree of tremor. Our study verified that the severity of tremor was correlated with the median nerve cross-sectional area. The exact mechanism for the relationship between tremor and median nerve abnormalities at the wrist in PD has not been established. Tremor in PD occurs mainly at the finger joints rather than the wrist, leading some to point out that repetitive movements of the fingers may not affect the wrist and carpal tunnel.17 However, metacarpophalangeal joint movements are driven by the finger flexor tendons, which may cause median nerve displacement at the wrist, as seen in a kinematic study of motion in cadavers.18 Tremor involving the finger joints may cause friction between the flexor tendons and the median nerve and may cause median nerve enlargement. Although parkinsonian hand tremor is more prominent at finger joints, the tremor is also observed at wrist joints. Moreover, the tremor pattern at wrist joints is not a simple to-and-fro movement but rather a mixed pattern involving a rotational component. Thumb tremor in the classic “pill-rolling tremor” may also contribute to median nerve enlargement at the wrist. The results of our study showed a statistically significantly increased median nerve cross-sectional area in patients with PD compared to controls, with no statistically significant slowing of median nerve conduction or reduction in the amplitude. Our results differed from those of the previous study by Yucel et al,10 which showed a significant reduction in the median nerve amplitude in the second finger and a higher incidence of carpal tunnel syndrome in patients with PD compared to controls. Median nerve enlargement at the wrist is the main finding in sonographic studies of carpal tunnel syndrome. In using median nerve cross-sectional area cutoff values, sonography has been reported to have high sensitivity and specificity. Klauser et al19 proposed diagnosis on the basis of median nerve cross-sectional area cutoff values using a difference in the median nerve cross-sectional area of greater than 2 mm2 between the level of the proximal pronator quadratus muscle and the level of the carpal tunnel, and this measurement has been shown to diagnose carpal tunnel syndrome with 99%
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accuracy. In using median nerve cross-sectional area cutoff values, the sensitivity and specificity for diagnosis of carpal tunnel syndrome depend on the selected threshold according to the laboratory (8.5–12.0 mm2).19,20 In our study, a small number of cases in the PD group (6 of 82 hands) met the diagnosis of carpal tunnel syndrome by nerve conduction studies alone; however, more cases in the PD group (29 of 82 hands) met the diagnostic criteria by the median nerve cross-sectional area on sonography even with a relatively high diagnostic threshold of greater than 12.0 mm2. The discrepancy between electrodiagnostic testing and sonographic results might be due to different pathophysiologic mechanisms between median nerve swelling in patients with PD and idiopathic carpal tunnel syndrome. Median nerve swelling in patients with PD may be due to friction of the median nerve at the wrist as well as compression. The symptom severity measured by the Boston Questionnaire did not correlate with the median nerve crosssectional area in this study, in contrast to a study of patients with carpal tunnel syndrome without PD, in which it did.21 We hypothesize that involuntary movements of the hands may relieve the symptoms of carpal tunnel syndrome in patients with PD. In our study, tremor was related to median nerve enlargement at the wrist in patients with PD. We hypothesize that abnormal movements may result in nerve irritation and a subsequent cross-sectional area increase. Although many patients had clinically irrelevant median nerve enlargement, the possibility of future transition to symptomatic carpal tunnel syndrome should be considered. Further study is needed to identify predictive factors for transition from asymptomatic median nerve enlargement to symptomatic carpal tunnel syndrome in patients with PD. A limitation of our study was its small sample size, and blinding of the examiner to the patient group may not have been complete if participants had tremor or other signs of PD, although sonography was performed without any clinical information or knowledge of electrodiagnostic results. In addition, we only evaluated enlargement of the median nerve at the wrist and did not use additional diagnostic methods such as a comparison of the median nerve cross-sectional area between wrist and forearm, which was reported to have good accuracy in carpal tunnel syndrome diagnosis.19 In conclusion, we have demonstrated that median nerve cross-sectional area at the wrist in patients with PD was significantly larger than that in healthy control participants when diagnosed by sonographic studies. Tremor in patients with PD was correlated with sonographic findings of median nerve enlargement but not with impairment of median nerve conduction.
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Ford B. Pain in Parkinson’s disease. Mov Disord 2010; 25(suppl 1):S98– S103. Leibson CL, Maraganore DM, Bower JH, Ransom JE, O’Brien PC, Rocca WA. Comorbid conditions associated with Parkinson’s disease: a population-based study. Mov Disord 2006; 21:446–455. Ha AD, Jankovic J. Pain in Parkinson’s disease. Mov Disord2012; 27:485– 491. Tinazzi M, Recchia S, Simonetto S, et al. Muscular pain in Parkinson’s disease and nociceptive processing assessed with CO2 laser-evoked potentials. Mov Disord 2010; 25:213–220. Toda K, Harada T. Prevalence, classification, and etiology of pain in Parkinson’s disease: association between Parkinson’s disease and fibromyalgia or chronic widespread pain. Tohoku J Exp Med 2010; 222:1–5. Koh SB, Roh JH, Kim JH, et al. Ultrasonographic findings of shoulder disorders in patients with Parkinson’s disease. Mov Disord 2008; 23:1772– 1776. Jiménez MC, Vingerhoets FJ. Tremor revisited: treatment of PD tremor. Parkinsonism Relat Disord 2012; 18(suppl 1):S93–S95. Bartolić A, Pirtosek Z, Rozman J, Ribaric S. Tremor amplitude and tremor frequency variability in Parkinson’s disease is dependent on activity and synchronisation of central oscillators in basal ganglia. Med Hypotheses 2010; 74:362–365. Cartwright MS, Walker FO. Neuromuscular ultrasound in common entrapment neuropathies. Muscle Nerve 2013; 48:696–704. Yucel A, Yilmaz O, Babaoglu S, Acar M, Degirmenci B. Sonographic findings of the median nerve and prevalence of carpal tunnel syndrome in patients with Parkinson’s disease. Eur J Radiol 2008; 67:546–550. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967; 17:427–442. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003; 18:738–750. Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation and application of a Parkinson’s disease quality of life questionnaire and its associated measures. J Neurol 1998; 245(suppl 1):S10– S14. Soyupek F, Yesildag A, Kutluhan S, et al. Determining the effectiveness of various treatment modalities in carpal tunnel syndrome by ultrasonography and comparing ultrasonographic findings with other outcomes. Rheumatol Int 2012; 32:3229–3234. Levine DW, Simmons BP, Koris MJ, et al. A self-administered questionnaire for the assessment of severity of symptoms and functional status in carpal tunnel syndrome. J Bone Joint Surg Am 1993; 75:1585–1592. Stevens JC. AAEM minimonograph #26: the electrodiagnosis of carpal tunnel syndrome. American Association of Electrodiagnostic Medicine. Muscle Nerve 1997; 20:1477–1486.
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17. Yucel A, Yilmaz O, Babaoglu S, Acar M, Degirmenci B. Erratum to “Sonographic findings of the median nerve and prevalence of carpal tunnel syndrome in patients with Parkinson’s disease” [Eur J Radiol 67 (3) (2008) 546–550]. Eur J Radiol 2008; 68:499–502. 18. Ugbolue UC, Hsu WH, Goitz RJ, Li ZM. Tendon and nerve displacement at the wrist during finger movements. Clin Biomech (Bristol, Avon) 2005; 20:50–56. 19. Klauser AS, Halpern EJ, De Zordo T, et al. Carpal tunnel syndrome assessment with US: value of additional cross-sectional area measurements of the median nerve in patients versus healthy volunteers. Radiology 2009; 250:171–177. 20. Cartwright MS, Hobson-Webb LD, Boon AJ, et al. Evidence-based guideline: neuromuscular ultrasound for the diagnosis of carpal tunnel syndrome. Muscle Nerve 2012; 46:287–293. 21. Padua L, Padua R, Lo Monaco M, Aprile I, Tonali P. Multiperspective assessment of carpal tunnel syndrome: a multicenter study. Italian CTS Study Group. Neurology 1999; 53:1654–1659.
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ORIGINAL RESEARCH
Is Median Nerve Enlargement at the Wrist Associated With Tremor in Parkinson Disease? Seung Nam Yang, MD, PhD, Hyo Jeong Kang, MD, Joon Shik Yoon, MD, PhD, Sun Jae Won, MD, Woo-Keun Seo, MD, PhD, Seong Beom Koh, MD, PhD
Article includes CME test
Objectives—Tremor is one of the cardinal features of Parkinson disease (PD) and may cause cumulative trauma-related injury to nerves of the hands. The aim of this study was to assess the electrodiagnostic and sonographic features of patients with PD and to assess the effect of tremor in PD on the median nerve. Methods—We studied 31 hands of healthy control participants (n = 16; mean age ± SD, 60.25 ± 14.67 years) and 81 hands of patients with PD (n = 42; 64.95 ± 11.13 years). Motor symptoms were measured by the Unified Parkinson’s Disease Rating Scale III. Median nerve conduction studies and sonographic cross-sectional area measurements were performed in all participants. Results—The median nerve cross-sectional area in patients with PD (10.71 ± 2.79 mm2) was significantly larger than that in the control group (7.40 ± 1.05 mm2; P < .05). However, there was no significant difference in median nerve electrodiagnostic findings between the PD and control groups. The median nerve cross-sectional area was associated with the severity of the tremor but not with the Unified Parkinson’s Disease Rating Scale motor score.
Received January 6, 2014, from the Department of Physical Medicine and Rehabilitation, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea (S.N.Y., H.J.K., J.S.Y.); Department of Physical Medicine and Rehabilitation, Yeouido St Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea (S.J.W.); and Department of Neurology, Korea University College of Medicine, Seoul, Korea (W.-K.S., S.B.K.). Revision requested January 22, 2014. Revised manuscript accepted for publication April 2, 2014. Address correspondence to Seong Beom Koh, MD, PhD, Department of Neurology, or Joon Shik Yoon, MD, PhD, Department of Physical Medicine and Rehabilitation, Korea University College of Medicine, 80 Guro-gu, Gurodong, Seoul, Korea. E-mail: [email protected], rehab46@ korea.ac.kr Abbreviations
PD, Parkinson disease; PDQ, Parkinson’s Disease Questionnaire; UPDRS, Unified Parkinson’s Disease Rating Scale doi:10.7863/ultra.33.12.2079
Conclusions—Tremor in PD is associated with median nerve enlargement but not with impairment of median nerve conduction. Key Words—median nerve; musculoskeletal ultrasound; Parkinson disease; sonography; tremor
P
arkinson disease (PD) is a progressive movement disorder that may result in musculoskeletal problems and deformity.1–3 Musculoskeletal problems in PD are mainly related to parkinsonian rigidity, akinesia, dystonia, and postural abnormalities.1 Muscle cramps, tightness, frozen shoulder, arthritis, finger deformities, and spinal deformities commonly accompany PD.1,4–6 Tremor is one of the cardinal manifestations of PD, and repetitive hand movements may cause cumulative trauma-related injury and hand pain.7 High-resolution sonography has been used to assess nerve disorders. The most common and reproducible finding of entrapment neuropathy is nerve enlargement just proximal to the site of entrapment. Although the cause of nerve enlargement is not well understood, axoplasmic damming as well as inflammatory and vascular components are thought to contribute to nerve disorders.8,9
©2014 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2014; 33:2079–2083 | 0278-4297 | www.aium.org
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Yang et al—Median Nerve Enlargement in Parkinson Disease
One previous study described sonographic findings of the median nerve and the prevalence of carpal tunnel syndrome in PD.10 In that study, carpal tunnel syndrome was more prevalent in patients with PD compared to a control group, and patients with PD had a higher crosssectional area of the median nerve at the wrist, but there was no statistically significant difference between patients with PD and controls. The authors suggested that tremor might be a risk factor for development of carpal tunnel syndrome in PD; however, the correlation between the degree of tremor and median nerve enlargement at the wrist was not investigated. The aim of this study was to compare the median nerve enlargement at the wrist between patients with PD and control participants and to verify the correlation between the degree of tremor and median nerve enlargement at the wrist.
Bradykinesia and Hopokinesia” items. All participating patients were asked to complete the Parkinson’s Disease Questionnaire (PDQ-39)13 to assess impairment of their health-related quality of life. For subjective evaluation of hand symptoms, patients completed the Boston Questionnaire,14 which contains 11 items assessing symptom severity and 8 items regarding functional status.15 Electrodiagnostic Examinations Median motor and sensory nerve conduction studies using the antidromic technique were performed in the supine position on patients with PD and controls with surface electrodes according to standard protocols. The hand temperature of the participants was maintained at 32°C or warmer. A carpal tunnel syndrome diagnosis was made according to American Association of Electrodiagnostic Medicine criteria.16
Materials and Methods Participants A total of 82 hands from 41 consecutive patients with PD and 31 hands from 16 control volunteers were prospectively enrolled from the Department of Neurology of the Korea University Guro Hospital from January 2008 to February 2010. All patients met the clinical diagnostic criteria for PD, as described by the UK Parkinson’s Disease Society Brain Bank. Patients who had a history of carpal tunnel syndrome before the onset of parkinsonian motor signs were excluded. Neither patients nor controls had any diseases that can cause peripheral neuropathy, such as diabetes, amyloidosis, chronic renal failure, and alcoholism. All participants gave written informed consent to participate in this study. This protocol was approved by the regional Institutional Review Board of the Korea University Guro Hospital. Clinical Evaluation Patients underwent a neurologic examination and a clinical assessment. The modified Hoehn and Yahr stage11 was determined, and the degree of disease severity was quantified by Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores12 in the “on state” (ie, when the tremor was active) by a single movement disorder specialist. On the basis of the UPDRS motor scores, the severity of tremor was scored from 0 to 28 by the “Tremor at Rest” and “Action or Postural Tremor of Hands” items. The severity of rigidity was scored from 0 to 20 by the “Rigidity” item. Bradykinesia was scored from 0 to 40 by the “Finger Taps,” “Hand Movements,” “Rapid Alternating Movements of Hands,” “Leg Agility,” “Arising From Chair,” and “Body
2080
Sonographic Examinations Sonographic examinations were performed by a boardcertified physiatrist with 10 years of experience in sonography. The examinations were performed without information about the clinical findings or electrodiagnostic results. An HDI 3500 ultrasound device (Philips Healthcare, Bothell, WA) with a 7–12-MHz linear array transducer was used for this study. Each participant was placed in the supine position with the elbow and wrist fully extended. The transducer was first used to obtain a transverse view of the median nerve at the distal wrist crease. The cross-sectional area of the median nerve was calculated by a direct method using a continuous boundary trace just within the echogenic boundary of the nerve. An effort was made to minimize additional pressure from the probe on the nerve. Statistical Analyses All statistical analyses were performed with SAS version 9.2 software (SAS Institute Inc, Cary, NC). Group differences in age, sex, and body mass index were evaluated by a t test and χ2 test. Continuous variables were tested for normality by the Shapiro-Wilk test. Logarithmic transformations were applied to the amplitude of the median compound muscle action potential, latency of the median sensory nerve action potential, and median nerve crosssectional area as needed to ensure normal distributions of these variables. To analyze the results, a general linear model was used. The compound motor action potential and sensory nerve action potential latency, amplitude of median nerve conduction, and cross-sectional area of the median nerve were compared between patients with PD and controls. Correlations between motor examinations
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as assessed by the UPDRS, latencies and amplitudes of the compound motor action potential and sensory nerve action potential, and cross-sectional area of the median nerves in patients were evaluated after adjustment for age, sex, body mass index, and hand side. P < .05 was considered statistically significant.
Results General Characteristics A total of 82 hands from 41 patients with PD (14 male and 27 female) and 31 hands from 16 control participants (5 male and 11 female) were enrolled in this study. The mean ages ± SDs of patients with PD and controls were 64.95 ± 11.13 and 60.25 ± 14.67 years, respectively. By modified Hoehn and Yahr staging, 12 patients were classified as stage 1 to 1.5; 6 were stage 2; 10 were stage 2.5; 11 were stage 3; and 2 were stage 4. The mean levodopa equivalent dose at the patient evaluations was 228.66 ± 274.96 mg/d (Table 1). Electrodiagnostic and Sonographic Findings The latencies and amplitudes of median nerves in patients with PD and controls revealed no statistically significant differences (P > .05). There were 6 hands in 5 of the 42 patients in the PD group and none in the control group that met the diagnostic criteria of carpal tunnel syndrome by the nerve conduction studies. The prevalence of carpal tunnel syndrome was not significantly different between patients with PD and controls (P > .05). On sonography,
Table 1. General Characteristics of Patients With PD and Controls Characteristic Age, y Male/female, n Body mass index, kg/m2 Duration of PD, mo Hoehn and Yahr stage, n 1–1.5 2 2.5 3 4 UPDRS motor examination (108) Severity of tremor (28) Severity of rigidity (20) Severity of bradykinesia (40) PDQ-39 (100)
PD
Control
64.95 ± 11.13 14/27 24.81 ± 3.33 38.66 ± 40.47
60.25 ± 14.67 5/11 23.33 ± 3.11
12 6 10 11 2 22.18 ± 17.11 1.75 ± 2.11 8.68 ± 7.31 7.68 ± 6.65 16.37 ± 12.43
Data are presented as mean ± SD where applicable. Numbers in parentheses are maximum scores.
the median nerve cross-sectional area of patients with PD (10.71 ± 2.79 mm2) was statistically significantly larger than that of the controls (7.40 ± 1.05 mm2; P < .05; Table 2). Correlation Between the Degree of Tremor and Sonographic Findings There was no significant correlation between total UPDRS motor scores and the median nerve cross-sectional area in patients with PD (P > .05); however, the severity of tremor was significantly correlated with the median nerve crosssectional area in patients with PD (P < .05). The severity of rigidity and bradykinesia had no significant correlation with the median nerve cross-sectional area (P > .05). There was no significant correlation between total UPDRS motor, tremor, rigidity, and bradykinesia severity scores and nerve conduction study results (P > .05). No significant correlation existed between the symptoms of carpal tunnel syndrome evaluated by the Boston Questionnaire and the median nerve cross-sectional area. There was no correlation between the PDQ-39 score and the median nerve cross-sectional area or nerve conduction study results (Table 3).
Discussion Table 2. Median Nerve Parameters in PD and Control Groups Parameter Median nerve CMAP Latency, ms Amplitude, mV Median nerve SNAP Latency, ms Amplitude, μV Median nerve CSA, mm2
PD
Control
P
3.60 ± 0.09 8.51 ± 0.31
3.54 ± 0.15 8.72 ± 0.65
.8637 .5938
3.28 ± 0.41 35.34 ± 1.63 10.71 ± 2.79
3.33 ± 0.08 40.78 ± 6.11 7.40 ± 1.05
.6995 .7123 .002
Data are presented as mean ± SD. P values represent overall differences across the groups by a general linear model. CMAP indicates compound motor action potential; CSA, cross-sectional area; and SNAP, sensory nerve action potential.
Table 3. Correlation of Motor Examination by the UPDRS and Median Nerve Cross-sectional Area in Patients With PD Parameter Total UPDRS motor score Severity of tremor Severity of rigidity Severity of bradykinesia Boston Questionnaire PDQ-39
P .7604 .0341 .8504 .8643 .5427 .6613
P values represent correlation with the median nerve cross-sectional area by a general linear model.
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We investigated the median nerve cross-sectional area at the wrist in patients with PD and healthy control participants. The median nerve cross-sectional area in patients with PD was significantly larger than that in the control group. Tremor in PD was correlated with median nerve enlargement but not with slowing of median nerve conduction. In a study by Yucel et al,10 tremor in patients with PD appeared to be the primary contributing factor for carpal tunnel syndrome; however, they did not prove any correlation between carpal tunnel syndrome and the degree of tremor. Our study verified that the severity of tremor was correlated with the median nerve cross-sectional area. The exact mechanism for the relationship between tremor and median nerve abnormalities at the wrist in PD has not been established. Tremor in PD occurs mainly at the finger joints rather than the wrist, leading some to point out that repetitive movements of the fingers may not affect the wrist and carpal tunnel.17 However, metacarpophalangeal joint movements are driven by the finger flexor tendons, which may cause median nerve displacement at the wrist, as seen in a kinematic study of motion in cadavers.18 Tremor involving the finger joints may cause friction between the flexor tendons and the median nerve and may cause median nerve enlargement. Although parkinsonian hand tremor is more prominent at finger joints, the tremor is also observed at wrist joints. Moreover, the tremor pattern at wrist joints is not a simple to-and-fro movement but rather a mixed pattern involving a rotational component. Thumb tremor in the classic “pill-rolling tremor” may also contribute to median nerve enlargement at the wrist. The results of our study showed a statistically significantly increased median nerve cross-sectional area in patients with PD compared to controls, with no statistically significant slowing of median nerve conduction or reduction in the amplitude. Our results differed from those of the previous study by Yucel et al,10 which showed a significant reduction in the median nerve amplitude in the second finger and a higher incidence of carpal tunnel syndrome in patients with PD compared to controls. Median nerve enlargement at the wrist is the main finding in sonographic studies of carpal tunnel syndrome. In using median nerve cross-sectional area cutoff values, sonography has been reported to have high sensitivity and specificity. Klauser et al19 proposed diagnosis on the basis of median nerve cross-sectional area cutoff values using a difference in the median nerve cross-sectional area of greater than 2 mm2 between the level of the proximal pronator quadratus muscle and the level of the carpal tunnel, and this measurement has been shown to diagnose carpal tunnel syndrome with 99%
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accuracy. In using median nerve cross-sectional area cutoff values, the sensitivity and specificity for diagnosis of carpal tunnel syndrome depend on the selected threshold according to the laboratory (8.5–12.0 mm2).19,20 In our study, a small number of cases in the PD group (6 of 82 hands) met the diagnosis of carpal tunnel syndrome by nerve conduction studies alone; however, more cases in the PD group (29 of 82 hands) met the diagnostic criteria by the median nerve cross-sectional area on sonography even with a relatively high diagnostic threshold of greater than 12.0 mm2. The discrepancy between electrodiagnostic testing and sonographic results might be due to different pathophysiologic mechanisms between median nerve swelling in patients with PD and idiopathic carpal tunnel syndrome. Median nerve swelling in patients with PD may be due to friction of the median nerve at the wrist as well as compression. The symptom severity measured by the Boston Questionnaire did not correlate with the median nerve crosssectional area in this study, in contrast to a study of patients with carpal tunnel syndrome without PD, in which it did.21 We hypothesize that involuntary movements of the hands may relieve the symptoms of carpal tunnel syndrome in patients with PD. In our study, tremor was related to median nerve enlargement at the wrist in patients with PD. We hypothesize that abnormal movements may result in nerve irritation and a subsequent cross-sectional area increase. Although many patients had clinically irrelevant median nerve enlargement, the possibility of future transition to symptomatic carpal tunnel syndrome should be considered. Further study is needed to identify predictive factors for transition from asymptomatic median nerve enlargement to symptomatic carpal tunnel syndrome in patients with PD. A limitation of our study was its small sample size, and blinding of the examiner to the patient group may not have been complete if participants had tremor or other signs of PD, although sonography was performed without any clinical information or knowledge of electrodiagnostic results. In addition, we only evaluated enlargement of the median nerve at the wrist and did not use additional diagnostic methods such as a comparison of the median nerve cross-sectional area between wrist and forearm, which was reported to have good accuracy in carpal tunnel syndrome diagnosis.19 In conclusion, we have demonstrated that median nerve cross-sectional area at the wrist in patients with PD was significantly larger than that in healthy control participants when diagnosed by sonographic studies. Tremor in patients with PD was correlated with sonographic findings of median nerve enlargement but not with impairment of median nerve conduction.
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