Neurol Sci DOI 10.1007/s10072-016-2612-z
BRIEF COMMUNICATION
Long-term whole-body vibration training in two late-onset Pompe disease patients Federica Montagnese1,2 • Simone Thiele1 • Stephan Wenninger1 • Benedikt Schoser1
Received: 23 February 2016 / Accepted: 12 May 2016 Ó Springer-Verlag Italia 2016
Abstract The treatment of late-onset Pompe disease (LOPD) relies on enzyme replacement therapy (ERT) and physiotherapy but the most appropriate exercise program is not yet established. Whole-body vibration training (WBVT) has showed promising results, improving motor performances in various populations. Our aim is to assess the effects of WBVT performed by two LOPD patients in addition to ERT and physiotherapy. A side-alternating WBVT lasting 2 years; clinical assessments included: manual muscle testing (MRC sumscore), knee extension and arm flection isometric strength (multi-muscle tester M3diagnos), timed function tests (10 m walking, standing-up from chair, ascending 4-steps), 6 min walking (6 MWT), motor disability (Walton Gardner-Medwin scale), pulmonary function. Follow-up evaluations performed for 9 years since ERT start (pre-WBVT and post-WBVT) are reported for comparison. MRC sumscore improved in both patients (Pt.1:41 ? 48, Pt.2:42 ? 47) as isometric strength of knee extension (Pt.1: ? 62 %, Pt.2: ? 26 %) and arm flection (Pt.1: ? 88 %, Pt.2: ? 66 %), 6 MWT improved in Pt.1 (?75 m). Timed function tests did not greatly change. Patients reported no significant CK elevation or WBVT-related complaints. WBVT may be safely used in LOPD and seems to moderately boost muscle strength in patients receiving ERT and physiotherapy for more than 3 years. Larger cohorts should be studied to better assess WBVT potential as adjunctive exercise tool in LOPD.
Keywords Late-onset Pompe disease Whole-body vibration Enzyme replacement therapy Side-alternating vibration
Introduction Late-onset Pompe disease (LOPD) is a pathologic condition resulting from genetic deficiency of alpha-acid glucosidase (GAA) manifesting during childhood or adulthood with a pre-symptomatic hyperCKemia or a proximal/axial weakness with/without respiratory impairment; it may then progressively worsen leading, in most severe cases, to wheelchair use and/or ventilator support. To date, the only causal treatment is enzyme replacement therapy (ERT) which stabilizes or improves the motor/respiratory functions in 2/3 of LOPD patients [1]. Whole-body vibration training (WBVT) is emerging as an effective, easy, mean to improve motor performances (muscle strength, power, mass, endurance) [2–4]; it acts applying, through an oscillating platform, vibrations that will stretch the muscle spindles inducing the reflex contraction of extrafusal muscle fibers (Tonic Vibration Reflex—TVR) [2]. Despite extensive literature supporting the beneficial effects of WBVT [2–4], only few studies investigated its use in neuromuscular diseases [6, 6]. Herein we report the effects of a 2 years WBVT performed by two LOPD patients already receiving ERT.
& Federica Montagnese
[email protected] 1
Department of Neurology, Friedrich-Baur-Institute, LudwigMaximilians-University, Ziemssenstraße 1a, 80336 Munich, Germany
2
Department of Neuroscience, University of Messina, Messina, Italy
Case report Methods Two LOPD patients (clinical details in Table 1), treated with ERT for more than 3 years and regular (twice a week) physiotherapy, performed a WBVT using a side-
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Fig. 1 Assessments trends before, during and after WBVT. a CK; b MRCss; c Functional timed tests (10 m walking test, ascending 4 steps, stand up from a chair); d 6 min walking test (6 MWT). Asterisk breast cancer treatment
alternating vibration platform (Galileo MedMÒ, Novotec Medical). For lower extremities, the patients stood on the platform (feet located 10 cm from central axis), knees and hips slightly flexed. For upper extremities, they maintained a semi-push-up position (elbows extended, knees on the floor) for 30s. The training included: 3 sessions/week, assisted by a physiotherapist, comprising two cycles of 3 min. (lower extremities) and two cycles of 30s. (upper extremities). The vibration frequency increased from 8 to 18 Hz, with 4 mm amplitude [6]. The WBVT lasted 2 years; clinical assessments were performed at 1 month, 1 and 2 years of WBVT and included: motor disability scale (Walton Gardner-Medwin Scale-WGMS), manual muscle testing (MRC sum-score), maximal isometric strength of knee extension and arm flection (multi-muscle tester M3diagnos, Schell), timed function tests (10 m walking test, standing-up from chair, ascending 4-steps), 6 min walking test (6 MWT) and pulmonary function (Forced vital capacity—FVC %).
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Plasma CK was measured at 1 week and 1–3–6–12– 18–24 months of WBVT as safety marker for vibrationinduced muscle damage. The follow-up evaluations performed yearly since the beginning of ERT (PRE-WBVT) and after the conclusion of WBVT (POST-WBVT) are reported for comparison (Table 1). Results Both patients regularly performed the 2-year WBVT without interruptions. All the assessments are reported in Table 1. CK did not change during the study and patients reported no WBVT-related side effects (itching, erythema, swelling, low-back pain, myalgia) (Fig. 1a). WGMS and pulmonary function (FVC %) remained steady over the course of WBVT, while MRCss improved in both patients (Fig. 1b, Table 1); concomitantly a gradual increase of knee-extensor (improvement of 62 % in Pt.1, 26 % in Pt.2) and arm flection (improvement of 88 % in Pt.1, 66 % in Pt.2) isometric strength occurred (Table 1). Functional tests did not clearly improve (only in Pt.1 6 MWT improved, ?75 m) (Fig. 1c–d).
Neurol Sci Table 1 LOPD patients clinical features and assessments performed before, during and after WBVT Pt. 1—female, 74 years
Pt. 2 – female, 52 years
Age at onset
41 years
20 years
Age at diagnosis
49 years
23 years
GAA mutations
c.-32-13T [ G/c.1942G [ A
c.-32-13T [ G/c.1564C [ G
Disease duration
31 years
30 years
Phenotype
Axial/proximal muscle weakness
Axial/proximal muscle weakness
Ventilator support
Never
Never
Walking aid
None
Cane
Age at ERT start
66
44
ERT
WBVT
post-WBVT
T0
T1
T2
T3
T0
T1
T2
T3
T0
T1
T2
Weight (Kg)
64
64
62
63
62
63
63
63
63
63
63
BMI
24.4
24.4
23.6
24.04
23.6
24.04
24.04
24.04
24.04
24.04
24.04
WGMS
2
2
2
2
2
2
2
2
2
2
3
MRC ss
42
47
49
45
41
43
46
48
50
46
44
6 MWT (m)
390
440
450
455
380
400
455
445
403
425
400
FVC % upright
105
86
103
98
88
86
91
90
86
89
76
10 m walk (sec)
10.84
8.93
7.98
8.20
8.3
7.16
8.84
8.31
8.54
9.31
10.2
Patient 1
Stand up from chair (sec)
1.59
1.42
1.3
1.87
2
2.3
1.44
1.04
1.65
2.6
3.2
4 steps up (sec) Knee exstensors bil. (Nm)a
4.58
3.69
3.20
4.24
5.7
4.58
2.85
2.9
3.2
5.5
5.8
np
np
np
np
95.3
102.3
127
154.4
np
np
np
Arm flection bil. (Nm)a
np
np
np
np
38.4
58.2
71.8
72.2
np
np
np
Patient 2 Weight (Kg)
60
61
60
61
60
60
60
60
60
60
60
BMI
19.6
19.9
19.6
19.9
19.6
19.6
19.6
19.6
19.6
19.6
19.6
WGMS
4
4
4
5
5
5
5
5
5
6
6
MRC ss
42
47
47
46
42
46
48
47
44
40
38
6 MWT (m)
255
260
280
280
243
256
260
141
160
230
262
FVC % upright
94
94
96
92
94
90
92
93
85
83
80
10 m walk (sec)
9.3
9.21
11.33
11.42
13.61
11.41
13.91
13.51
13.1
16
14.8
Stand up from chair (sec)
3.08
2.9
2.3
3.21
3.86
2.43
3.1
3.9
4.8
5.3
5
4 steps up (sec)
7.62
6.88
7.83
9.87
9.52
7.80
8.52
8.34
9.43
11.1
10.8
Knee exstensors bil. (Nm)a
np
np
np
np
46.2
49.1
48.5
58.2
np
np
np
Arm flection bil. (Nm)a
np
np
np
np
38.2
40.1
51.7
63.5
np
np
np
ERT enzyme replacement therapy (T0 = 2006, before ERT treatment; T1 = 12 months of ERT; T2 = 24 months of ERT; T3 = 36 months of ERT); WBVT whole-body vibration training (T0 = 2010, Baseline evaluations—48 months of ERT; T1 = 1 month of ERT ? WBVT; T2 = 12 months of ERT ? WBVT; T3 = 24 months of ERT ? WBVT); post-WBVT (T0 = 2012, 1 month after WBVT conclusion; T1 = 12 months after WBVT conclusion; T2 = 24 months after WBVT conclusion; BMI Body mass index; MRC ss medical research counsil sum score; WGMS Walton Gardner-Medwin Scale; 6 MWT = 6 min walking test; FVC forced vital capacity; Nm Nanometer a
Normal values regarding M3-diagnos system: knee exstension bil.: 398 nm ± 141; arm flection bil: 109 nm ± 41. np not performed
Discussion WBVT may offer some additional advantages over traditional physiotherapy as it is time-saving (few min/day) and adoptable also in severely disabled patients. It might be particularly suitable for LOPD patients, in whom fatigue, shortness of breath and myalgia often limit proper completion of some
traditional exercises. So far, only one case report described the effect of WBVT on a LOPD patient [6] showing improvements in 6 MWT (?116 m), jumping power and knee-extensor maximal isometric strength. This patient was however not receiving ERT and the WBVT lasted only 15 weeks. Our patients completed the 2-year WBVT showing good compliance and tolerability, confirming, as reported for
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Duchenne muscular dystrophy and spinal muscular atrophy patients [6], that WBVT may be safely used in neuromuscular patients. No conclusive statements can be drawn regarding WBVT efficacy in LOPD; however some promising results were achieved in our patients regarding muscle strength. As shown (Table 1), after 3 years of ERT (pre-WBVT) both patients lost the capacity of improvement in MRC, 6 MWT and timed function tests; which is in line with studies reporting major effects of ERT in the first year [1]. During the WBVT, the MRCss re-improved in both patients as confirmed by the increased maximal isometric strength of knee extension and arm flection. This muscle strength improvement, also found in other WBVT studies, may result from muscle adaptations to vibration training as observed in muscle biopsies of animal models and humans, where type-2 myofiber hypertrophy and increased muscle cross-sectional area were documented [7, 8]. The metabolic adaptive processes related to these structural changes in muscle tissue have not been specifically studied yet. It seems that WBVT determines an increased muscle perfusion, oxygen uptake and ATP turnover together with an increased expression of GLUT4 in muscle fibers thus favoring also glucose uptake [9, 10]. However, no histochemical changes (e.g. increased mitochondria) were observed in muscle specimens after WBVT [8]. Despite the improvement in muscle strength, no clear changes were observed on timed functional tests. The 6 MWT, as parameter of endurance, apparently improved in pt.1 (?75 m) and remained almost unchanged in pt.2 in the first year of WBVT, then it rapidly dropped probably due to a breast cancer that was diagnosed and treated (surgery and chemotherapy); nevertheless, she continued the WBVT on a regular protocol base. Overall, pt.1 apparently responded better than pt.2 to WBVT, this might be due to her less severe disability (WGMS 2) although, as known, LOPD progression greatly varies among patients. The examiner was not blinded to WBVT, this aspect, together with the few patients studied, should be considered as a limitation of the study. In conclusion, our patients achieved the best ERT efficacy within the first 2 years, later a stabilization/slow
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worsening of symptoms occurred. The WBVT is a safe adjunctive exercise tool that may allow further re-improvement of muscle strength in LOPD but a larger cohort of patients should be studied to assess its full efficacy. Compliance with ethical standards Conflicts of interest The authors have no conflicts of interest to disclose. All followed procedures were in accordance with the Helsinki Declaration of 1975, as revised in 2000 Informed consent Informed written consent was obtained from patients for being included in the study.
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