Arthritis & Rheumatism (Arthritis Care & Research) Vol. 57, No. 7, October 15, 2007, pp 1329 –1333 DOI 10.1002/art.22992 © 2007, American College of Rheumatology CONTRIBUTIONS FROM THE FIELD Musculoskeletal Reﬂex Function in the Joint Hypermobility Syndrome WILLIAM R. FERRELL,1 NICOLA TENNANT,2 RONALD H. BAXENDALE,3 MARION KUSEL,3 ROGER D. STURROCK4 Introduction Joint hypermobility syndrome (JHS) is a heritable disorder of the connective tissues characterized by hypermobility and musculoskeletal pain in the absence of overt signs of systemic inﬂammatory joint disease. The gene defect remains unknown and diagnosis relies upon clinical signs and symptoms (1). Although there is as yet no ﬁrm pathologic basis, this condition is increasingly recognized as a clinical entity (2) but has no deﬁnitive treatment and therefore poses a challenge to treatment. We previously observed a proprioceptive deﬁcit at the proximal interphalangeal joint (3) and the knee joint (4) of patients with JHS compared with age- and sex-matched controls, suggesting a neurophysiologic deﬁcit. More recently, we demonstrated that a home-based program of closed kinetic chain exercises resulted not only in quality of life and symptomatic improvement (as assessed by the Short Form 36 Health Survey and visual analog scores) as well as increased muscle power, but also, more signiﬁcantly, in enhanced knee joint proprioception (5). Having demonstrated the effectiveness of this home-based exercise program, we describe a more focused investigation of reﬂex function of muscles acting at the knee joint in patients with JHS. The question we sought to answer was whether, in addition to the known proprioceptive deﬁcits in patients with JHS, abnormalities of musculoskeletal reﬂex function occur and Supported by the Arthritis Research Campaign (15451). 1 William R. Ferrell, MB, ChB, PhD, FRCP: Centre for Rheumatic Diseases, Royal Inﬁrmary, Glasgow, and the Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, UK; 2Nicola Tennant, MA, MSc, MCS: Royal Inﬁrmary, Glasgow, Scotland, UK; 3Ronald H. Baxendale, BSc, PhD, Marion Kusel, HND: Institute of Biomedical & Life Sciences, University of Glasgow, Scotland, UK; 4Roger D. Sturrock, MD, FRCP: Centre for Rheumatic Diseases, Royal Inﬁrmary, Glasgow, Scotland, UK. Dr. Sturrock has received consultancies and/or honoraria (less than $10,000 each) from Abbott and Schering-Plough. Address correspondence to William R. Ferrell, MB, ChB, PhD, FRCP, Centre for Rheumatic Diseases, Royal Inﬁrmary, 10 Alexandra Parade, Glasgow, Scotland, UK G31 2ER. E-mail: email@example.com. Submitted for publication October 18, 2006; accepted in revised form February 22, 2007. AND if the same exercise program we previously found to be of beneﬁt in these patients could improve such dysfunction. Neurophysiologic analysis of reﬂex function in patients with JHS is presently lacking and this study is the ﬁrst to investigate this aspect. Patients and Methods Patients. Fifteen patients with JHS were recruited from the hypermobility clinic at Glasgow Royal Inﬁrmary. The diagnosis of JHS was based on the revised Brighton criteria (1), which for the present study required the presence of 2 major criteria or 1 major and at least 2 minor criteria. Major criteria included joint hypermobility score ⱖ4, based on the 0 –9 scoring system developed by Beighton et al (6), or arthralgia in ⱖ4 joints for ⱖ3 months. Minor criteria included other features associated with the syndrome such as dislocation/subluxation of joints, abnormal skin signs, herniae or prolapse, or soft tissue rheumatism (1). An additional entry criterion for the study was knee joint pain. Patients with JHS were predominantly female (13 of 15) with a mean ⫾ SD age of 25.9 ⫾ 8.1 years (range 14 –39 years). The mean ⫾ SD Beighton score was 6.6 ⫾ 1.8 (range 4 –9). Hypermobility was also scored using a modiﬁcation of the Contompasis system (maximum score 56) (7), and the mean ⫾ SD score was 34.6 ⫾ 4.4 (range 26 – 41). A parallel control group of 11 healthy individuals with normal mobility (9 female, mean ⫾ SD age 27.3 ⫾ 6.3 years, range 15–39 years, mean ⫾ SD Beighton score 0.7 ⫾ 1.0), recruited from staff and student volunteers unaware of the objectives of the study, was also examined on one occasion only. The study received approval from the local ethics research committee. Musculoskeletal reﬂex testing. Electromyographic (EMG) recordings were obtained from the rectus femoris muscle using a small skin mounted preampliﬁer with integrated surface electrodes. Prior to application, the skin was cleaned with alcohol to reduce impedance and improve the signal-to-noise ratio. Electrical signals were ampliﬁed ⫻1,000 (NL104; Digitimer, Welwyn Garden City, UK) and band pass ﬁltered (10 –3,000 Hz). The power spectrum of recorded EMG signals ranged from 10 to 300 Hz. A constant current stimulator (DS7A; Digitimer) was used to 1329 1330 Ferrell et al voluntary contraction, as judged by monitoring on a screen the integrated EMG recorded from quadriceps femoris and maintaining this at a ﬁxed level on the screen. A total of 60 pulses were delivered and the responses were digitized using a CED 1401 interface (Cambridge Electronic Design, Cambridge, UK) at 1 kHz and stored on a personal computer for detailed ofﬂine analysis using Spike 2 software, version 2.15 (Cambridge Electronic Design). The recorded signal was processed by averaging poststimulus time, and segmental reﬂex responses typically occurred within 20 – 40 msec of the stimulus (Figure 1B). A reﬂex response was considered to have occurred if the rectiﬁed averaged signal exceeded 2 SDs from the baseline, calculated from an average of the 30-msec period preceding the electrical stimulus. Previous work (8) has demonstrated that in healthy persons with normal mobility the reﬂex is stable, with the coefﬁcient of variation between trials ranging from 0.08 to 0.18 (mean ⫾ SEM 0.13 ⫾ 0.02). Reﬂex modulation was calculated by dividing the reﬂex area by the control area. The reﬂex area was deﬁned as the product of the magnitude of the EMG signal by the time interval during which the reﬂex response exceeded 2 SDs. For the control area, the area of the EMG signal was calculated for the same time interval but during the prestimulus period. Study design. The study design involved repeated pretesting on 2 occasions followed by postintervention testing. Reﬂex function was assessed in patients with JHS on 2 occasions 8 weeks apart, during which time no intervention was performed. The second measurement permitted assessment of the stability of the reﬂex across the 8-week period. The patients then undertook an 8-week homebased exercise program of closed kinetic chain exercises as previously described (5), after which reﬂex function was tested once again. For the control group, measurements were only obtained on 1 occasion. Two patients moved away and therefore dropped out of the study before the second measurement and the exercise program, but the ﬁrst measurement was obtained for both patients. Figure 1. A, Diagrammatic representation of the recording and stimulation arrangements. B, Electromyographic (EMG) recordings (average of 60 sweeps) obtained from one subject with normal mobility with the knee extended (0° ﬂexion) and ﬂexed (20° ﬂexion). Electrical stimulus applied at time 0. QF ⫽ quadriceps femoris; F ⫽ femur; P ⫽ patella; T ⫽ tibia. deliver rectangular pulses (width 0.2 msec) at 1 Hz transcutaneously via monopolar electrodes to the common peroneal nerve at the ﬁbular neck at 1.3 times the motor threshold. This was sufﬁcient to cause a minor twitch of the anterior tibial muscles accompanied by a mild tapping sensation. The experimental setup is illustrated in Figure 1A. The knee joint was ﬁxed at a speciﬁed position and participants were required to perform an isometric contraction of the thigh extensors at 20% of the maximum Statistical analysis. Data are presented as the mean ⫾ SD or mean ⫾ SEM. Comparisons were performed using analysis of variance (ANOVA) or t-tests as appropriate for interval scale data and chi-square or Fisher’s exact test for nominal scale data (Sigmastat; SPSS, Chicago, IL), all tests being 2-tailed with P values less than 0.05 being considered signiﬁcant. Results The reﬂex response was present in all controls (n ⫽ 11) with the knee extended (0° ﬂexion) and the magnitude reduced on knee ﬂexion, as illustrated in Figure 1B for a single participant. The latency of the reﬂex was 18 – 41 msec, consistent with a segmental oligosynaptic spinal reﬂex pathway. By contrast, responses in patients with JHS were more variable (Figure 2A), with the reﬂex present in 8 (53%) of 15 patients but absent in 7 (47%) of 15 patients; the difference between the control and JHS groups was signiﬁcant (2 ⫽ 4.85, 1 df, P ⬍ 0.01). However, the reﬂex latency onset in the control group did not differ signiﬁ- Musculoskeletal Reﬂex Function in Joint Hypermobility Syndrome 1331 cantly (unpaired t-test; t ⫽ 0.43, P ⫽ 0.64) from the JHS group (mean ⫾ SEM 26.1 ⫾ 1.4 msec versus 27.1 ⫾ 1.0 msec). When reﬂex testing was repeated in the patients with JHS (2 of whom dropped out from the study after the ﬁrst test) after 8 weeks, we found that the reﬂex remained absent in patients who did not show the reﬂex at the ﬁrst assessment (Fisher’s exact test; P ⫽ not signiﬁcant [NS]; n ⫽ 6), whereas it persisted in the other patients (Fisher’s exact test; P ⫽ NS; n ⫽ 7). Mean ⫾ SEM reﬂex modulation, expressed as the percent change of the reﬂex area divided by the control area, was 104% ⫾ 2.3% in patients with JHS whose reﬂex was absent compared with 133% ⫾ 6.3% in patients showing the reﬂex; this difference was signiﬁcant (unpaired t-test; t ⫽ 4.08, P ⫽ 0.0013). The effect of home-based exercise was tested in the patients with JHS to establish whether the reﬂex could now be elicited. Following the 8-week exercise program, the reﬂex was demonstrable in all patients in whom the reﬂex could not previously be elicited (Fisher’s exact test; P ⫽ 0.002), as illustrated in Figure 2B for one patient. For the 7 of 13 patients who showed the reﬂex at the previous 2 tests, this was unchanged by the exercise program (Fisher’s exact test; P ⫽ NS). Although it is well recognized that in individuals with normal mobility the reﬂex is modulated by knee joint position and invariably diminishes on movement into ﬂexion, the effect of hyperextension is unknown and was investigated. As anticipated, the reﬂex was maximal with the knee at 0° ﬂexion and decreased on ﬂexion, but surprisingly the reﬂex also diminished upon hyperextension of the knee, as shown in Figure 3A for a single patient. This was true for all 7 patients with JHS who were tested (Figure 3B), and this ﬁnding was signiﬁcant (one-way ANOVA; F ⫽ 4.32, P ⫽ 0.02). Interestingly, the magnitude of reﬂex attenuation was similar despite the fact that the degree of hyperextension (10°) was much less than the extent of ﬂexion (30°). Discussion Figure 2. A, Electromyographic (EMG) recordings (averages of 60 sweeps) from one patient with joint hypermobility syndrome (JHS) showing a reﬂex response (upper panel, reﬂex denoted by arrow) and another patient with JHS whose response was absent (lower panel). Knee held at 0° ﬂexion in both patients. B, Three EMG recordings (average of 60 sweeps) obtained from the same JHS patient showing the absence of a reﬂex response on initial testing (pre-exercise 1), after 8 weeks without intervention (pre-exercise 2), and following an 8-week home-based exercise program of closed kinetic chain exercises (post-exercise) when a segmental reﬂex is present (arrow). Knee held at 0° ﬂexion in all cases. There is increasing evidence indicating that subtle neurophysiologic abnormalities occur in patients with JHS. Autonomic dysfunction has been described in this patient group (9) and we previously demonstrated reduced proprioceptive acuity in the ﬁnger joints (3) and knee joints (4) of these patients. Therefore, it is perhaps not unexpected to discover that reﬂex function is also impaired, although not in all patients with JHS. This reﬂex arises from stimulation of group I afferent ﬁbers in the common peroneal nerve that evoke non-monosynaptic excitation of quadriceps motoneurons (10). Group Ib afferent ﬁbers are thought to constitute the afferent limb of the musculoskeletal reﬂex through an oligosynaptic pathway (11), which is consistent with the short reﬂex latency observed in the present study. The reﬂex is invariably present in individuals with normal mobility with the knee at 0° of ﬂexion (12), therefore its absence in almost half of the patients with JHS is striking, although it is unclear why the reﬂex could be elicited in the other half of this patient group. One clue might be that those patients in whom the reﬂex 1332 Figure 3. A, Averaged rectiﬁed electromyographic (EMG) recordings (60 sweeps) from the same patient with joint hypermobility syndrome (JHS) at 3 knee joint positions: ﬂexed, extended, and hyperextended. Dashed lines indicate 2 SDs and reﬂex responses are considered to be signiﬁcant when the signal exceeds 2 SDs (shaded area). Both ﬂexion and hyperextension resulted in reduced magnitude of responses compared with the control position (0° ﬂexion). B, Comparison of reﬂex responses (expressed as a percentage of the response in the control position, 0° ﬂexion) at different knee joint positions in 7 patients with JHS (mean ⫾ SEM). * P ⬍ 0.05, signiﬁcant difference from the control position. could be elicited were more physically active when questioned about their daily activities. Unfortunately, quantitative data were not collected as part of this investigation, so this hypothesis remains unproven. A remarkable observation was that in all patients failing to show a reﬂex initially, a reﬂex could be elicited following the exercise program. This ﬁnding parallels our previous observation that proprioception improved following the same exercise program, and suggests that similar mechanisms may be at work, perhaps via facilitation of interneuronal pathways. As anticipated, the reﬂex diminished on knee ﬂexion, but surprisingly, hyperextending the knee diminished rather than enhanced the reﬂex. This ﬁnding implies that there is an optimal position for eliciting the reﬂex and Ferrell et al hyperextension of the joint is disadvantageous. In functional terms, the signiﬁcance of the reﬂex is that it clearly indicates facilitation of thigh extensor motoneurons as the knee is extended, but only up to a point. Such facilitation is likely to be important for bracing the knee at heel strike in anticipation of load bearing, and it is interesting in this context that patients with JHS can describe the knee as “giving way,” often when negotiating stairs. The decreasing facilitation of knee extensor motoneurons upon hyperextension of the knee provides a plausible neurophysiologic explanation for this phenomenon. The study design had clear limitations, being semicontrolled and lacking a patient-oriented outcome. Future studies should be designed to incorporate appropriate patient-oriented outcome measures as well as improved control of the variables. It is conceivable that pain could have affected the reﬂex. However, this is unlikely to be the case because all patients experienced knee joint pain at the beginning of the study, and yet in 7 patients the reﬂex was absent whereas in 8 patients it was present, suggesting that pain does not inﬂuence this reﬂex pathway. It has been shown that proprioception is unaffected by pain (13), therefore it is likely that a segmental spinal reﬂex is even less likely to be affected. The advantage of reﬂex testing is that it provides a highly objective method for assessing neurophysiologic function in patients and is not readily subject to conscious inﬂuences. A disadvantage is the requirement for recording equipment and procedures, which are not translatable to the clinical environment. However, the robustness of the technique and absence of subjective bias make it suitable for investigating neurophysiologic function in other musculoskeletal diseases where reﬂex dysfunction is suspected. Analysis of neurophysiologic function in rheumatologic diseases has been limited, but such an approach offers the prospect of better understanding of neurologic dysfunction and assessment of the effectiveness of physiotherapeutic intervention. AUTHOR CONTRIBUTIONS Dr. Ferrell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Ferrell, Tennant, Sturrock. Acquisition of data. Tennant, Baxendale, Kusel, Sturrock. Analysis and interpretation of data. Ferrell, Baxendale. Manuscript preparation. Ferrell, Tennant, Sturrock. Statistical analysis. Ferrell, Baxendale, Sturrock. REFERENCES 1. Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol 2000;27:1777–9. 2. Grahame R, Bird H. British consultant rheumatologists’ perceptions about the hypermobility syndrome: a national survey. Rheumatology (Oxford) 2001;40:559 – 62. 3. Mallik AK, Ferrell WR, McDonald AG, Sturrock RD. Impaired proprioceptive acuity at the proximal interphalangeal joint in patients with the hypermobility syndrome. Br J Rheumatol 1994;33:631–7. 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