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 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
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 ≥4, based on the 0–9 scoring system developed by Beighton et al (6), or arthralgia in ≥4 joints for ≥3 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 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 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.
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 home-based 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.
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.
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 (χ2 = 4.85, 1 df, P < 0.01). However, the reflex latency onset in the control group did not differ significantly (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°).
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 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 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.
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.