The precise natural history of the skeletal muscle channelopathies is not extensively documented, but development of a proximal myopathy is recognized, especially in the periodic paralyses. Whether the myopathy is related to the severity and frequency of paralytic attacks is unclear6, 19
. There is some evidence that development of myopathy may be associated with increasing age6, 20
. In addition, moderately elevated CK (1000–2000 U/L) and moderate to severe myalgia are reported in the skeletal muscle channelopathies, although there is no evidence to link these directly to the presence of myopathy or to explain their pathogenesis.
A characteristic history in conjunction with specialized neurophysiologic techniques21
allows a diagnosis in the majority of cases of skeletal muscle channelopathy, and it is rare that a muscle biopsy is now performed in the UK.
In our three cases a clinical diagnosis of skeletal muscle channelopathy had been made prior to the muscle biopsy and was later confirmed genetically. Biopsy was performed due to additional clinical features that were deemed unusual or severe for a muscle channelopathy. In case 1 the proximal myopathy could have been attributed to the myopathy that is reported in periodic paralysis, but the very high CK (2729 U/L) was considered to be atypical. The severe myalgia and moderate elevation of CK (1109 U/L) reported in case 2 are also described features of the channelopathies, and we cannot exclude the possibility that at least some of the myalgia is due to myotonia. However, as the myalgia became severe enough to be the patient’s primary complaint a biopsy was performed. The initial complaint of muscle swelling in case 3 is not a typical feature of the muscle channelopathies, and with the later development of significant myalgia, a biopsy was felt to be warranted. We suggest that the clinical features of weakness, myalgia and significantly elevated CK in these three cases are secondary, at least in part, to the observed inflammatory process.
The biopsy findings in these cases do not fulfil all morphological criteria for IIM, particularly the lack of invasion of intact fibers. However upregulation of MHC class I expression (cases 1 and 3) is supportive, and it is not unreasonable that a diagnosis of IIM had been made in these cases, especially when each was considered in isolation. There are numerous examples of other genetic muscle disorders in which inflammatory infiltrates have been observed and even diagnosed as IIM22
. We cannot exclude the possibility that the observed inflammatory process is a coincidental finding, and two independent pathologies (channelopathy and IIM) are present in each of the three individuals. This seems to be statistically unlikely.
Whether this inflammatory response plays a potential pathogenic role in the development of the myopathy is not known. Morphology data is reported for the skeletal muscle channelopathies, especially the periodic paralyses, but in many cases it pre-dates the availability of genetic testing. A vacuolar myopathy and/or tubular aggregates support the diagnosis of periodic paralysis. With improved electrophysiologic and genetic diagnostic methods, muscle biopsy is now less common. Without a larger number of biopsy samples from similar cases it is not possible to know how accurately inflammatory muscle infiltrates may correlate with the clinical presentation.
Although there was some improvement in symptoms and a reduction in CK with prednisone in two cases, in one case high dose prednisone induced a severe paralytic attack, although low dose steroids were better tolerated. Worsening of the paralytic symptoms of periodic paralysis with glucocorticoids has been reported23
. Other immunosuppressive agents had no clear additional benefit.
Based on these observations, we suggest that a diagnostic muscle biopsy should be considered in cases of skeletal muscle channelopathy that present with the symptoms of severe myalgia and/or subacute weakness and an accompanying elevated CK (>1000 U/L) to ascertain the presence of any inflammatory infiltrates. The therapeutic benefit of immunosuppressants is not established, but our cases may indicate that steroids could have a role. The optimal dose is undetermined, and higher doses may be detrimental such that caution with their use is recommended.
The statistical evidence indicates that the coexistence of an inflammatory process and skeletal muscle channelopathy is very unlikely to be purely coincidental. The possible implications this may have for our understanding of the mechanisms of muscle damage in the skeletal muscle channelopathies remains to be explored.