Muscle relaxation measured perfectly with magnetic brain stimulation (TMS) Valuable method for neurologist's toolbox

In some patients with muscle problems, the problem is caused by the muscles not relaxing properly. This may be caused by an inherited muscle disease. But muscles that relax too slowly are not easy to diagnose. Joery Molenaar developed a method that can reliably demonstrate this. He also immediately used them to further map some muscle diseases. Molenaar will receive his doctorate from the Radboudumc on April 16.

General practitioners see many people with muscle problems. "If they have weaker and thinner muscles, can no longer hold things properly or have difficulty standing on their legs, then as a doctor you know that they have problems tightening the muscles," says neurologist Joery Molenaar. "But there is also a large group that actually has problems relaxing the muscles. If that happens too slowly, they can suffer from pain, cramping and stiffness. But such delayed muscle relaxation is difficult to diagnose in the consultation room. Yet it is important, because sometimes there is an underlying, inherited muscle disease."

Reliable method

As a neurologist/clinical neurophysiologist working at Rijnstate, Molenaar regularly sees patients who have been referred on suspicion of such delayed muscle relaxation. With the naked eye, this is not easy to determine and immediately starting a muscle biopsy or genetic testing is rather invasive and expensive. Having the patient tighten and release the muscles produces inaccurate measurements. Therefore, Molenaar set out to find a relatively simple but reliable method to measure muscle relaxation.

Shutting down the control

That method is now in place. Equipment needed: a handle to squeeze, connected to a computer and also a TMS device. Molenaar describes the procedure: "The patient squeezes the handle as hard as possible, the computer registers the squeezing force, and when it is at its maximum, we deliver a painless magnetic pulse with the TMS device precisely at the center of the head where the motor cortex is located. That pulse stops the control of muscle force for a quarter of a second, allowing us to precisely and perfectly timed measure the rate of muscle relaxation. The method works for young and old, male and female, health and disease."

Brody's disease

Molenaar has used the method to give more attention to those people who have been under-reported both in the consulting room and the medical literature: those with overactive muscles, with muscles that do not relax properly. For example, his doctoral research shows that in patients with Brody's disease - a genetic muscle disease due to mutations in the ATP2A1 gene - there is a distinct and characteristic delay in muscle relaxation. He also extensively mapped the clinical features of this disease. "Among other things, we found that delayed muscle relaxation during tightening of the limbs and eyelids is the main characteristic of this muscle disease. The first symptoms appear in childhood and increase slightly throughout life. Muscle strength was generally unaffected and several patients were even remarkably muscular."

Difficulty running and jumping

In nemaline muscle disease type 6, another inherited muscle disease caused by mutations in the KBTBD13 gene, delayed muscle relaxation causes, among other things, rapid movements such as jumping, running or climbing stairs to be difficult. Using the TMS method, it was shown that delayed muscle relaxation is also involved in this muscle disease. In addition, in collaboration with colleagues in Amsterdam, research in muscle biopsies showed that the cause of the problems arise from changes in the thin filament of the muscles. "In this way we try to visualize the various muscle diseases as comprehensively as possible: from research on the total patient to laboratory research on small parts of the muscle cell," says Molenaar.

Disease-causing mutation?

The new method allows patients to be screened not only for underlying muscle disease. Molenaar: "We can also use it properly to monitor whether the patient is deteriorating or not, for example; simply by looking at whether the rate of muscle relaxation decreases over the years. In the development of new drugs, we can also quickly assess whether a drug has an effect on the condition or not. In addition, when muscle disease is suspected, broad genetic testing is increasingly being done, in which many variations in genes are found. The question is then: does such a variation, such a mutation, cause the disease or not? With our method, we can demonstrate fairly quickly whether that mutation is pathogenic or not. If we see normal muscle relaxation, then it is most likely not a pathogenic mutation."

Valuable addition

Molenaar sees a lot of potential for the new method. Not directly for general practice, but more for use in hospitals, the second line. Then there has already been a preselection of patients and, moreover, many hospitals already have equipment with which TMS - transcranial magnetic stimulation - can be applied. "With blood tests, electromyography, ultrasound and other techniques, the neurologist's toolbox is already pretty well stocked," Molenaar says. "But for patients with delayed muscle relaxation, our method is a valuable asset."

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