By Jay Furst

McArdle's sign, a distinctive muscle weakness that affects patients with spinal cord disease, was first noted more than 30 years ago. The namesake of the "sign," M.J. McArdle, was a professor of neurology in London, and one of his patients with advanced multiple sclerosis needed to extend his neck and tip his head back to maintain a steady gait.

Since then, Dr. McArdle's "sign" hasn't been researched as an indicator of multiple sclerosis, says Brian Weinshenker, M.D., a Mayo Clinic neurologist and MS specialist.

Dr. Weinshenker and colleagues at Mayo Clinic and two other institutions conducted research on McArdle's sign a few years ago and in July published findings in Mayo Clinic Proceedings that indicate the sign is "entirely specific" to MS and has "potential diagnostic utility for MS in certain clinical situations."

Dr. Weinshenker, who has observed and tested for McArdle's sign since the 1980’s, says the vast majority of patients with MS who manifest McArdle's sign are unaware that they're extending their neck to address motor weakness until it's brought to their attention by a neurologist.

"Most patients with MS who have spinal cord disease – which is the majority of MS patients – experience a detectable change in strength that's reduced or increased with head flexion," he says. "This phenomenon is not regularly detected in patients with any other spinal cord condition."

"To my knowledge, this observation by a systematic study of a large number of patients with MS and controls is unique and original — there has been no systematic study of differences between strength with neck extended and flexed to follow up McArdle’s observation," says Dr. Weinshenker, the study's principal investigator.

Finger muscle strength offered clues

The researchers used a torque cell, which converts mechanical input into an electrical output signal, to record finger extensor muscle strength as a measure of McArdle's sign. The study included 52 patients with multiple sclerosis, 24 with other types of spinal cord diseases that are often confused with MS, and five with nerve injuries in their arms who were evaluated at Mayo Clinic in 2016 and 2017. Also included was a control group of 25 healthy patients.

The researchers developed protocols to test and measure finger extensor strength, first with the neck extended (head tipped back) and then with the neck flexed (head tipped forward. Each patient performed multiple trials.

On clinical examination, at least some increased weakness with neck flexion was detected in 42 of the participants with MS, 10 with other types of myelopathy, and one who was otherwise healthy. But when using the precise measurements of the torque cell, it was found that a 10% or greater reduction in strength (more than 50% reduction was seen in some patients) was seen exclusively in patients with MS and in approximately 65% of those patients.

"We were able to confirm in this blinded study —done without knowledge of the patient's diagnosis by the person operating the recording device — that McArdle's sign was seen exclusively in MS patients and not in patients who may have been misdiagnosed with MS and instead had different spinal cord diseases or other causes," said Dr. Weinshenker, who has focused on MS research at Mayo Clinic for nearly 30 years.

McArdle's sign is most evident in MS patients who have greater degrees of weakness and higher levels of disability. For this study, researchers didn't study enough patients to be precise about the relationship of level of disability, stage of MS or duration of disease and the presence of McArdle’s sign. However, McArdle's sign also was detected in patients who had only mild disability and in one patient who had solitary sclerosis in the spinal cord.

"Detecting this sign increases the likelihood that a patient with spinal cord disease has MS as the cause," said Dr. Weinshenker, who received the Dystel prize for outstanding research on MS from the American Academy of Neurology in 2011. "This makes it possible to recognize and distinguish MS from other explanations of spinal cord disease and provide the appropriate treatment."

In addition to measuring muscle strength, the research team used techniques such as decomposed electromyography to analyze and assess the effects of neck position on muscle activity. The findings need to be validated by more extensive research, and while McArdle's sign may be a reliable marker for MS, it would not replace magnetic resonance imaging and other well-established criteria for diagnosing MS.

"The data offers a unique biomechanical and neurological biomarker that has high specificity and sensitivity," says Nathan Schilaty D.C, Ph.D., associate professor of physiology at the Mayo Clinic College of Medicine and Science, who assisted with the biometric testing. The testing and assessments can be replicated easily at other medical centers, Schilaty says.

Findings validate years of study

Though the study didn't focus on the pathophysiology of McArdle's sign, Dr. Weinshenker says it may be the result of conduction block, which occurs in MS patients and is caused in this case by stretching of the spinal cord. Patients with prominent McArdle’s sign may respond well to drugs that are available to treat the effects of conduction block, such as dalfampridine, a potassium-channel blocker that's used to enhance conduction in nerves that are demyelinated to improve MS patients' ability to walk.

A better understanding of McArdle's sign also could also be used to recommend physical therapy that better utilizes neck extension to enhance the patient's ability to walk. Dr. Weinshenker is now working with Ernest (Matt) Hoffman, D.O, Ph.D., a Mayo Clinic neurologist, and other colleagues to detect evidence for stretch-induced conduction block, using a technique called motor-evoked potentials.

The study results were reassuring after decades of observing McArdle's sign in his patients, Dr. Weinshenker says.

"Sometimes one can wonder whether the subtle difference in strength with neck flexion is real or imagined, so demonstrating in a systematic way that we can measure this phenomenon validates my observations over all these years," he said. "It provides the base of evidence we need to move forward and study the significance of this sign for diagnosis, predicting responders to drugs for conduction block and even for selecting patients who are good candidates for remyelination studies."

Watch Dr. Weinshenker talk about his recent McArdle's sign research:

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