A Pattern Recognition Approach to Myopathy With Dr. Margherita Milone

While genetic testing has replaced muscle biopsy in the diagnosis of many genetic myopathies, clinical assessment and the integration of clinical and laboratory findings remain key elements for the diagnosis and treatment of muscle diseases.

In this episode, Casey Albin, MD, speaks with Margherita Milone, MD, PhD, FAAN, FANA, author of the article “A Pattern Recognition Approach to Myopathy” in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue.

Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia.

Dr. Milone is a professor of neurology and the director of the Muscle Pathology Laboratory at Mayo Clinic College of Medicine and Science in Rochester, Minnesota.

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Host: @caseyalbin

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast.

Dr Albin: Hello, this is Dr Casey Albin. Today I'm interviewing Dr Margherita Milone on her article on a pattern recognition approach to myopathy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, Dr Milone. Thank you so much for joining us. I'll start off by having you introduce yourself to our listeners.

Dr Milone: Hello Casey, thank you so much for this interview and for bringing the attention to the article on muscle diseases. So, I'm Margherita Milone. I'm one of the neuromuscular neurologists at Mayo Clinic in Rochester. I have been interested in muscle disorders since I was a neurology resident many years ago. Muscle diseases are the focus of my clinical practice and research interest.

Dr Albin: Wonderful. Thank you so much. When I think about myopathies, I generally tend to think of three large buckets: the genetic myopathy, the inflammatory myopathies, and then the necrotizing myopathies. Is that a reasonable approach to conceptualizing these myopathies?

Dr Milone: Yeah, the ideology of the myopathies can be quite broad. And yes, we have a large group of genetic muscle diseases, which are the most common. And then we have immune-mediated muscle diseases, which include inflammatory myopathies as well as some form of necrotizing myopathies. Then we have some metabolic myopathies, which could be acquired or could be genetic. And then there are muscle diseases that are due to toxins as well as to infection.

Dr Albin: Wow. So, lots of different etiologies. And that really struck me about your article, is that these can present in really heterogeneous ways, and some of them don't really read the rule book. So, we have to have a really high level of suspicion, for someone who's coming in with weakness, to remember to think about a myopathy. One of the things that I like to do is try to take us through a little bit of a case to sort of walk us through how you would approach if someone comes in. So, let's say you get, you know, a forty-year-old woman, and she's presenting with several months of progressive weakness. And she says that even recently she's noted just a little bit of difficulty swallowing. It feels to her like things are getting stuck. What are some of the things when you are approaching the history that would help you tease this to a myopathy instead of so many other things that can cause a patient to be weak?

Dr Milone: Yes. So, as you mentioned, people who have a muscle disease have the muscle weakness often, but the muscle weakness is not just specific for a muscle disease. Because you can have a mass weakness in somebody who has a neurogenic paralysis. The problem with diagnosis of muscle diseases is that patients with these disorders have a limited number of symptom and sign that does not match the large heterogeneity of the etiology. So, in someone who has weakness, that weakness could represent a muscle disease, could represent an anterior horn cell disease, could represent a defect of neuromuscular junction. The clinical history of weakness is not sufficient by itself to make you think about a muscle disease. You have to keep that in the differential diagnosis. But your examination will help in corroborating your suspicion of a muscle disease. Let's say if you have a patient, the patient that you described, with six months’ history of progressive weakness, dysphagia, and that patient has normal reflexes, and the patient has no clinical evidence for muscle fatigability and no sensory loss, then the probability that that patient has a myopathy increases.

Dr Albin: Ah, that's really helpful. I'm hearing a lot of it is actually the lack of other findings. In some ways it's asking, you know, have you experienced numbness and tingling? And if not, that’s sort of eliminating that this might not be a neuropathy problem. And then again, that fatigability- obviously fatigability is not specific to a neuromuscular junction, but knowing that is a hallmark of myasthenia, the most common of neuromuscular disorders. Getting that off the table helps you say, okay, well, it's not a neuromuscular junction problem, perhaps. Now we have to think more about, is this a muscle problem itself? Are there any patterns that the patients describe? I have difficulty getting up from a chair, or I have difficulty brushing my hair. When I think of myopathies, I historically have thought of, sort of, more proximal weakness. Is that always true, or not so much?

Dr Milone: Yeah. So, there are muscle diseases that involve predominantly proximal weakness. For example, the patient you mentioned earlier could have, for example, an autoimmune muscle disease, a necrotizing autoimmune myopathy; could have, perhaps, dermatomyositis if there are skin changes. But a patient with muscle disease can also present with a different pattern of weakness. So, myopathies can lead to this weakness, and foot drop myopathies can cause- can manifest with the weakness of the calf muscles. So, you may have a patient presenting to the clinic who has no the inability to stand on tiptoes, or you may have a patient who has just facial weakness, who has noted the difficulty sealing their lips on the glasses when they drink and experiencing some drooling in that setting, plus some hand weakness. So, the muscle involved in muscle diseases can vary depending on the underlying cause of the muscle disease.

Dr Albin: That's really helpful. So, it really is really keeping an open mind and looking for some supporting features, whether it's bulbar involvement, extraocular eye muscle involvement; looking, you know, is it proximal, is it distal? And then remembering that any of those patterns can also be a muscle problem, even if sometimes we think of distal being more neuropathy and proximal myopathy. Really, there's a host of ranges for this. I really took that away from your article. This is, unfortunately, not just a neat way to box these. We really have to have that broad differential. Let me ask another question about your history. How often do you find that patients complain of, sort of, muscular cramping or muscle pain? And does that help you in terms of deciding what type of myopathy they may have?

Dr Milone: Many patients with muscle disease have muscle pain. The muscle pain could signal a presence of inflammation in skeletal muscle, could be the result of overuse from a muscle that is not functioning normally. People who have myotonia experience muscle stiffness and muscle pain. Patients who have a metabolic myopathy usually have exercise-induced muscle pain. But, as we know, muscle pain is also very nonspecific, so we have to try to find out from the patient in what setting the pain specifically occurs.

Dr Albin: That's really helpful. So, it's asking a little bit more details about the type of cramping that they have, the type of pain they may be experiencing, to help you refine that differential. Similarly, one of the things that I historically have always associated with myopathies is an elevation in the CK, or the creatinine kinase. How sensitive and specific is that, and how do you as the expert sort of take into account, you know, what their CK may be?

Dr Milone: So, this is a very good point. And the elevation of creatine kinase can provide a clue that the patient has a muscle disease, but it is nonspecific for muscle disease because we know that elevatio