Genetic variants that underlie skeletal muscle channelopathies and rhabdomyolysis can also cause persistent and progressive muscle weakness. The availability and expanded use of genetic testing allows for the identification of new genes causing periodic paralysis and rhabdomyolysis.

In this episode, Teshamae Monteith, MD, FAAN speaks with Hani Kushlaf, MD, MS, FAAN, author of the article "Muscle Channelopathies and Rhabdomyolysis" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue.

Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.

Dr. Kushlaf is a professor of neurology and pathology as well as the director of the Neuromuscular Division, director of Neuromuscular Research, and director of the Neuromuscular Medicine Fellowship in the Department of Neurology and Rehabilitation Medicine and the Department of Pathology and Laboratory Medicine at the University of Cincinnati College of Medicine in Cincinnati, Ohio.

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Host: @headacheMD

Guest: @HaniKushlaf

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 Monteith: This is Dr Teshamae Monteith. Today I'm interviewing Dr Hani Kushlaf about his article on muscle channelopathies and rhabdomyolysis, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Hi, Hani. How are you?

Dr Kushlaf: Good. How are you doing? Thank you for having me.

Dr Monteith: Well, thank you for coming on our podcast. So why don't you introduce yourself?

Dr Kushlaf: So, I'm Hani Kushlaf. I'm a professor of Neurology and Pathology in the Department of Neurology and Rehabilitation Medicine at the University of Cincinnati in Cincinnati, Ohio.

Dr Monteith: And what got you interested in muscle disorders?

Dr Kushlaf: So, this is a long story. At first in residency, I was interested in epilepsy, but the moment I started doing a rotation in neuromuscular, I became enamored with neuromuscular disorders. I remember seeing the first patient in the rotation who had myofibrillar myopathy, and I found out that there is very little known about muscle disease at the time. So, I became very interested and I immediately changed direction as I started doing nerve conduction studies and EMGs and having that procedure base, I just decided that I want to pursue neuromuscular disorders.

Dr Monteith: Well, that doesn't sound like a long story. It sounds like love at first sight.

Dr Kushlaf: Yes, I think part of it is not very far from neuromuscular disorders and that it does have some electrophysiology involved. But muscle disease and nerve disorders, they need that detailed neurologic examination, which I love in terms of doing the localization exercise.

Dr Monteith: Great. So why don't we talk about the objectives of your article?

Dr Kushlaf: This article was written to review muscle channelopathies that include myotonic disorders and periodic paralysis, and also rhabdomyolysis, with emphasis on genetic causes of rhabdomyolysis more than acquired causes.

Dr Monteith: So, why was this update so important?

Dr Kushlaf: I think this area of muscle disorders hasn't seen a lot of progress in recent years, but there are interesting findings that we're learning that spark, hopefully, more research into the area, because we do have significant gaps that are related to understanding pathophysiology of some of these disorders. For example, in patients with periodic paralysis, it's clearly known now that these patients over time develop muscle weakness, and the muscle weakness is unrelated to how many episodes of weakness they have---basically, the episodic paralysis part of the disease. So, this is an important finding that I think we need to look more into it and understand that these disorders actually progress, even though that they may not have episodes of paralysis. In addition, there are genetic therapies that have been introduced into most of neuromuscular medicine at this time, including muscle disorders, while this specific part of muscle diseases has not had that luxury yet. And I'm hoping over time that there will be an introduction of gene therapies for these diseases.

Dr Monteith: Great. So, it sounds like there's some clinical advances, then, as well as genetic advances. Now, you also spoke about rhabdomyolysis and that there's newer ways of thinking about that from perhaps when I was in residency. So why don't you update me on these newer approaches?

Dr Kushlaf: The rhabdomyolysis… first, the definition of it is changing. We used to use a cut off, a CK of about a thousand, to call it rhabdomyolysis. And very recently it's clear that that level of CK is not sufficient to call it rhabdomyolysis. So, now the level went up in terms of exertion of rhabdomyolysis, up to ten thousand, has to be more than ten thousand. And in patients who haven't had exercise, the level is up to five thousand. So, it's no longer actually one thousand. And that refinement in the definition is important because there are some patients who exercise all the time and they may exercise at an athletic level and they have very high CK's. And those patients should not be labeled as having rhabdomyolysis. Basically, they are doing strenuous physiologic exercise. In addition, not only the definition of rhabdomyolysis is changing, it is our approach to which disorders to consider first and how we should work up patients with rhabdomyolysis. So, acquired rhabdomyolysis remains the most important etiology to be ruled out first. So, I always tell my fellows and residents that, think about acquired rhabdomyolysis first before you think about the genetic disorder. After you rule out the fact that it is not a toxic or metabolic or medication-induced rhabdomyolysis, then think about a genetic etiology. But when you get that consultation from the hospital that the patient has rhabdomyolysis and we want you to figure it out, always look at the medication list and make sure that there isn't anything on it that causes, actually, a rhabdomyolysis. And in many instances, you find out that it's actually a toxic or metabolic etiology for the rhabdomyolysis.

And as part of this article, there's also an acronym that's now being used to identify those patients who would benefit from genetic testing. The acronym is called RHABDO. It's as is the word, RHABDO. R refers to Recurrent exertion of rhabdomyolysis. So, it's not just one episode. And the H refers to HyperCKemia, and the hyperCKemia should persist more than eight weeks after the episodes of rhabdomyolysis. And if it is exertional, then the person has not done an unaccustomed exercise. So, they have changed the way that they do exercise and now they are exercising for two hours instead of one hour or they have introduced a new way of exercise into their exercise regimen. Then that should not be considered. It's not considered necessary to test these patients for a genetic cause. Also, the muscle enzyme typically, in genetic causes of rhabdomyolysis, goes more than fifty times above the upper limit of normal, which is more than a thousand. So that has to be taken into account. And then for the D it's Drugs and medications. This has to be ruled out before you say yes, we need to find the genetic cause of rhabdomyolysis. And then the O, it's basically family history. If you find that there is other family members who are affected or they have a high CK, then of course that would point you toward doing genetic testing.

Dr Monteith: Great. So, it sounds like there's some advances there in how we approach these patients. In what way is this practice changing? You mentioned, you know, really important to rule out these potentially reversible causes first.

Dr Kushlaf: Yeah. So, once you identify the theology, it becomes easier to manage the patient. So, if it is a statin-induced rhabdomyolysis, you know that you want to stop the statin and you are not going to have this problem again. So, that's quite important. The statins, of course, will have to not be reintroduced in the future for that specific patient who developed statin-induced rhabdomyolysis. But for the genetic causes of rhabdomyolysis, if you go down the path of genetic rhabdomyolysis, of course we have no cures for these disorders. We may have treatments. One of the conditions that I have alluded to as one of the case presentations in the article is a patient who has riboflavin responsive multiple acid CoA dehydrogenase deficiency, and I wanted to highlight this disorder because it's a disorder not to be missed. It does have a treatment, which is riboflavin, and that comes from the name riboflavin-responsive. So that's why I put there in the article as part of the manuscript. However, some of these disorders, once you find the genetic etiology, there may be a way of preventing it in the future generation. Family planning, reproductive medicine technologies, can help in this instance and prevent this disease from occurring in the future generations.

Dr Monteith: So, why don't we move on to episodic skeletal disorders? What is your general approach for these types of diseases?

Dr Kushlaf: Muscle channelopathies, skeletal muscle channelopathies, are ultra-rare disorders. And part of the issue is not giving them a high index of suspicion in the diagnostic process. So, these patients typically come to us in clinics with very vague symptoms, and they may have lived with these symptoms for a very long time. So, they may have muscle pain, they may have fatigue, they may have muscle stiffness. Even though in most instances they do not tell you that they have muscle stiffness, they will tell you that when I wake up in the morning, I feel like I walk like a robot. My legs feel rigid, something like that. The word stiffness is not usually in the vocabulary of patients. When they come to see you and you examine them and you find out that the muscle strength is normal, you may not think much about the myotonic disorder. And that's where the issue is. You always have to keep these disorders in your differential diagnosis. So, you elicit for myotonia and for paramyotonia on examination, look at the muscle size, see if there is any muscle hypertrophy that happens in fluoride channelopathies, and that will typically guide you toward the diagnosis.

And also ask about whether their symptoms get worse in a cold environment. So, sometimes they tell you they don't like winter because during winter everything is not doing well. They may report that they even feel like they cannot move their face because of facial stiffness in wintertime, especially in states where it snows outside and patients will be walking outside. So, these are things, typically, that give you clues about the diagnosis. But in patients who are affected minimally with the disease, sometimes you do not catch them, really, till they come to the EMG lab because of another reason. If they develop a neck pain and someone thinks that they may have a cervical radiculopathy and they want to do an EMG on them, or if they develop carpal tunnel symptoms, they send them to the EMG lab for carpal tunnel. And the moment we see them in the EMG lab, we start doing the needle examination and we find out that there is myotonic discharges in every muscle that we stick with the needle. And we're like, well, this person must have a myotonic disorder. And you ask them more about their symptoms. They may have symptoms, but they will tell you that they have ignored them for too long because it's something that they live with throughout their lives since childhood. They thought this is what is normal for them and this is what normal people might have. They may have aches and pains here and there and that is normal. So, these are clues, typically, for the diagnosis. Once you find the myotonia, your next bet to identify the exact genetic abnormalities to do genetic testing. And nowadays I think the field has benefited from the availability of free genetic testing so we can find out which channel is affected and then move on toward freezing that disorder.

Dr Monteith: So, you spoke about nondystrophic myotonia. What are some bedside tips to try and really get at the diagnosis?

Dr Kushlaf: So as I said, first is, look at the muscle build of the patient. So, these disorders, chloride channelopathies---so, the autosomal dominant and autosomal recessive chloride channelopathies---can cause muscle hypertrophy. So, these patients can have an athletic appearance even though when you ask them, do you exercise? I don't exercise at all. Do you lift weights? I don't lift weights at all. And they look like bodybuilders, so that's something to think about. Also eliciting the myotonia and typically we elicit the myotonia by using, of course, the reflex hammer. You can either tap on the phenol eminence and notice the myotonia in the thumb as it moves inward and stays in that position for some time. Depending on the severity of the myotonia, you can tap on the extensor digitorum in the forearm and notice the middle finger as it gets up and gets stuck for some time before it goes down. You can also ask patients to squeeze your fingers and then release quickly. Squeeze forcefully, of course, and find out how long does it take them to release their fingers, and that way you can identify the myotonia.

Also, you may need to repeat the elicitation of myotonia several times because it can be not myotonia but paramyotonia, which is the opposite of myotonia. It's basically worsening of the myotonia as you keep doing the eliciting activity. So, the more they squeeze your fingers, the more difficult it is for them to improve. While the warm up phenomenon, which is the opposite of paradoxical myotonia, is, for them, as they repeat squeezing, they are able to do it better and better. They would be able to release more quickly with each attempt. In some patients, you can also ask them to close their eyes if they have facial myotonia, to close their eyes forcefully and see how quickly does it take for them to open their eyes. You may see that they do not open their eyes quickly. Or if you repeat in patients with paramyotonia, if you ask them to close and open, close and open, close and open, there will come a point where they really cannot open their eyes anymore, and that tells you there is paramyotonia. Of course, if you find paramyotonia, then you know that this is a sodium channel abnormality, that the genetic testing would just confirm that.

Dr Monteith: And what about for periodic paralysis? Is there anything new in the field?

Dr Kushlaf: Periodic paralysis… if I can say one thing about periodic paralysis, it's to talk about Andersen Tawil syndrome. It's an ultra-rare disorder also, but the episodes of paralysis that happens in patients with Andersen Tawil syndrome, they occur either with hypokalemia, so it can be hypokalemic---like, exactly hypokalemic periodic paralysis---or with hyperkalemia. So, it's hyperkalemic periodic paralysis. It doesn't really matter whether it's hyperkalemic or hypokalemic. These patients they typically have dysmorphic features. And the most common dysmorphic feature, and I chose a picture for the article, is a patient who has a small mandible. That is the most common dysmorphic feature. There are other dysmorphic features which include short stature, hypertelorism---which is the distance between eyes, the eyes become widened. Also, scoliosis and low-set ears. So, the ears are lower than the level of the eyes. So, these are dysmorphic features one can look for, but they do not exist in every patient with Andersen Tawil syndrome.

The problem with Andersen Tawil syndrome is that these patients, as opposed to hyperkalemic and hypokalemic periodic paralysis, they have cardiac involvement. And the cardiac involvement can be deadly. So, it's very important that these patients are identified quickly. And anyone who has episodic weakness should have an EKG and should have halter monitoring to recognize if there are any arrhythmias or EKG abnormalities. So, one can identify anything that needs to be corrected from the cardiac standpoint. I think that is the most important point about periodic paralysis. Overall, these disorders… I mean, they are disabling and they can have huge effect on patient's life in terms of productivity and employment. And the diagnosis can be very difficult, especially that we do not know all the genes that are associated with periodic paralysis. Right now, the genetic testing that's available to us includes five genes that are associated with periodic paralysis. But I think we need to know more. There's a proportion of patients who do not have an identifiable abnormality at this time. So, I think as time goes on, we'll recognize more causes for periodic paralysis.

Dr Monteith: I'm just reading your really great article, and it sounds like there's a lot of variability in presentation from I'm not feeling that well or I'm not feeling my best for mild disease, and then very severe disease where the whole body can be weak without alteration in consciousness.

Dr Kushlaf: That's correct. So, my patients tell me that you never know when you're going to develop episodes of weakness. And sometimes they can recognize the precipitant, sometimes they cannot. Stress, sometimes, is a precipitant. At times, they really cannot tell what happened. And the weakness can be affecting one limb or more than one limb. It can be isolated to an arm or isolated to one leg. And that is the issue with the diagnosis, is that for those who do not suspect periodic paralysis, they are labeled as a functional neurologic disorder and they do not get the care that they need. I'm hoping that this article will shed a light on how to think about these disorders and how to diagnose them because treating them can have a significant impact on patient's life.

Dr Monteith: How useful are these laboratory tests?

Dr Kushlaf: So, in any patients where I suspect periodic paralysis, I would always do thyroid function testing to rule out hyperthyroidism because it can cause episodes of paralysis similar to hyperkalemic and hypokalemic paralysis. And I also do EKG and halter monitoring to make sure that I'm not missing the cardiac manifestations of Andersen Tawil syndrome. On top of that, then I would do genetic testing. And the genetic testing, as I said, at this time includes five genes. So, we will recognize any genetic abnormality that comes on that genetic testing. And if it is negative and I still have a high suspicion for the disease, I will do a long exercise test. The long exercise testing is, we record from a muscle in the hand---it's called the productive digit minimi---and stimulate the unknown nerve. We record, typically, baseline responses and then exercise the muscle for five minutes and keep recording after five minutes of exercise for up to forty minutes after. We're looking for a change in the amplitude of the motor response that typically happens over time.

Dr Monteith: Great. Well, thank you so much for being on our podcast.

Dr Kushlaf: I appreciate it. Thank you very much.

Dr Monteith: Again, today I've been interviewing Dr Hani Kushlaf, whose article on episodic skeletal muscle disorders, muscle channelopathies, and rhabdomyolysis appears in the most recent issue of Continuum on muscle disease. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

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