Many people with neuromuscular diseases have experienced the frustration of going from doctor to doctor trying to find an explanation for their symptoms. One of the great advantages of an MDA clinic is that its staff is familiar with each of the 40 diseases MDA covers.

In the following interview, MDA Medical Consultant Dr. Lawrence Z. Stern (identified as LS below), who is also the director of the MDA clinic at the University of Arizona Health Sciences Center in Tucson, discusses the importance of proper diagnosis and how it's accomplished.

CORRECT DIAGNOSIS VITAL TO PROPER TREATMENT

Why is it important to have a disease diagnosed correctly?

LS: The most important reason is that some neuromuscular diseases are treatable. For example, chronic polymyositis is treatable, but in the past was, and to some extent still is, misdiagnosed as limb-girdle muscular dystrophy, which isn't treatable, at least at present. Myasthenia gravis, which is sometimes difficult to diagnose early on, is also treatable. There are others that are less successfully treated, but still treatable. So you do want to get the right diagnosis.

Is limb-girdle muscular dystrophy over-diagnosed?

LS: Not so many years ago, LGMD was a frequent diagnosis in the clinics, because anything that presented with weakness of the pelvic and shoulder girdles, and which was slowly progressive, was often called that. But we now know that, in addition to polymyositis, there are a host of other diseases that can cause this same set of symptoms, and can look, at least superficially, like LGMD. Chronic spinal muscular atrophy used to be, and possibly still is, called LGMD. Some of the metabolic myopathies, for example hereditary carnitine deficiency, can look like LGMD as well.

It sounds like there isn't much that actually is limb-girdle dystrophy!

LS: Oh no, there are many cases of genetically identifiable LGMD. But it has been overdiagnosed in the past.

Are ALS and SMA often confused with one another?

LS: They shouldn't be, though certainly if you have adult-onset SMA it could be mistaken for the early stages of lower motor neuron ALS. But that wouldn't be common. (Motor neurons are specialized nerve cells that control the movement of voluntary muscles. Upper motor neuron damage results in weakness, muscle stiffness and exaggerated reflexes. Lower motor neuron damage causes muscle wasting and twitching, as well as weakness and diminished reflexes.)

Could you explain why?

LS: Most cases of SMA begin in childhood, though there are patients whose first symptoms show up when they are adults. The onset of ALS is usually in later adulthood, but there are certainly exceptions to that as well. So there is a period of overlap there. At least initially, SMA and ALS can affect the same set of motor neurons, so many of the symptoms and signs of the two are the same. However, ALS also affects the upper motor neurons, and that becomes the basis for distinguishing between the two, if it has been difficult in the beginning.

Can a disease of the brain look like a neuromuscular disease?

LS: Any time a patient presents with weakness, one has to consider disorders of the neuromuscular unit. However, there are disorders that don't involve the neuromuscular unit per se, that may lead the patient to describe weakness as a major symptom. Parkinson's disease, for example, does not produce weakness early on, but the patient may perceive the motor deficit as weakness. Fatigue may be confused with weakness, too. Also, the double vision of multiple sclerosis may mimic the same symptom in myasthenia gravis, while some of the upper motor neuron involvement of MS can look like ALS. This Shouldn't be a difficult differential diagnosis, however.

In these cases, does the disease need to progress to allow distinction between them?

LS: A neurologist should have no difficulty distinguishing between ALS and MS. Other cases may be quite tricky, though. For example, there are a number of diseases that a rheumatologist would treat which cause achiness in muscle and tissue surrounding muscle, such as polymyalgia rheumatica and fibromyositis. These are often confused with polymyositis. Differentiating between these is important, because the treatments are different.

For a person whose diagnosis is unclear, would you ever start him on medication used to treat one of the diseases, to see if it helps?

LS: Generally speaking, no. In polymyositis, the treatment of choice is prednisone, and this is also used in treating polymyalgia rheumatica, but the dosage and duration differ between the two. It wouldn't be wise to treat these patients with steroids before confirming the diagnosis, just to see what happens, because steroids can make you feel better nonspecifically. This can mask the ineffectiveness of the treatment. You may be treating the wrong disease, and end up in trouble from side effects, which may even include weakness.

How do you tell the difference between these two diseases?

LS: It can be difficult. We would do a muscle biopsy (removal and examination of a tiny piece of tissue), and look for certain specific changes associated with one or the other disease. On the other hand, biopsies always introduce a sampling error: You can miss an area of change in the biopsy, unless you do a careful search on the specimen from the right muscle.

Can a biopsy give a false positive result?

LS: This is much less likely, although you can have some difficulty. For instance, a biopsy from someone with facioscapulohumeral muscular dystrophy can look similar to that of myositis.

How would you distinguish these?

LS: Through the history. You see, the most important element in diagnosis is the taking of the history. The physician's ability to hear what the patient is saying, and to understand what the patient is trying to tell him, is the most important diagnostic capability that a physician has. That communication is essential to correct diagnosis. Too often, it doesn't occur. There may be time constraints, or it may be a problem with the attitude of the physician or the patient.

Is it the physician's responsibility to draw out information?

LS: I was taught in medical school that it's the physician's responsibility to take as much time as necessary to listen to everything the patient has to say, to interrupt or interject as little as possible, and to ask no leading questions. And this is very valuable -- it's how you get the most information. However, it may take hours! So we have to modify that somewhat. On the other hand, when I ask, "So what's the problem?" some patients reply "You're the doctor! I came in here so you could tell me!" In those cases, I'll have to ask more questions. But I still want the patient to do most of the talking.

Why is it important for the patient to do the talking?

LS: The words patients use to describe their symptoms I find to be particularly valuable. How a patient describes a pain or a weakness can be as informative as its location. Sometimes it's necessary for me to offer a choice of adjectives, but I would rather they find one themselves, because I can evaluate that choice a lot better. The more that the patient has been able to go over his symptoms and his history in his own mind, the more effectively he can present his story in a readily interpretable form. On the other hand, patients are not trained as physicians, so they Can't be expected to know What's important medically and what Isn't. For the same reason, I'm not in favor of the history being taken by a non-physician helper, or simply using a questionnaire, no matter how exhaustive.

Do you want patients to arrive with their full medical history on paper for their first visit with you?

LS: It may be useful for the patient to refer to if he has had a complicated medical history, because it's easy to forget in front of a strange new doctor. But I don't like to see it before I do the history or physical exam, because it's too easy to miss the forest for the trees - to pursue a tangent brought up in the previous medical history That's really irrelevant to the problem that has brought the patient in. I usually like to take it for reading afterward, rather than during the exam.

What is the role of the physical exam?

LS: While the history is most likely to elicit the cause of the problem, the physical exam is designed to determine where, and ideally what, the problem is. In the history, the patient describes the symptoms, while in the exam, the physician looks for signs of a particular disease. It's good to do a fairly complete neurological exam if you're seeing a patient for the first time, since you may see things that aren't expected based on the history.

What is the difference between a symptom and a sign?

LS: A symptom is a complaint that the patient has, while a sign is an observation of clinical relevance that the physician makes during the examination. Certain critical signs are tested for as part of every first neurological exam, such as Babinski's sign.

What is Babinski's sign?

LS: Babinski was a French neurologist of the 19th century who described a response, or reflex, that is indicative of upper motor neuron lesion (injury) or dysfunction. The reflex is part of a primitive withdrawal reflex, present in newborns, but which disappears after the first year of life as the nervous system matures. Reappearance of this reflex indicates a problem in the corticospinal tract, those neurons in the central nervous system responsible for controlling muscle.

Can you describe the sign?

LS: If you apply some sort of noxious stimulus to the outer edge of the sole of the foot, such as scratching along it with a key or fingernail, a newborn's big toe will be pulled up involuntarily. After about a year, the big toe will go down from the same stimulus. With damage to the upper motor neurons, the toe once more goes up. It's a deceptively simple sign that tells you a great deal about damage to the nervous system.

Can it tell you what the cause of the problem is?

LS: No. It could be due to stroke, a blood clot, multiple sclerosis, ALS, SMA or some other disease.

Would ALS with bulbar onset (initially affecting speech, chewing and swallowing) also show Babinski's sign?

LS: Yes. Generally people have both bulbar and corticospinal damage together, though the symptoms may not show up together.

What else do you look for in the physical exam?

LS: The distribution of weakness. For example, in Charcot-Marie-Tooth disease Type 1A, weakness and wasting arefound most prominently in the distal muscles, those farthest from the trunk, while in SMA, the weakness is more proximal (near the center of the body). Distribution is also important for distinguishing among the muscular dystrophies. The name "facioscapulohumeral" muscular dystrophy states the distribution of the primary weakness: in the facial muscles, the scapular muscles of the back and the proximal arm muscles, surrounding the humerus (the long bone of the upper arm).

What is the role of lab testing in diagnosis?

LS: In certain cases, the history and the physical exam cantake you to a point, and then you need to differentiate. If it's clear from the exam that you are dealing with a primary muscle disease, and the history suggests a genetic origin, some details of the history may narrow it down a little closer, but still you may have difficulty saying for sure. For example, a patient may have a genetic primary muscle disease that looks and sounds like dystrophy, but you don't have anyone else in the family affected. The patient is a boy, young enough so that it could be Duchenne dystrophy, or a severe form of Becker dystrophy. On the other hand, it could be one of the other dystrophies. In this case, you may need a muscle biopsy to distinguish among the possibilities, or perhaps genetic testing.

Or, you may have a patient with the very earliest stages of ALS, and clinically it appears to be very localized. You can't be sure from the history and the physical exam that it isn't due to a single, potentially treatable lesion, like a herniated disc or a tumor. Before you would embark on other diagnostic procedures or therapies, you would want to know how extensive the denervation (loss of nerve function) is, whether it perhaps extends further than you are able to see on your exam. An EMG might be helpful in that instance.

What is an EMG?

LS: An electromyogram, which is performed in order to record the electrical activity in a person's muscle. It's usually done by inserting a needle into the muscle. The needle picks up all the electrical activity in the surrounding area, which is then recorded on a chart. In this way, one can assess whether, at rest, there is electrical silence as there should be, or whether there is electrical activity going on even at rest, which is abnormal. We can look for signs that suggest either that the muscle or the neuron may be the problem. One can also look for unusual waveforms that might occur in, say, myotonia. One can also measure the conduction velocity, the speed at which impulses are carried along peripheral nerves, which would be abnormal in a number of diseases, including CMT. In addition, using other conduction techniques, one can evaluate the function of the neuromuscular junction, looking for the possibility o myasthenia gravis.

Could you do a diagnosis without a clinical exam, just on the basis of lab work?

LS: No, because you need to know which muscles are involved in terms of weakness. The EMG doesn't tell you anything about what's weak or not weak. And besides, it's not a picnic to do. You're sticking needles in people's muscles, and it can be quite uncomfortable for the patient. So you don't want to sample every muscle in the body. Instead, you want to do as little as possible, and tailor your exam to answer specific questions that are raised by the history and physical exam. Most electromyographers, although not required to, or even asked to by the referring physician, will do a mini-neurological exam as part of their EMG in order to be able to do a better assessment. This shows how important the physical exam is.

What about a muscle biopsy? When would that be appropriate?

LS: As I noted before, if you're looking for the specific nature of a primary muscle disease or, from time to time, if you're not sure whether you're dealing with a primary muscle disease or a neuronal disease. When you're looking to confirm a diagnosis of polymyositis, that's the only way to do it. Similarly, if you're trying to confirm a diagnosis of a specific genetic myopathy, in most cases you need a biopsy.

Couldn't you do a blood test for a myopathy instead?

LS: For certain ones you could. But, for example, a blood test will not distinguish between Duchenne and Becker muscular dystrophies, whereas the dystrophin analysis done on the muscle itself will.

Are there situations where you wouldn't want or need to do lab tests?

LS: Yes, certainly. Often patients come with a whole battery of tests already having been done, some of which probably weren't necessary. In other cases, if you have a rather typical history and examination of, say, ALS, there's no lab test really necessary to make the presumptive clinical diagnosis. However, there are conditions that can cause an ALS-like picture, so in some cases one would want certain tests.

For example?

LS: Certain immunological tests, to make sure the motor neuron disease isn't occurring as a consequence of a tumor or an immunological abnormality that might be treated. Recently, I saw a woman who had been diagnosed with ALS, but in fact she had severe arthritis in her spine, which was damaging her nerves. We found the real problem using an MRI scan.

You've expressed from time to time a certain distrust of lab results when they conflict with the clinical picture. Is that fairly common?

LS: It's not very common if you're choosy about what tests you do, and know exactly what you're looking for with each test. As an example, there are several different tests that measure the activity of certain enzymes that are normally present in the blood. This group of enzymes is often abnormal in liver disease, and several are usually abnormal in people with muscle diseases who have perfectly normal livers. As a group they are referred to and ordered as "liver function" tests. If you order a liver function test and get a result back with an abnormality of the SGOT enzyme, for example, it might mean a liver abnormality, and you might start a search for hepatitis, or end up doing a liver biopsy. However, SGOT is usually quite elevated in Duchenne and Becker dystrophies, so the SGOT result may have nothing to do with the liver being abnormal, and if you don't know that, you might go off on the wrong track.

As another example, elevated levels of the enzyme creatine kinase in the blood are indicative of muscle damage. There are several forms of creatine kinase. It's often thought by cardiologists that what's called the MV fraction is specific for damage to the heart, but, in fact, it's often elevated in people with muscle diseases, and reflects the process of regeneration. The EMG is a subjective test, and, therefore, subject to all kinds of interpretive differences. So the nonspecificity of certain tests is important to know, and the way that tests are generally reported may be misleading if you aren't careful.

Can either the EMG or CK level rule out a particular diagnosis?

LS: Yes. If you have a newborn boy who is the son of a Duchenne dystrophy carrier, one can check the newborn's CK level. If it's normal or close to normal, that would exclude the possibility of Duchenne dystrophy, even though it's way too early to show any signs.

Would an elevated level at that point mean a definite Duchenne diagnosis?

LS: No, because there could be a number of other reasons for the elevation. In that case, the level could be suggestive, but not diagnostic. On the other hand, with a muscle biopsy, since you are taking a small piece of muscle, and only examining a small piece of a small piece, you could easily miss something. In polymyositis, for example, where there may be focal pockets of inflammation, you may not see it on biopsy. So you can't necessarily exclude diagnosis from a negative result there.

And the positive result?

LS: As we said, there are other diseases that show some of the same muscle changes as polymyositis, such as FSH dystrophy. There are subtle differences on the muscle biopsy, and a real expert may be able to distinguish them, but it's very difficult. It's easier to look at the patient: you'd rely on the history and the physical exam to bring out the differences.

Should patients routinely get a second opinion after they receive a diagnosis?

LS: It doesn't hurt and, overall, I would say probably yes. Because everybody makes mistakes. You don't want to miss a treatable condition, nor do you want to be diagnosed as having a fatal disease when you don't have one, because that can mess up your life no end also. But it's not only that. Different physicians address different issues, so you could go to two very competent neurologists, who could concur on the diagnosis of, say, ALS, agreeing 100 percent on what was wrong. Yet you could learn different things from the two, so that both visits would be very worthwhile. What's not necessary very often is that you have a complete battery of tests done by competent people at a good place, then go to someplace else which requires the whole battery of tests all over again. That part should be looked at askance in most cases. But certainly a second look doesn't hurt at all.

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