Getting a Correct Diagnosis in Neuromuscular Disease

The diagnostic process in neuromuscular disease involves following many clues and rounding up the usual -- and not so usual -- suspects

*Note: In the print edition of Quest, this article was titled "Rounding Up the Usual -- and Not So Usual -- Suspects."

The scene is familiar to everyone who watches crime dramas. The safe has been opened, and the hotel guests' jewelry and other valuables are missing. What happened, and when, and who's responsible?

Although criminal investigations rely on computer searches, fingerprints, traces of material left at the scene and DNA analysis, these tools are used by human beings who apply a process of deductive reasoning that turns the spotlight on a progressively smaller number of suspects, until the true culprit is identified.

Who had access to the safe? Where was the security guard? What wealthy, jewelry-stashing guest was staying at the hotel? Who knew about her?

It's only when those questions are answered that chemical analysis of fingerprints, clothing fibers and DNA samples take their place in the solution of the crime.

A similar process applies to determining a diagnosis from a collection of symptoms that could indicate any of several neuromuscular diseases. It takes modern technology and skillful investigators to figure out the culprit — the exact diagnosis.

Surveying the scene

Chances are the neuromuscular disease specialist's office isn't the first stop for most patients. It's likely that a patient has at least seen a primary care physician or pediatrician beforehand, and, in many cases, the road has been very long indeed.

The child whose speech is slow to develop may spend years with hearing and speech specialists before it's noticed that her facial muscles are weak from an infantile-onset muscular dystrophy. The fit-appearing young man may have spent months with a mental health professional trying to sort out why he can't seem to tolerate much exercise. And the woman with double vision from weakened eye muscles may have had several appointments in the ophthalmology clinic hoping for the lenses that can correct her problem.

But when these trails haven't led to satisfactory diagnoses, an MDA neuromuscular clinic may at last bring the whole picture into view.

David Chad, director of the MDA clinic at the University of Massachusetts Medical Center in Worcester, describes the diagnostic process as a series of tests of hypotheses.

Each hypothesis generates or eliminates suspects in the case. And each may lead to the use of specialized technology.

"As you take the history and examine the patient, you're testing your hypotheses," Chad says. In neuromuscular diseases, the first hypotheses have to do with the location of the primary problem.

Neuromuscular specialists are accustomed to dividing the disorders they treat into three location categories:

• nerve (which has two subcategories, motor neuron and peripheral nerves)
• neuromuscular junction (where nerve and muscle meet) and
• muscle

By the time a doctor even starts considering expensive and invasive tests, Chad says, he or she "should have a pretty fair idea of which of those three categories the problem is in."

Watching and listening

The trained eye of the neuromuscular disease specialist begins observing even before the "meter is officially running," Chad says. He notices how the patient gets — or doesn't get — out of the waiting room chair, how he shakes hands, how he walks (or doesn't) to the examination room.

He notices the patient's general appearance, posture and gait. Is marked atrophy (loss of muscle bulk) visible even with clothes on?

Atrophy puts the spotlight on the nervous system, Chad says. "In muscle disease, after a while, muscles do get kind of small," he says, " but in neurogenic (nervous system) disease, atrophy is prominent."

Along with atrophy the doctor watches for muscle twitches (fasciculations). These may suggest the problem is with the motor neurons.

Careful observation is combined with careful listening — "history taking" — to understand as much about the problem as possible before undertaking diagnostic tests.

The doctor will want to know exactly what the patient has trouble doing. Is it hard to climb stairs, put dishes away on a high shelf, use keys?

If there's trouble walking, is it because the knees "give way," or because the foot flops down and trips the patient?

Does strength or function vary with the time of day? Does it change with rest, food intake or environmental temperature? Is strength better at the start of exertion or a little later on?

Problems in speaking, swallowing, breathing and keeping the eyes open may be discovered during history taking.

Weakness that arises from a problem with the neuromuscular junction is in some ways the easiest to diagnose, Chad says, because of its fluctuating character.

The most common type of junction-related problem is myasthenia gravis (MG), a problem on the muscle side of the nerve-to-muscle connection in which nerve signals aren't received properly by the muscle. People with MG typically feel better in the morning or early in their physical exertions than they do later on, Chad says. " They're pretty strong when they start out on a task and weaken as they continue," he notes. Doctors call this " fatigable weakness," and they listen for descriptions of it as a clue. (See "Managing Myasthenia." )

In another junction disorder, Lambert-Eaton myasthenic syndrome (LEMS), the weakness also fluctuates, but in the opposite direction.

In LEMS, Chad says, "the person feels weak and may have a little fatigability, but as you test him, the muscle that starts out weak seems to strengthen." LEMS involves a defect on the nerve side of the neuromuscular junction. The nerve ending fails to release its chemical signals effectively.

In contrast, weakness from a muscle disease or motor neuron disease is usually stable with respect to time of day or exercise repetitions, even though it may progress slowly over weeks, months or years.

Rapidly progressive weakness casts the expert's suspicions toward an inflammatory myopathy like polymyositis or dermatomyositis, while weakness that progresses over a period of years suggests a degenerative process like muscular dystrophy or a motor neuron disease.

Weakness that sounds more like fatigue or exhaustion shifts the spotlight to a metabolic problem, in which the muscle has trouble burning fuel for energy. It could also signal psychological depression or other illnesses.

The doctor may want to observe the patient getting up from the floor, stepping onto a low stool, walking down a corridor and so forth, sometimes timing these activities.

Finger function can be tested by having the patient tap rapidly or manipulate pegs on a board. Mouth muscles may be assessed by having the patient pronounce tongue-twisting phrases.

Just a few more questions

After a period of watching and listening, the examiner is ready to perform a physical exam. For neuromuscular specialists, the tool kit contains a soft rubber or plastic hammer, a slightly sharp object, a dull object, a small flashlight and a tuning fork.

In a basic evaluation of muscle strength, the physician tries to bring out the described weakness in the exam room, sometimes pitting his or her own strength against the patient's.

Chad often starts from the top — with the patient's eye muscles.

"You have the patient look up at your finger, held at the level of his or her forehead," Chad explains. The average person can do this for about a minute or so without getting too tired, he says. "If your [examiner's] arm tires before they do, you know they're OK," he adds.

The muscles that move the eyes and the muscles of the face are often checked next.

To evaluate neck strength, the examiner pushes against the patient's forehead and the patient tries to push forward. Then the doctor presses the back of the head and the patient pushes back against the examiner's hand.

Muscle testing, Chad says, is pretty much "picking a muscle group and pushing on it."

One test of arm strength has the patient lift the arms to shoulder level (making wings) and the examiner trying to push them down.

This can be repeated for many different muscle groups.

Physicians have developed a scale that judges a muscle from a strength level of 5 down to 0. A muscle with normal strength is rated 5, while one that is slightly weak, where the examiner has to exert considerable force to overcome its power, is rated 4+. A score of 2 is for a considerably weak muscle, while 1 means there's only a flicker of movement. A score of 0 means there was no observed muscle contraction.

Checking reactions

During the physical exam, the doctor also investigates the patient's reflexes — automatic muscle contractions that can reveal whether a pathway from the sensory nerves to the spinal cord and back out via the motor nerves to the muscle is intact.

Most reflex testing in the neuromuscular clinic looks at deep tendon reflexes, also known as muscle stretch reflexes. Typically, the examiner taps with a soft hammer over a partially stretched muscle at the elbows, wrists, knees and ankles.

As with strength testing, reflex responses are scored numerically. A score of 2+ is for a normal response, while a 0 indicates no reflex, and a 3+ or 4+ indicate an abnormally brisk (overactive) reflex.

Deep tendon reflexes are often lost or diminished in peripheral nerve conditions (such as Charcot-Marie-Tooth disease or Friedreich's ataxia) and especially brisk in amyotrophic lateral sclerosis (ALS). They may be normal in spinal muscular atrophy and in many muscle diseases (dystrophies and myopathies) in the early stages. Late muscle disease often shows reduced reflex activity.

The examiner tests the Babinski reflex by scraping the sole of the foot with a somewhat sharp object. Normally, the foot flexes, with the toes curled down. If instead the big toe extends — goes up and out — with the other toes fanning outward, the Babinski is positive, indicating possible damage in the nerve cells or the fibers that run between the brain and spinal cord. ALS features this kind of damage.

The doctor may check the patient's eye reflexes using a small flashlight. Hearing and touch can be tested using a vibrating tuning fork and sharp and dull objects.

Lab reports

Just as in a forensic investigation, laboratory testing complements the evidence that can be collected through the investigator's eyes and ears alone.

In neuromuscular disease diagnosis, the step after the history and physical exam is often to get a serum (blood) creatine kinase (CK) level.

CK is a protein found in abundance inside muscle cells and to some extent in the blood. When muscle cells deteriorate, especially if they're surrounded by fragile membranes (as in some dystrophies), they break apart, spilling CK into the bloodstream and raising the blood CK level.

The CK test helps doctors pin down the location of the primary defect causing muscle weakness. The CK is very high where there's acute muscle destruction, such as in some phases of muscular dystrophy, inflammatory muscle disease and some metabolic muscle conditions.

CK may be mildly elevated in nerve diseases, presumably because muscle degenerates when it loses nerve stimulation.

Other blood tests are performed if symptoms suggest them. Specialized immune-system proteins called antibodies may be measured, and their presence is extremely incriminating for inflammatory muscle diseases like MG and LEMS.

Wiretapping

Electrodiagnostic testing can measure the speed and strength of signals from nerve to muscle, as well as the pattern of signals coming from muscles themselves. It's a little like using a wiretap to listen to suspects' conversations.

"Different kinds of patterns bespeak different diagnostic categories," Chad says. He calls electrodiagnosis a "window into pathology [abnormality]."

In tests of signal speed — nerve conduction velocity (NCV) tests — surface electrodes are used on a test limb. They feel like a mild electric shock.

Slow conduction suggests certain types of peripheral nerve diseases, and reduced signal size suggests other types.

A test of muscle electrical activity — electromyogram (EMG) — requires inserting small needle electrodes into the muscles. It hurts a bit.

Muscle electrical testing can reveal myotonia, the inability of muscles to completely relax after use, even if it's too subtle to be noted on the physical exam. That may shift the diagnostic investigation to certain muscle diseases.

Electrical patterns are different in a muscle that's degenerating because of a muscle disease and one that's degenerating because it's lost nervous system signals. Junction-related disorders have their own distinctive electrical patterns.

Chad considers electrical testing to be a "powerful diagnostic helper" and a "logical extension of the clinical examination."

The pathologist's report

Biopsies of muscle, and occasionally of nerves, used to be a mainstay of definitive diagnosis. In biopsies, a sample of tissue from the affected area is removed and examined by a pathologist, often in conjunction with the neuromuscular specialist. Genetic testing has in some situations replaced the biopsy. But it can still be useful.

"You may get a genetic test and it comes back negative," Chad says. "At that point, you may want to look at a piece of muscle with a muscle biopsy." (Nerve biopsies are less common, since they may cause long-lasting numbness.)

A muscle biopsy sample can reveal the structure of the muscle cells in a way that nothing else can. As with electrical testing, hidden clues can be unearthed.

The nature of the degenerative or inflammatory process can be seen under the microscope, and abnormal deposits of proteins or carbohydrates can be observed with staining. Missing proteins can be detected through the use of molecular " magnets" (probes), which stick to proteins when they're present and fail to do so when they aren't.

Telltale signs, such as lack of dystrophin in Duchenne muscular dystrophy, patchy dystrophin in Becker MD or deposits of glycogen (stored sugar) in acid maltase deficiency (Pompe's disease), can confirm or refute a tentative diagnosis.

Chad likes to use the muscle biopsy to confirm his suspicions that a muscle disease involves the type of inflammation that's responsive to certain drugs before reaching for the prescription pad.

"If I'm going to put them on prednisone [a powerful but dangerous anti-inflammatory medication], I can do it with confidence, because I'm not treating them blindly," he says. "I'm exposing them to a risky treatment, but with good reason."

DNA evidence

DNA has become a household word, largely because of its increasing role in celebrated criminal trials and in police dramas. " DNA evidence" is considered as valuable in a courtroom as anyone's testimony these days

This, too, has some parallels with the diagnostic process. But, as with criminal trials, there are some caveats.

DNA tests, which detect disease-causing alterations in specific genes, are simple for the patient to undergo. They usually only require a blood sample (or in some cases, a tissue sample from the inside of the cheek). But they have special implications for family decisions (see "The Pros and Cons" ), as well as being expensive — up to thousands of dollars, not always fully covered by insurance.

For one thing, explains Cheryl Scacheri, a senior genetic counselor with GeneDx of Gaithersburg, Md., DNA testing "isn't always straightforward." One reason is that each DNA test is designed to look for flaws in only one gene, and sometimes only for certain types of flaws in that gene.

Before she moved to GeneDx about a year ago, Scacheri counseled MDA clinic patients at Children's National Medical Center in Washington. There, she saw many families with Duchenne MD who were disappointed with their DNA test results.

"It's very nice when you have a patient who presents the clinical symptoms of a condition like Duchenne dystrophy, such as enlarged calf muscles and a high CK level, and you order the DNA blood test and it shows a deletion [missing part of the gene]," she says. "That's a very neat package."

But then, she continues, "there's the patient who has all the clinical symptoms and a high CK but doesn't have a deletion. That can be very confusing to parents."

The confusion in this case is, as Scacheri puts it, "in the biology." Only about 60 percent of boys with DMD have a deletion in the very large dystrophin gene, and that's the only kind of genetic flaw that can be picked up by the typical DNA test for DMD.

About 40 percent have other types of changes in the gene for dystrophin that can't be picked up. They need specialized testing that's only available in a few U.S. centers and costs about $1,000, although that may improve soon.

Karen Krajewski, a genetic counselor who sees patients with suspected peripheral nerve disorders at Wayne State University in Detroit, says she's seen "a lot of changes" since she graduated from her master's program in 1997.

At that time, she says, only two DNA tests were available to diagnose Charcot-Marie-Tooth disease (CMT), a peripheral nerve disorder that can occur because of flaws in any of at least 14 genes.

There are now easily available tests for flaws in six CMT genes. But, Krajewski explains, even this vastly increased repertoire of DNA tests doesn't completely solve the uncertainty issue. In part, that's because there are genetic causes of CMT for which there are still no tests. But even those tests that are available can't always tell a doctor whether or not a particular genetic change is responsible for the disease or is just a harmless variation.

"It's important that the person reading the results and interpreting them understands what they're reading," Krajewski says. That person is sometimes the neurologist, depending on his or her background in molecular genetics, but it may also be a geneticist or genetic counselor.

In a CMT test, the lab may find no alterations in the examined genes; or it may find an alteration that's known to cause CMT; or it may find an alteration whose significance is "indeterminate" or unknown. "Indeterminate" means it may not cause disease, or it may.

In the case of an indeterminate sequence change, Krajewski says, more steps can be taken. One option is to send the sample to a research lab for further evaluation.

Sometimes, it's necessary to test several members of the family to see how the gene change correlates with the disease. If all the affected relatives have version A of the DNA sequence and the unaffected relatives have version B, it's pretty clear that this gene is the culprit in this family. If, on the other hand, some affected family members have version A and others have B, the change may only be an insignificant variation, and the true genetic problem may lie elsewhere.

Despite these pitfalls and caveats, genetic testing has been a great boon to the diagnostic process for neuromuscular disease and saved many patients the discomfort and expense of a surgical biopsy or even electrodiagnostic testing.

Building the case

DNA testing, fingerprint analysis, wiretaps and video cameras have made it easier to track down criminals, but they haven't replaced the judgment of knowledgeable investigators.

Despite all the new technology, and all the new categories of neuromuscular disease that have arisen from the research of the last two decades, the physician and the patient still have to confront the real situation in the clinic — the man who can no longer climb ladders, the child who's falling, the woman who's seeing double.

It's the combination of the patient's history, the doctor's careful observations and the lab reports that together lead to a diagnosis that answers the family's questions. Until a diagnosis is reached, a doctor can't begin to help the patient alleviate some of the symptoms and prepare for future effects of the disease.

Getting a Correct Diagnosis: A Case History

1. The Search is On...

Fred (not his real name) is a 53-year-old man of German and Russian ancestry who lives in New York state.

He's come to the Muscular Dystrophy Association clinic because of increasing weakness of his thigh muscles and some weakness of his grip over the last several years. He has no obvious muscle atrophy.

He gets out of a chair with difficulty, using the chair arms for support, and shakes hands weakly. His gait is somewhat halting, and he reports he occasionally uses a cane or scooter to cover distances. He picks up his feet and doesn't trip over them.

He says his mother, now deceased, had severe weakness of her proximal (close to the trunk) leg muscles, and couldn't easily rise from low furniture. She was very overweight, however, and he attributed her mobility problems to that. His father died young of tuberculosis. His half-brothers don't appear to have been affected by any neuromuscular condition.

Fred says he's recently had great difficulty with stairs, particularly ladders, which he sometimes must use in his job on construction sites. However, he remembers that 15 years ago when he was playing with his young son on the floor, he had problems getting up and had to hold onto furniture.

He developed cataracts in both eyes in his 30s but only recently had them removed, after they began to interfere with his vision.

Suspects

Fred probably has a neuromuscular junction disease such as myasthenia gravis (MG) or Lambert-Eaton syndrome (LEMS) or a muscle disease. Diseases of the peripheral nerves generally cause more atrophy and more weakness of the distal (far from the trunk) muscles than he has. A motor neuron disease like ALS or SMA is possible.

His mother's symptoms indicate a possible hereditary disease.

2. The Search Goes On...

Examination

Fred's muscle strength is normal except for a score of 4+ in his neck muscles, arm-extending muscles, hip-flexing muscles, knee-extending muscles, and toe flexors and extensors. His grip is slightly weak at 4+. Strength doesn't decrease or increase with repeated trials.

He's unable to rise from the floor or from a low chair without using his hands. He's unable to do a sit-up with his arms behind his head.

Several areas seem normal: touch and pain sensation, skin condition, twitches (fasciculations), obvious cardiac or respiratory problems.

His deep tendon reflexes are normal except at the ankles, where they're slightly decreased, at 1+.

He says he's not overly sleepy during the day, doesn't fatigue easily with exercise and doesn't believe he has any special problems with his memory or intellect. Examiner notices Fred has enlarged calves and frontal balding.

Suspects

NOT LIKELY: Peripheral nerve disease still looks unlikely, since reflexes aren't decreased.

Neuromuscular junction disorders usually worsen with repeated tests of strength, although LEMS usually improves. This patient stayed the same, nearly ruling out these disorders.

POSSIBLE: Adult-onset spinal muscular atrophy (SMA), which involves proximal weakness, or amyotrophic lateral sclerosis (ALS). But both usually show some fasciculations, and ALS usually shows brisk, overactive reflexes.

MOST LIKELY: A muscle disease. Good candidates are:

• inclusion-body myositis (IBM), an acquired muscle disease that usually affects men in Fred's age group
• inflammatory muscle diseases polymyositis (PM) and dermatomyositis (DM), though pain is often involved with these and a skin rash is common with DM
• adult-onset acid maltase deficiency (AMD, or Pompe's disease), caused by a metabolic problem in which glycogen (stored sugar) builds up in muscle cells
• late-onset muscular dystrophy, such as limb-girdle (LGMD) or myotonic dystrophy (MMD) (his distribution of weakness is most typical of type 2 MMD, but type 1 is more common)
• thyroid myopathy (TM), which can sometimes cause fairly severe weakness.

3. The Search Goes On...

Tests

Thyroid function is normal.Creatine kinase (CK) level is normal.

Blood sugar is somewhat high.

Serum antibodies often found in PM and DM are absent.

Nerve impulses are conducted at a normal speed and with normal strength.

Electrical testing of the muscles shows signs of myotonia — a lack of muscle relaxation — and degeneration of some muscle fibers.

Suspects

RULED OUT: The normal CK level suggests this isn't PM or DM or LGMD; lack of antibodies suggests it isn't PM or DM. TM is ruled out by the normal thyroid tests. Nerve tests rule out ALS and SMA.

LESS LIKELY: Fred's CK is low for AMD, but this disease sometimes shows myotonia.

NEW FRONT-RUNNER: The finding of myotonia — unlikely in the other diseases being considered — tips the balance toward MMD.

4. The Search Is Narrowed...

DNA Test

Type 1 MMD: negative

Muscle Biopsy 

Sample taken from Fred's thigh muscle shows evidence of muscle degeneration typical of a moderately severe muscular dystrophy or acquired muscle disease. It shows no evidence of glycogen accumulation.

Suspects

RULED OUT: The lack of glycogen accumulation eliminates AMD. The DNA test eliminates MMD1.

POSSIBLE: IBM is still possible, though it usually doesn't feature myotonia.

The tentative diagnosis is type 2 MMD.

5. And the Culprit Is...

Type 2 MMD: positiveDNA Test

Diagnosis

Type 2 MMD

The myotonia, cataracts, high blood sugar, calf enlargement, family history and balding can all be explained by this diagnosis.

This is a genetic disease, inherited in a dominant fashion on chromosome 3. (A flawed gene from one parent can cause the disorder.) It appears to be particularly common in people of German and Eastern European ancestry. It's likely that Fred's mother also had type 2 MMD.

Fred's 18-year-old son has a 50 percent chance of having inherited the chromosome 3 genetic mutation from his father. The young man shows no signs of the disease, and the family and physician decide to wait until he is older to discuss genetic and other testing options with him.