What is a Normal Result and What is a CMT Result?
One of the best diagnostic tools that doctors have available to them for assisting with diagnosing Charcot Marie Tooth disease is a Nerve Conduction Study. A Nerve Conduction Study, or NCS for short, and sometimes coupled with Electromyogram, or EMG for short, provides a detailed snapshot of the nerve conduction characteristics of each peripheral nerve that the doctor assesses. These tests are part of the electrodiagnostic toolbox. The evaluating doctor chooses which peripheral nerves to assess based on many factors. Typically, when the doctor suspects CMT, and there is no established family history, they will opt to assess, or “look at” peripheral nerves in both the upper and the lower extremities—the arms and the legs. The approach, though, is usually symptom driven, and by doctor discretion. What information does the doctor gain by testing the nerves, and what makes these tests so diagnostically valuable?
The diagnostic value of performing an NCS, and sometimes including an EMG in conjunction with the NCS, is such that the resulting data provides the necessary information the doctor requires for determining if the suspected CMT is even CMT at all, and if it is CMT, the type of CMT that it most likely is. When it is CMT, the electrodiagnostic data will reflect peripheral nerve conduction characteristics that are consistent with that which CMT is known to exhibit. Further, the data garnered can show if the CMT is a demyelinating type—CMT1, or if the CMT is an axonal type—CMT2, or if the CMT is somewhere in between—Intermediate CMT, and when it’s Intermediate CMT, interpreting the peripheral nerve conduction characteristics can be difficult.
When the doctor determines that symptoms point to CMT, the data from an NCS can confirm what the doctor suspects. The data returned by the test does not represent a pass/fail, positive/negative, yes/no result though. Instead, the doctor interprets the data to mean something that is tangible. The doctor then has to answer the proverbial question. Is it CMT, or is it not CMT? When the doctor feels that clinical symptoms are consistent with CMT, and the doctor determines that the electrodiagnostic data is consistent with CMT, the consensus is that the doctor can diagnose CMT based upon this information. How, though, does the doctor know if the electrodiagnostic data suggest that the CMT is a Type 1, or if the CMT is a Type 2, or if the CMT is a type somewhere in between? The answer is in the data set.
A Shocking Good Time
Electrodiagnostics can be an invaluable diagnostic tool for doctors. However, just as with evaluating the clinical symptoms of CMT, electrodiagnostics cannot be relied upon as a stand-alone diagnostic tool. The nerve conduction characteristics of CMT are not absolute. While demyelinating CMT and axonal CMT can be discernible by their respective nerve conduction characteristics, there are many variables. With these variables in mind, there is a consensus on nerve conduction characteristics that are consistent with demyelinating CMT (CMT1), that are consistent with axonal CMT (CMT2), and then characteristics that are consistent with Intermediate CMT.
Although there are many evaluated metrics in nerve conduction studies, there are four metrics that appear frequently in CMT electrodiagnostic reports and in published research/case study papers regarding CMT. The four metrics that frequently appear are Nerve Conduction Velocity, or NCV, Compound Muscle Action Potential, or CMAP, Sensory Nerve Action Potential, or SNAP, and F-Wave Latency, often referred to as F-Wave. All these fancy words might be intimidating, but they do not have to be.
Before we can discuss what indicates CMT on nerve conduction study, we first must discuss what the fancy words are that make up the metrics we will be discussing. The metric that receives the most attention where CMT is concerned is Nerve Conduction Velocity, or NCV for short. NCV is the metric that represents the constant speed at which the nerve transmits a signal. The NCV value is expressed as meters per second, or m/sec. Compound Muscle Action Potential (sometimes called Compound Motor Action Potential, depending on author), or CMAP, is a measurement of how well a motor nerve, a nerve that controls a muscle, transmits a signal. The CMAP value measures in millivolts, or mV. Sensory Nerve Action Potential, or SNAP, is a measurement of how well a sensory nerve, a nerve that transmits sensory stimuli (touch, hot, cold, etc.), transmits a signal. The SNAP value measures in microvolts, or µV. F-Wave Latency, or F-Wave, is a measurement of the time it takes for a signal to travel the full length of a motor nerve. The F-Wave value measures in milliseconds, after 2 standard deviations, or 2-SD msec, and sometimes 2σ msec. The CMAP, SNAP, and F-Wave Latency metrics are each distance dependent, meaning that the value given comes from a specified length. See? Nothing to it. Now that we know what the metrics represent, we need to discuss the normal values of each before we can discuss the abnormal values that are consistent with CMT.
Each of the parameters discussed have an associated normal value range. Normal NCV is ~60 m/sec in the upper extremities, and ~48 m/sec in the lower extremities. These values are the excepted normal for both motor and sensory nerves. The normal values of conduction velocity are easy to explain. The normal values for the other metrics are different for each nerve, and therefore, take a little longer to discuss. We will start with the normal values for the motor nerves.
Starting in the lower extremities, the Peroneal Nerve has a normal CMAP amplitude of 2mV or higher, over a 9cm distance. The Peroneal Nerve controls the muscles that pick up the foot, invert the foot, and extend the toes. The Tibial Nerve has a normal amplitude of 3mV or higher, over an 8cm distance. The Tibial Nerve controls the muscles that rotate the legs, bend the knees, rotate the ankle, and flex the toes. In the upper extremities, the Median Nerve has a normal CMAP amplitude of 4mV or higher, over a 7cm distance. The Median Nerve controls the muscles of the forearm, the thumb, the index finger, and the middle finger. The Ulnar Nerve has a normal CMAP amplitude of 6mV, also over a 7cm distance. The Ulnar Nerve controls the muscles that bend and move the hand, the muscles that control the ring finger, and the muscles that control the pinky finger. The Radial Nerve has no established normal CMAP values. And now, the sensory nerves.
For the sensory nerves, the Sural Nerve, in the lower extremities, has a normal SNAP amplitude of 6µV, over a 14cm distance. The Sural Nerve provides sensation in the lower legs and feet. Moving to the upper extremities, the Median Nerve has a normal SNAP amplitude of 20µV, over a 14cm distance. The Median Nerve provides sensation for the forearm, thumb, index finger, and one-half of the ring finger, including the nail bed. The Ulnar Nerve has a normal SNAP amplitude of 10µV, also over a 14cm distance. The Ulnar Nerve provides sensation for the other one-half of the ring finger, and sensation for the pinky finger. The Radial Nerve has a normal SNAP of 20µV, over a 10cm distance. The Radial Nerve provides sensation for most of the arm and most of the back of the hand. Still with me? Good. On to the F-Wave Latency normal values.
What the F?
F-Wave Latency is a measure of the length of time it takes a signal to travel the full length of a nerve. It is easy to see that the length of a given nerve will dictate how long it takes a signal to travel its entire length. If you think of it like walking a hallway at your normal pace, the longer the hallway, the longer it takes to get to the end. The time it takes to get to the end of the hallway is a representation of F-Wave Latency, or F-Wave. Because the normal F-Wave value for each nerve is dependent on its overall length, there is an accepted normal value that correlates with overall patient height. The taller a person, the longer a given nerve will be, and the longer it takes a signal to travel the full length of that nerve. For sake of even more confusing details though, we will discuss the normal values for a person who is 5 feet 11 inches.
In the lower extremities, the normal F-Wave value for the Peroneal Nerve in somebody who is 5 feet 11 inches is 51-2D msec (51milliseconds, after 2 standard deviations). The normal Tibial Nerve F-Wave value is 57-2D msec. In the upper extremities, the normal F-Wave value for the Median Nerve is 30-2D msec, and the normal F-Wave value for the Ulnar Nerve in somebody who is 5 feet 11 inches is 31-2D msec. Piece of cake.
I know what you are thinking. All of this is a lot of very technical information about a lot of very technical things. You are right. Nerve Conduction Study is very technical, and that is why it takes a highly trained doctor to interpret the results of these studies. Now, however, you are familiar with the terms and the normal values associated with those terms when you see them on a test report. Electrodiagnostic reports for CMT might not be as intimidating for you now. You do not have to worry though. You do not have to commit any of this to memory, and there is not going to be a test. But having now discussed what all the normal values are, we can move onto what any abnormal values might represent as they relate t0 CMT.
That’s Not Normal
Knowing the normal values of the common metrics used in the electrodiagnostics of CMT is only half the battle. Sure, discussing the normal values of each is very technically involved, but we must first know what the normal values are so that we can know when the values are abnormal. It is critical to be familiar with those normal values as we discuss what is abnormal, and then as we discuss how those abnormal values can help a doctor to discern between that which is a demyelinating type of CMT (CMT1), that which is an axonal type of CMT (CMT2), and that which is an Intermediate CMT. As with all things CMT, there is always an exception to the rule. Obtaining nerve conduction characteristics is only one piece of the CMT diagnostic puzzle, and the results cannot serve as a stand-alone diagnostic tool. However, there is a consensus on some general values that depict the three main types of CMT—demyelinating, axonal, and Intermediate.
Type 1 CMT is demyelinating. Typically, the nerve conduction characteristics of demyelinating CMT are such that conduction velocity becomes uniformly slowed, diffuse, and stable. The stability makes conduction blocking rare. Nerve conduction blocking is a condition that occurs when there is a difference of CMAP amplitude at either end of the nerve. There usually is not a difference in demyelinating CMT. Usually, NCV values are less than 38 m/sec, are often ~20 m/sec, and can be as low as 4 m/sec in severe cases. CMAP amplitudes are often normal to only slightly reduced, and F-Wave responses are usually prolonged. These values are typically uniform in all nerves without much change over time, but some sensory nerve SNAP values can progress to become absent. EMG can show evidence of denervation. The nerve conduction characteristics of axonal CMT can be drastically different, and more complex.
Type 2 CMT is axonal. Typically, the nerve conduction characteristics of axonal CMT are such that conduction velocities can range from ~38 m/sec to just slower than normal. CMAP values are typically below 4mV, and SNAP values are typically less than 10µV. Sural Nerve SNAP responses can often be absent, and Phrenic Nerve (the nerve that controls the diaphragm) can exhibit reduced CMAP amplitude values also. EMG can reveal signs of chronic denervation. Contrasting with the stable values typically present in demyelinating CMT, the values in axonal CMT can vary from nerve to nerve, and they can change drastically over time.
Often, in axonal CMT, the longer nerves will exhibit abnormal characteristics before the shorter nerves. The nerves of the lower legs (Peroneal, Tibial, Sural) can often exhibit worse characteristics than the nerves of the hands (Median, Ulnar, Radial), and sometimes the nerves of the lower legs will exhibit these abnormal values while the nerves of the hands can show almost no discernible abnormality. For these reasons, axonal CMT sometimes carries the description, “length-dependent motor and/or sensory neuropathy,” and sometimes, “length-dependent distal motor and/or sensory neuropathy.” Both refer to axonal CMT. This variability in nerve conduction characteristics in the same person can make diagnostic interpretations difficult for the doctor, and that translates into frustration for the CMTer. Then, there is Intermediate CMT.
Intermediate CMT is an interesting diagnosis from a nerve conduction characteristic standpoint. Intermediate CMT gets its name not from the associated disease severity, but from the nerve conduction characteristics that are associated with Intermediate CMT. The nerve conduction characteristics that are consistent with demyelinating CMT (CMT1) are straightforward. The nerve conduction characteristics that are consistent with axonal CMT (CMT2) are not as cut-and-dry as those typically associated with demCMT1, but the characteristics are specific enough, despite their inherent variability, that a doctor can interpret them to be axonal CMT. Intermediate CMT, however, exhibits nerve conduction characteristics that overlap that which is characteristic of demyelinating CMT and that which is characteristic of axonal CMT. This presents a difficult diagnostic challenge for the doctor. A skilled doctor, however, can interpret the nerve conduction characteristics to be consistent with Intermediate CMT. Do you remember when I mentioned that there are some variables to these rules? Well, in keeping in the spirit of CMT, the nerve conduction characteristics commonly associated with the three main types of CMT are not absolute.
But What About…
All the discussed nerve conduction characteristic values are only a general rule-of-thumb meant to help guide the diagnosing doctor. These parameters, however, are not written in stone. The doctor still needs to interpret the data to mean something, and then translate that data into diagnostic relevance, if any. Even with the distinct differences exhibited by demyelinating CMT and axonal CMT, a doctor cannot rely only on nerve conduction characteristics to make their diagnosis. The doctor has to consider the nerve conduction characteristics with the overall diagnostic findings as they build the complete picture. As with all things CMT, there is always an exception to the rule, and especially with nerve conduction characteristics.
The distinction between demyelinating and axonal CMT is not always clear. Published literature depicts many exceptions to the rule of distinction. In a large study of CMTers with 1A, researchers report that nerve conduction velocities range from 17-20 m/sec. Yet, in other studies, researchers report that nerve conduction velocities in 1A range from 10-42 m/sec, breaching the 38 m/sec threshold for CMT2. CMT1A is not alone in this defiance of the rules. CMT1B can be quite the anarchist.
Typically, in CMT, nerve conduction velocities that are near normal present in CMT2, but not in CMT1. However, in CMT1B, although typical nerve conduction velocities are 5-15 m/sec, studies have shown that nerve conduction velocities can exhibit a range of 4-59 m/sec, far exceeding the 38 m/sec ceiling threshold for CMT1. In one paper, researchers report normal nerve conduction velocities in younger members of a family with 1B, whereas older relatives in the same family had severely slowed nerve conduction velocities. In another study of a single family with 1B, nerve conduction velocities were significantly slower than what is associated with 1A, yet in another study, researchers compared 119 CMTers who had 1A to 10 CMTers who had 1B, and found no nerve conduction velocity differences. Adding to the diagnostic confusion with demyelinating CMT, let me introduce you to the nerve conduction velocities exhibited in CMTX1.
X-Linked CMT subtype 1, that is, CMTX1, has a disease process that is primarily demyelinating. We know this because the underlying responsible gene mutation is in a gene that codes a molecular process in peripheral nerve myelin. However, nerve conduction characteristics tend to be more variable than what is typically associated with demyelinating CMT, and axonal features are more common. Nerve conduction characteristics can be asymmetrical like what is typically associated with axonal CMT. Nerve conduction block can also occur with CMTX1, unlike what is typically seen in other demyelinating types of CMT. The nerve conduction velocity range in CMTX1 is typically 25-43 m/sec in men, and 31-50 m/sec in women, falling well within that of Intermediate CMT. The consensus is that the difference between men and women is because of the number of X chromosomes each have. Although the nerve conduction characteristics depict an Intermediate CMT, we know that CMTX1 is demyelinating because of its underlying responsible gene mutation.
The responsible mutation for CMTX1 is a mutation in the GAP JUNCTION PROTEIN, BETA 1 gene (GJB1). To generalize, in peripheral nerve myelinating Schwann cells, the GJB1 gene facilitates the transfer of nutrients, ions, and other molecules to the inner most myelin layers. The responsible mutation causes a dysfunction of those transfers. Therefore, and despite its electrodiagnostic characteristics, CMTX1 is a demyelinating CMT. This example perfectly illustrates that making the distinction between demyelinating CMT and axonal CMT cannot rest solely on nerve conduction characteristics.
The examples we discussed are just a small snippet of the exceptions to the rules for CMT nerve conduction characteristics that can serve as a guide to the doctor when differentiating between demyelinating, axonal, and Intermediate CMT. These few examples also demonstrate that the doctor cannot rely solely on electrodiagnostic findings to diagnose CMT. Electrodiagnostic findings are only one part of the diagnostic picture for CMT, just as are clinical symptoms. As discussed and demonstrated, the nerve conduction characteristics, when considered together with clinical symptoms and patient complaints, can be sufficient for the doctor to diagnose CMT. The limit to this is being able to pinpoint the exact subtype. Outside of an established family history of genetically confirmed CMT, the only way to know the exact subtype is through genetic testing. True to form with CMT though, when a genetic test does not identify the underlying responsible genetic cause, but nerve conduction characteristics and clinical symptoms are consistent with CMT, the non-confirmatory genetic test result is not a reliable diagnostic tool. The genetic test for CMT is not required for diagnosing CMT, but only for pinpointing the exact subtype.
