Testing for LEMS

David Gerber, MD: Steve, it might be helpful at this point to go over how we diagnose and test for LEMS [Lambert-Eaton myasthenic syndrome].

Steven Vernino, MD, PhD: As neurologists, when we see conditions that make us think about paraneoplastic neurological syndromes, a number of cancers come to mind, but small cell lung cancer is at the top of that list for all the reasons you mentioned. We know that, relevant to LEMS, many small cell lung cancer lines have been studied that express neuronal channels, including a voltage-gated calcium channel, which is important for the survival of those cells. When the immune system wants to identify and kill cancer cells, it sees these antigens in that context, and that starts an appropriate immune response in some cases. Patients who have paraneoplastic syndromes like Lambert-Eaton myasthenic syndrome may have a better outcome with respect to their cancer for a variety of reasons. This is an autoimmune condition, and that means that it’s caused by the immune system. In this case we can associate Lambert-Eaton myasthenic syndrome with the production of an antibody against a particular voltage-gated calcium channel, one that’s present in small cell lung cancer cells in many cases, and in the same calcium channel that’s present at the neuromuscular junction, in particular on the presynaptic side, so the side of the synapse of the neuromuscular junction where the acetylcholine will be released. These calcium channels are responsible for letting calcium into the presynaptic junction, and that calcium leads to the release of the acetylcholine molecules, which ultimately binds to the muscle and causes it to contract. You can imagine that if you have something that’s binding to the voltage-gated calcium channels at that spot, preventing them from working well, there’s less calcium that comes into the presynaptic junction, fewer of the acetylcholine neurotransmitters that get released, and as a result, the muscle will not react in the typical way. That produces weakness because of this impaired communication.

That leads to our techniques in diagnosing and testing for Lambert-Eaton myasthenic syndrome because we’re looking for that characteristic impairment in the communication between the motor nerve and the muscle. We can do that many ways, but for the most part it starts with our neurological examination. We try to identify weakness of certain muscles in these patients and particularly the proximal muscles where they’re complaining of weakness. These patients may have a peculiar phenomenon called facilitation, where the muscle may be initially weak, but with repetitive testing and exertions, the muscle may get stronger. This is a subtle finding that could be difficult for people who aren’t trained as neuromuscular physicians to pick up on. Patients will describe this phenomenon, that they have a lot of trouble getting up and going, but once they’ve walked a little, they feel better. The other area where we can see facilitation is in testing for reflexes. When you test reflexes, like tapping the patellar tendon, many patients with Lambert-Eaton syndrome have no response; they have reduced or no reflexes. If you exert the muscle, having them do quadriceps contractions, and then immediately test, the reflex may return for a few seconds but then go away again. That’s almost pathognomonic of Lambert-Eaton myasthenic syndrome. But it takes experience and a good reflex hammer; we don’t expect oncologists to pick up that sort of thing.

There’s the initial suspicion based on the patient’s history or neurological examination of the muscles, and then we have several tools that we can use. One is electrodiagnostic testing, where we can take the patient to the EMG [electromyography] laboratory. Two major tests we do are nerve conduction studies and the needle electromyography test. In the nerve conduction test, we place electrodes on the skin, over the muscle, and send a shock to the muscle nerve, recording the amount of contraction, this is called the compound muscle action potential [CMAP]. In Lambert-Eaton myasthenic syndrome, CMAPs are usually small, maybe 10% of normal, in all muscles, not just in the ones that are clinically weak. If we give a test called repetitive stimulation, where we give repeated stimulations of that nerve 2 to 3 times a second, we’ll see that that muscle response become even smaller. We see a decremental response on the repetitive stimulation, which is like what we see in the other neuromuscular junction disorder, myasthenia gravis, or in a condition like botulism that causes a poisoning of the neuromuscular junction. You see this decremental response, and that’s diagnostic of a problem in the neuromuscular junction, not Lambert-Eaton particularly. In Lambert-Eaton syndrome, you can look for this facilitation by having the patient do contractions of the muscle, or by giving a high-frequency stimulation to get some of that calcium mobilized in the neuromuscular junction. You’ll see the size of that muscle action potential get larger and then gradually get smaller again. The decrement on repetitive nerve stimulation and a facilitation after exercise is convincing for Lambert-Eaton myasthenic syndrome, or perhaps some other rare conditions, but it’s suspicious.

For the other part of electrodiagnostic testing, the needle EMG, we stick a needle into the muscle of interest and look at the little muscle action potentials as they occur. What we see in these neuromuscular junction disorders, and especially in Lambert-Eaton myasthenic syndrome, is variability or what’s called jitter of the muscle action potentials. In other words, they’re not stable. They don’t fire at the same every time, they vary between getting bigger and smaller because there’s instability in that communication between the nerves and muscles. Those 2 tests can be diagnostic of Lambert-Eaton myasthenic syndrome. We also have a serological test. We’ve discussed the autoimmune nature of LEMS, and the association with antibodies against the voltage-gated calcium channel, in particular the P/Q-type channel. Antibodies against the P/Q-type voltage-gated calcium channel are commonly found in Lambert-Eaton myasthenic syndrome, regardless of whether it’s autoimmune- or cancer-related. That test, in some cases is considered to be 90% to 95% sensitive. If we suspect Lambert-Eaton syndrome and the antibody test is negative, we often scratch our head and wonder if that’s not the right diagnosis. The antibody test is available at commercial labs, at various places, so that’s often the first test people will do because sometimes the advanced electrodiagnostic testing is not readily available. Those are the 2 tools we use, but you have to suspect the diagnosis to think about order those tests. They are good at confirming the diagnosis of Lambert-Eaton syndrome. We’ll return later to discuss the pros and cons, or pitfalls, about the antibody testing.

Transcript edited for clarity.