Treatment Options for LEMS

Steven Vernino, MD, PhD: David has explained the approach we would take for treating small cell lung cancer in the most appropriate way. In terms of the Lambert-Eaton myasthenic syndrome, we have a number of options that we can consider. This is a condition where the communication between the nerve and muscle at the neuromuscular junction is impaired. What can we do to strengthen that connection? That’s why we have many symptomatic medications for that purpose. Probably the oldest of those are the acetylcholinesterase inhibitors. Today we use pyridostigmine, but there are other varieties of that. That’s a medicine that increases the availability of acetylcholine, and once it’s released, allows it to stay in the neuromuscular junction a bit longer. That’s typically used for the postsynaptic neuromuscular junction disorders like myasthenia gravis.

Then we have a treatment that can help to increase the presynaptic function, the amount of acetylcholine that’s released with each action potential, by inhibiting the potassium channels at the presynaptic terminal, which prolongs the action potential and helps the calcium channels that are still there stay open longer. We get more calcium influx and more acetylcholine release. Those potassium channel inhibitors, the aminopyridines, the one that’s typically used in the cases of neuromuscular junction disorders is amifampridine, or 3,4-diaminopyridine. We don’t want these potassium channel inhibitors getting into the central nervous system because overstimulation of nerves there can lead to seizures. The monopyridines, like 4-aminopyridine, cross the blood-brain barrier, but diaminopyridine does not. Amifampridine is thought to largely remain in the peripheral nerve system, where it can strengthen this neuromuscular junction transmission. Sometimes we’ll use both amifampridine and pyridostigmine together to strengthen both the presynaptic and the postsynaptic side of the neuromuscular junction, and for many patients that is enough to give them the strength to function well.

Beyond that, we think about what we can do to treat this autoimmune condition and get rid of these antibodies that are causing problems with the voltage-gated calcium channel. When someone’s in cancer therapy, many of the chemotherapy drugs are providing some degree of immunosuppression, checkpoint inhibitors notwithstanding. We generally don’t add additional immunotherapy, with the exception of patients who are having a hard time acutely, perhaps they need a surgical procedure where we worry about clinical worsening because of the anesthesia.

We can use short-term therapies like plasma exchange, plasmapheresis, or intravenous immunoglobulin [IVIG]; these are treatments that will help remove or neutralize these pathogenic antibodies in the short term. Plasmapheresis is a treatment where we take the blood out, we do a bit of a dialysis procedure to remove the plasma and the antibodies in the plasma, and that can help in the very short term, after just a few treatments. But unfortunately, the antibodies will return over the course of several weeks, and the symptoms generally return. Similarly with IVIG, which is an infusion of normal antibodies, it works in a variety of different ways, but essentially to reduce the levels of pathogenic antibodies in the circulation. Those are good short-term treatments to get someone out of a difficult situation, to help them through a procedure, or to offset some worsening due to adverse effects of their cancer treatment. Those are very valuable sorts of treatments.

For patients who do not have cancer, we usually initiate some sort of immunotherapy longer term that could include an immunosuppressant agent like azathioprine, mycophenolate, or cyclosporine, or a newer agent like rituximab. Because Lambert-Eaton syndrome is rare, almost none of these have been studied in double-blind placebo-controlled trials and proven to be effective. The exception is amifampridine, where there have been trials that show the drug—amifampridine, again, is the presynaptic inhibitor of calcium channel function—improves symptoms in Lambert-Eaton syndrome and has been FDA approved for that purpose. We use that in combination with other off-label treatments to help our patients. And again, it’s individualized based on the situation.

Transcript edited for clarity.