Long-term study shows how LEMS treatment changes over disease course

Amifampridine, the active ingredient in Firdapse, provides clinical benefits for people with Lambert-Eaton myasthenic syndrome (LEMS), while use of immunosuppressive treatments increases over the disease course, according to a single-center study spanning more than 30 years in the Netherlands.

In addition, about one in four patients had begun symptomatic or immunosuppressive treatment before receiving a LEMS diagnosis, potentially because they had initially been misdiagnosed with another condition with similar symptoms.

“This retrospective study provides a comprehensive longitudinal overview of pharmacological treatment patterns in LEMS,” the researchers wrote. “Amifampridine provides significant clinical benefits and remains the cornerstone of LEMS therapy.”

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The study, “Longitudinal overview of symptomatic and immunosuppressive drugs in LEMS,” was published in the Journal of Neuromuscular Diseases.

LEMS is a rare autoimmune disorder in which self-reactive antibodies interfere with nerve-muscle signaling, resulting in muscle weakness that most commonly affects the hip and thigh muscles, making walking and climbing stairs more difficult.

The study notes that about 60% of people with LEMS have an associated malignancy, most commonly small cell lung cancer (SCLC), an aggressive cancer, meaning about 40% have no associated malignancy.

Firdapse, commonly used as a first-line treatment for LEMS, is an oral therapy approved in the European Union for adults with LEMS; in the U.S., the therapy is approved for patients ages 6 and older. Its active ingredient, amifampridine, works by restoring nerve-muscle communication.

In the Netherlands, two forms of amifampridine are available: Firdapse’s immediate-release tablets and a modified-release tablet produced by the pharmacy of Leiden University Medical Center (LUMC).

“The LUMC is a nationwide referral center for LEMS in the Netherlands, and as a result the majority of LEMS patients in the Netherlands are or have been treated by a neurologist at the LUMC at some point during their disease course,” the researchers wrote.

To investigate how LEMS treatment changed over time, researchers retrospectively analyzed the medical records of 70 LEMS patients (66% women) seen by a neurologist at LUMC.

Participants had been diagnosed with LEMS between 1992 and 2023 and had lived with the disease for a median of six years. The median follow-up was nearly five years. Individual follow-up times ranged from less than one month to about 28 years.

SCLC-associated LEMS was less common in the study than non-tumor LEMS (23% vs. 77%). The researchers said this likely reflected referral bias because cancer care often predominates for people with SCLC-associated LEMS, making them less likely to be referred to LUMC for long-term neuromuscular follow-up.

Most patients started amifampridine early after diagnosis

All participants used amifampridine at some point, and most (91%) started it within six months of diagnosis. At latest assessment, 93% used the modified-release formulation, either alone (78%) or combined with Firdapse (15%).

Because formal outcome measures were not consistently recorded, the researchers created a four-point “leg score” to describe how leg weakness affected daily function. A score of zero meant no leg weakness, while a score of three meant needing a walking aid or having difficulty with daily activities.

After starting amifampridine, leg scores improved in 57% of patients with available scores, with one-, two-, and three-point reductions reported in 48%, 7%, and 2% of patients, respectively. The overall score change was statistically significant, and similar improvements were seen among patients who had or had not received pyridostigmine or immunosuppressive therapy before or at the same time as amifampridine.

Patients who had tried both formulations generally reported fewer side effects and more stable symptom control with the modified-release version. Those who preferred Firdapse most often cited its faster onset of effect.

Several patients described the benefits of amifampridine: “I can stand on 1 leg again for the first time in 4 years,” one patient said. “I can walk better, I feel fit, I can sit for longer,” another said, while a third mentioned, “After the first tablet I could walk again, I can now walk my evening round again.”

More than half of patients reported side effects from amifampridine, most often paresthesia — tingling or pins-and-needles sensations — in 41.4%. Still, only five patients (7%) discontinued the drug, four of them because of remission.

Most participants (81%) used pyridostigmine at some point during their disease course. Sold as Mestinon for myasthenia gravis (MG), another rare autoimmune disease that causes muscle weakness, pyridostigmine is also commonly used off-label for LEMS.

Pyridostigmine use was common but often discontinued

About one-third (32%) stopped pyridostigmine, most often due to side effects (50%) or a lack of clinical benefit (39%). Gastrointestinal complaints were the most frequently cited reason for stopping pyridostigmine (28%).

Use of immunosuppressive drugs increased over the disease course. Within six months of diagnosis, 23% of patients had started immunosuppressive treatment. At five years, 14 of 34 patients with follow-up data were receiving it. The most commonly used agents were prednisolone (49%) and azathioprine (42%).

About one-third (30%) used plasma exchange and/or intravenous immunoglobulin at some point during their disease course. Both treatments can help ease LEMS symptoms, although they work differently: plasma exchange removes disease-driving antibodies from the blood, while IVIG helps reduce harmful autoimmune activity.

Notably, 26% had already started symptomatic or immunosuppressive treatment before receiving a LEMS diagnosis. The researchers said this most likely reflected treatment for an initial diagnosis of MG, although prior diagnoses were not systematically recorded.

“Longitudinal data on medication use indicate that symptomatic treatment is typically initiated early and maintained throughout the disease course,” the researchers wrote. “Amifampridine, predominantly administered as a modified-release formulation, demonstrated clear clinical benefit, although residual functional impairments remained common.”