Update on Amifampridine as a Drug of Choice in Lambert-Eaton Myasthenic Syndrome

US Neurology, 2014;10(2):ePub ahead of print

Abstract:

Lambert-Eaton myasthenic syndrome (LEMS) is a disabling autoimmune disorder involving impairment of neuromuscular transmission and producing serious muscle weakness, for which few effective medications are currently available. 3,4-diaminopyridine (3,4-DAP, INN/USAN: amifampridine) is the leading treatment for LEMS and has been available for over 25 years as an unapproved drug under treatment and expanded access protocols filed with the US Food and Drug Administration (FDA) or from compounding pharmacies in the US. Administering the correct dose of 3,4-DAP is critical—overdosing can increase the risk for seizures and other adverse events, while underdosing can result in a substantial loss of efficacy or even treatment failure. Two recent studies have shown a wide variation in the 3,4-DAP content of compounded preparations. A tablet formulation of 3,4-DAP phosphate salt (FIRDAPSETM) has been licenced in Europe with orphan medicinal product status since 2009 and appears to be as efficacious as the base in relieving the symptoms of LEMS. The product has also received orphan drug status in the US and is currently being evaluated in a multicenter, double-blind, placebo-controlled phase III trial to support New Drug Application (NDA) approval in the US. A recent safety trial in healthy volunteers using doses at and above normal levels has shown no effect on QT intervals, heart rate, or cardiac depolarization. Based on available clinical trial data, amifampridine phosphate was recently given Breakthrough Therapy designation by the FDA, which may enable fast-track NDA approval, thus increasing the potential for more patients with LEMS to receive an effective therapy.

Keywords: Amifampridine/3,4-diaminopyridine/3,4-DAP, Lambert-Eaton myasthenic syndrome, potassium ion channel blockers, compounded drugs clinical trial evidence, treatment, expanded access protocols
Disclosure: Shin J Oh, MD, has no conflicts of interest to declare. Jörn Peter Sieb, MD, has received honoraria or consultation fees from BioMarin, Temmler, and Valeant.
Acknowledgments: Editorial assistance was provided by James Gilbart, PhD, and Katrina Mountfort, PhD, at Touch Medical Media.
Received: April 10, 2014 Accepted April 15, 2014
Correspondence: Shin J Oh, MD, Department of Neurology, University of Alabama at Birmingham, UAB Station, Birmingham, Alabama 35294, US. E: shinjoh@uab.edu
Support: The publication of this article was supported by Catalyst. The views and opinions expressed are those of the authors and not necessarily those of Catalyst.

Lambert-Eaton myasthenic syndrome (LEMS) is a uncommon, but debilitating, neuromuscular disorder that is estimated to affect 2.32 people per million in Europe1 with a prevalence of up to 3,000 cases in the US.2 The disease has an autoimmune etiology in which autoantibodies bind to P/Q-type voltage-gated calcium channels (VGCCs) and decrease the release of acetylcholine at the synapses affecting peripheral cholinergic neurotransmission.3 The impaired function of the VGCCs decreases the secretion of acetylcholine and disrupts synaptic transmission at neuromuscular junctions and certain autonomic nerve terminals leading to muscular weakness and symptoms of autonomic dysfunction.2,4–6

More than half the patients with LEMS, particularly male smokers aged over 50 years, present with an underlying malignancy, usually small cell lung cancer (SCLC).7,8 However, there are also case reports on a wide variety of lung and non-lung malignancies observed in LEMS patients. The peak age of onset of non-tumor LEMS is 35 years with a second peak at 60 years, whereas paraneoplastic LEMS occurs primarily in middle-aged and older adults, with a median age of onset of 58 years.9 Non-paraneoplastic LEMS can be associated with other organic-specific autoimmune disorders.10 Paraneoplastic cerebellar degeneration can also occur in cancer-associated LEMS cases.11

The diagnosis of LEMS can be challenging since the clinical presentation of sub-acute progressive fatigue and weakness is unspecific. As a result, diagnosis is often delayed from many months up to even decades.10 Clinical suspicion is the key for the diagnosis of LEMS. The symptoms of LEMS are frequently mistaken for those of myasthenia gravis (MG). In contrast to MG, oculo-bulbar paresis is rare and reflexes are reduced or absent in LEMS.

The most common clinical presentation of LEMS is proximal muscle weakness (more pronounced in the hip girdle than in the shoulder girdle) and easy fatigability. The classic triad of LEMS includes proximal leg weakness, hyporeflexia or areflexia, and cholingergic dysautonomia (dry mouth, impotence, and orthostatic hypotension).12 Tendon reflexes are reduced or absent, but it is important to note that they may be preserved early in the course of the illness. Cranial muscles may also be involved with symptoms such as ptosis, facial weakness, dysphagia, dysarthria, and difficulty chewing. Cranial muscle weakness is usually milder and rarer than in MG and it occurs after the onset of limb-girdle weakness. Additional symptoms of autonomic dysfunction include reduced salivation, erectile dysfunction, dryness of the eyes, and reduced sweating.13 The presence of an annoying dry mouth in patients with unexplained muscular fatigability is characteristic of LEMS. A transient improvement in muscle strength and reflexes immediately after brief exercise is classically observed in LEMS patients and is pathognomonic of LEMS.14

Diagnosis of LEMS is based on an assessment of clinical symptoms in conjunction with electrophysiologic parameters and antibody testing. Repetitive nerve stimulation (RNS) test is the electrophysiologic study of choice for the diagnosis of LEMS. RNS test demonstrates the characteristic so-called ‘LEMS triad’, including (see Figure 1):

  • Low Compound Muscles Action Potential (CMAP) amplitude.
  • Decremental responses in the low-rate (2–5 Hz) stimulation.
  • Marked incremental responses (facilitation) of the CMAP amplitudes in the high-rate stimulation (HRS) (50 Hz) in the RNS test or after voluntary muscle contraction over a brief (10 second) period of time.12

For the brief exercise test, 10-second exercise is critical.15 A more than 100 % increase in the CMAP in the HRS or after brief exercise is almost pathognomonic of LEMS. A recent study showed that a more than 60 % increment after brief exercise or during HRS is sufficient for the diagnosis of LEMS.12 The diagnosis of LEMS may be confirmed by radioimmunoassay of VGCC antibodies, which are believed to be the main pathogenic factors in LEMS,16 and P/Q VGCC antibodies are detected in 85 % of patients with clinically and electrophysiologically defined LEMS.17,18 In seronegative LEMS patients, without detectable VGCC antibodies, the electrophysiologic findings are less pronounced.19

Because of the high prevalence of SCLC in LEMS, it is mandatory to perform a careful tumor screening, especially in patients with a history of smoking. SCLC is usually identified within 2 years of the diagnosis of LEMS. Computed tomography (CT)-thorax scans detected most of the tumors found and was far more sensitive than chest X-rays.20 [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) may have an additive value in tumor screening in selected cases.

The Advent of an Effective Treatment
Symptomatic Treatment
A range of medications have been tried with varying success as treatments for LEMS, but due to the rarity of the condition, few randomized controlled trials (RCTs) have been conducted apart from 3,4-diaminopyridine (3,4-DAP), which has been more thoroughly investigated and is discussed in the next section.

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Keywords: Amifampridine/3,4-diaminopyridine/3,4-DAP, Lambert-Eaton myasthenic syndrome, potassium ion channel blockers, compounded drugs clinical trial evidence, treatment, expanded access protocols