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Neuromuscular Disorders 3,4-diaminopyridine Phosphate in the Treatment of Lambert–Eaton Myasthenic Syndrome Jörn Peter Sieb Professor, Department of Neurology, Hanse-Klinikum Stralsund and University of Bonn Abstract 3,4-diaminopyridine (3,4-DAP, amifampridine) is the leading treatment for Lambert–Eaton myasthenic syndrome (LEMS), an autoimmune disorder with impaired neuromuscular transmission, for which few effective medications are currently available. 3,4-DAP has been available as a therapy for LEMS in special treatment programmes for approximately 25 years. As an unlicensed drug, doses for oral administration are required to be compounded by local, hospital or other compounding pharmacies from the base chemical. Administering the correct dose of 3,4-DAP is critical; overdosing can increase the risk of 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 (22.2–125.2 %, n=9) and (53.5–128.5 %, n=21), thereby reflecting the possibility of patients receiving dosages that might be above safety limits or even markedly below efficacy limits. This inconsistency results from the variable quality and instability of the base chemical and compounding errors. A formulation of 3,4-DAP phosphate salt has now been licensed in Europe and the US with orphan medicinal product status and appears to be as efficacious as the base in relieving the symptoms of LEMS. Keywords Amifampridine, compounded drugs, Lambert–Eaton myasthenic syndrome, potassium ion channel blockers, neuromuscular transmission, myasthenia gravis Disclosure: Jörn Peter Sieb has received honoraria or consultation fees from BioMarin, Temmler and Valeant. Acknowledgements: Editorial assistance was provided by Touch Briefings and funded by BioMarin Europe Limited. Received: 9 February 2012 Accepted: 5 March 2012 Citation: European Neurological Review, 2012;7(1):56–61 Correspondence: Jörn Peter Sieb, Department of Neurology, Grosse Parower Strasse, 18437 Stralsund, Germany. E: j.sieb@klinikum-hst.de Support: The publication of this article was funded by BioMarin Europe Limited. The views and opinions expressed are those of the author and not necessarily those of BioMarin Europe Limited. Lambert–Eaton myasthenic syndrome (LEMS) is a rare neuromuscular disorder affecting around 1/100,000 people in Europe, although because it may go undiagnosed in many patients, its true prevalence may be considerably higher. 1 LEMS results from insufficient synaptic release of acetylcholine, which disrupts peripheral cholinergic neurotransmission. This is caused by autoimmune antibodies directed against the P/Q-type voltage-gated calcium channels (VGCCs). The loss of functional VGCCs reduces the calcium-dependent quantal release of the neurotransmitter acetylcholine. This lowers the safety margin for synaptic transmission at both the neuromuscular junction and certain autonomic nerve terminals leading to muscular weakness and symptoms of autonomic dysfunction. 2–5 Over half the patients with LEMS, particularly male smokers aged over 50 years, present with an underlying malignancy, usually small cell lung cancer (SCLC). 6,7 However, there are also case reports on a wide variety of lung and non-lung malignancies observed in LEMS patients such as breast cancer 8 and neuroblastoma. 9 The peak age of onset of non-tumour 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. 10 Non-paraneoplastic LEMS can be associated with other organic-specific autoimmune 56 disorders. 11 Paraneoplastic cerebellar degeneration can also occur in cancer-associated LEMS cases. 12 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. 11 The symptoms of LEMS are frequently mistaken for those of myasthenia gravis or depression. In a recent study, initial misdiagnosis occurred in 58 % of British and Dutch cases. 13 The most common clinical presentation of LEMS is proximal muscle weakness (more pronounced in the hip girdle than in the shoulder girdle). 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 than in myasthenia gravis 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. 14 The presence of an annoying dry mouth in patients with unexplained muscular fatigability is a diagnostic ‘red flag’ for LEMS. Diagnosis of LEMS is based upon assessment of clinical symptoms in conjunction © TOUCH BRIEFINGS 2012