Medication Summary
Medical therapy is tailored for each patient and might include various combinations of the drugs listed below. Therapy is best coordinated with the primary care physician and appropriate consultants.
The initial pharmacotherapy for Lambert-Eaton myasthenic syndrome (LEMS) is with agents that increase the transmission of acetylcholine (ACh) across the neuromuscular junction, either by increasing the release of ACh or by decreasing the action of acetylcholinesterase. Treatment of the associated cancer may also decrease the weakness and other symptoms.
Amifampridine, a voltage-dependent potassium channel blocker, is indicated for treatment of LEMS. Blocking voltage-dependent potassium channels prolongs presynaptic cell membrane depolarization, which enhances calcium transport into nerve endings. The increased calcium facilitates exocytosis of acetylcholine-containing vesicles, which, in turn, enhances neuromuscular transmission. [8, 9]
If these treatments are not effective and the patient has relatively mild weakness, aggressive immunotherapy may be warranted. In such cases, plasma exchange (PEX) or high-dose intravenous immunoglobulin (IVIg) may be used initially to induce rapid, albeit transitory, improvement.
Immunosuppressants should be added for more sustained improvement. Prednisone and azathioprine, the most frequently used immunosuppressants, can be used alone or in combination. Cyclosporine may benefit patients with LEMS who are candidates for immunosuppression but cannot take or do not respond well to azathioprine.
IVIg, given in a course of 2 g/kg over 2-5 days, also induces clinically significant temporary improvement in many patients. The frequency of improvement in response to repeated courses of treatment has not been determined.
Potassium Channel Blockers
Class Summary
Blocking voltage-dependent potassium channels prolongs presynaptic cell membrane depolarization, which enhances calcium transport into nerve endings.
Amifampridine (Firdapse, Ruzurgi)
Increases intracellular calcium concentrations in nerve endings by blocking voltage-dependent potassium channels. The increased calcium facilitates exocytosis of acetylcholine-containing vesicles, which, in turn, enhances neuromuscular transmission. It is indicated for LEMS in adults and children as young as 6 years old.
Cholinergic Agonists
Class Summary
Cholinergic agonists produce symptomatic improvement in strength, autonomic symptoms, or both in some patients with LEMS. They act by inhibiting the breakdown of ACh, which is intended to help compensate for the relative lack of ACh quanta release in LEMS. They usually do not provide a significant improvement; however, a few patients with mild disease may note some difference.
Acetylcholinesterase inhibitors do not usually produce dramatic improvement in LEMS, but they may provide relief from weakness or dry mouth in some patients. Pyridostigmine is the preferred agent and should be administered for several days before assessing response.
Pyridostigmine bromide (Mestinon, Regonol)
Pyridostigmine blocks ACh hydrolysis by cholinesterase, resulting in ACh accumulation at synapses and increasing stimulation of cholinergic receptors at myoneural junction.
In most of the literature, the consensus seems to be that monotherapy with a cholinesterase inhibitor is ineffective. It is in combination with drugs such as 3,4-diaminopyridine that cholinesterase inhibitors may have some slight benefit.
Guanidine
Guanidine is thought to act by increasing free intracellular calcium concentrations through inhibition of mitochondrial respiration by blocking potassium channels, and thus prolonging the nerve terminal action potential. This increases release of ACh after nerve impulses and may decrease rates of repolarization and depolarization of muscle cell membranes. It temporarily improves strength in many patients with LEMS. Maximal effect may take 2-3 days. It is indicated in adults to reduce symptoms of muscle weakness and easy fatigability associated with LEMS.
Immunosuppressants
Class Summary
If the therapies already described are ineffective, more aggressive immunotherapy may be indicated. Therapy can take the form of plasma exchange or high-dose IVIg, with the potential for more long-term immunosuppression, usually with prednisone or azathioprine.
Prednisone (Rayos)
Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. The combination of corticosteroid therapy with azathioprine may be more effective than steroid monotherapy.
Azathioprine (Imuran, Azasan)
Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may inhibit formation of immune cells, possibly reducing activity of immune system.
Blood products
Class Summary
Agents in this category may be used to improve clinical and immunologic aspects of LEMS. They may decrease autoantibody production and increase solubilization and removal of immune complexes. IVIg can be an effective treatment for LEMS.
Intravenous immunoglobulin (IVIg) (Gamunex-C, Gammagard, Carimune NF, Octagam, Privigen)
Features of IVIg that may be relevant to efficacy include neutralization of circulating antibodies through anti-idiotypic antibodies; downregulation of proinflammatory cytokines, including interferon gamma; blockade of Fc receptors on macrophages; suppression of inducer T and B cells and augmentation of suppressor T cells; blockade of the complement cascade; promotion of remyelination; and a possible increase in cerebrospinal fluid (CSF) immunoglobulin (IgG).
-
Characteristic responses to repetitive nerve stimulation in patient with Lambert-Eaton myasthenic syndrome. (A) Responses elicited from hand muscle by stimulation of nerve at 3 Hz. Amplitude of initial response is less than normal, and response is decremental. (B) Responses as in A, immediately after voluntary activation of muscle for 10 seconds. Amplitude has increased. (C) Responses in hand muscle elicited by 20-Hz stimulation of nerve for 10 seconds. Response amplitude is less than normal initially, falls further during first few stimuli, then increases and ultimately becomes more than twice initial value.
-
Compound muscle action potentials elicited from hand muscle before and immediately after maximal voluntary activation of muscle for 10 seconds. Amplitude is small initially, increasing almost 10 times after activation.
