Diagnosis of LEMS is based on clinical symptoms and signs, electrophysiological studies, and antibody testing.

Electromyography initially shows a small amount of electrical activity in the muscle. After high frequency repetitive stimulation or exercise, there is increased activity in the muscle.

Anti-VGCC antibodies are detectable in around 85% of LEMS patients and when detected they are highly specific for the condition, or by measuring VGCC antibodies in the blood.

Screening for SCLC is a very important part of the diagnostic workup for LEMS. A chest CT (and sometimes FDG-PET) scan will usually form the basis of this screening. Depending on the risk profile, a negative initial screen will be repeated at suitable time intervals. A recently discovered tumor marker antibody directed against SOX, which is found in 65% of SCLC LEMS patients as opposed to only 5% of non-tumor LEMS patients may help guide clinical practice in the future.