Lambert-Eaton myasthenic syndrome

This is an uncommon condition in which the command travelling from nerve to muscle fails to get through properly. The signal arrives, but the release of the chemical messenger at the junction is too small, and the muscle does not contract at full strength. Hence the main complaint: weakness that begins in the thighs, makes standing up and climbing stairs hard work, and builds over weeks or months. In roughly half of those affected there is a lung tumour behind it, almost always a small-cell carcinoma, and the weakness appears before the tumour itself becomes visible. The syndrome therefore carries a double meaning: it is a condition to be treated, and at the same time a reason to go looking deliberately for another one.

How it begins

The onset is nearly always insidious, and for the first few months people put it down to age or tiredness. The typical sequence runs like this: first stairs become hard work and getting out of a chair or a bath needs the arms; then the walk changes and becomes rolling; later the weakness reaches the shoulders and arms.

There is almost always a second, less obvious element as well — a disturbance of the autonomic nervous system, the one that governs what is not under conscious control:

• a dry mouth, often the earliest and most constant feature, sometimes with a metallic taste;
• dry eyes;
• light-headedness and darkening of vision on standing, from a drop in blood pressure;
• constipation;
• reduced sweating;
• erectile dysfunction in men.

Less often there is slight drooping of the eyelids, double vision, unclear speech and difficulty swallowing. The muscles ache, and the tendon reflexes are reduced or cannot be elicited at all.

One feature almost makes the diagnosis on its own: strength briefly improves after exertion. Squeeze a hand a few times or tense a muscle, and for the next half minute it works better, while a reflex that had gone absent comes back for a moment. The doctor looks for this sign deliberately, and patients sometimes notice it themselves — "once I've got moving, the stairs are easier."

What goes wrong in the signal

Where the nerve ending meets the muscle there are channels that let calcium into that ending. It is the calcium that triggers the release of acetylcholine, the substance that tells the muscle to contract.

In this syndrome the immune system makes antibodies against those calcium channels. Fewer channels remain, less calcium enters, less acetylcholine is released, and the signal weakens. The mechanism also explains why warming up helps: with repeated impulses the calcium has time to build up, and transmission is restored for a short while.

Why the immune system starts doing this is only partly understood. In the tumour-related form the explanation is that small-cell carcinoma cells carry those same calcium channels on their surface; the immune system attacks the tumour and the healthy nerve endings along with it. In people without a tumour the syndrome behaves like an ordinary autoimmune disease and is more often accompanied by others — thyroid disease, type 1 diabetes, vitiligo.

The link with lung cancer

This is the most important part of the subject. In about half of cases the syndrome turns out to be paraneoplastic — caused by a tumour — and almost always that tumour is a small-cell lung cancer. The weakness usually runs ahead of every other sign of the tumour by months, and sometimes by two or three years.

The risk of the tumour-related form is higher in current and former smokers, in people past forty or fifty, and in those whose illness advances quickly and reaches swallowing and speech early on. In a young non-smoker with a slow onset the likelihood of a tumour is appreciably lower, but even then it is not ruled out entirely.

The practical conclusion is a single one: investigation of the lungs is obligatory in every version of the syndrome. A CT scan of the chest is the usual starting point, with a PET scan if that is negative. And, most importantly, the search does not stop there: if no tumour is found, the scans are repeated every few months for around two years. It is not worth opting out of those repeats — they are precisely what gives the chance of catching a cancer at a stage when it can still be treated with intent to cure.

Why this is not myasthenia gravis

The names are alike and the mechanisms are neighbours, but these are different diseases and they are often confused. The differences show up in the history alone.

• The order in which muscles are affected. Myasthenia gravis usually starts at the eyes: a drooping lid and double vision are the first symptom and for a long time the only one. Here the eyes are affected late and mildly, and everything begins with the legs.
• The response to exertion. In myasthenia strength falls with use and everything is worse by evening. Here a brief effort adds strength for a short time.
• The reflexes. In myasthenia they are preserved; here they are reduced or absent.
• Autonomic complaints. Dry mouth, constipation and a drop in blood pressure on standing are not typical of myasthenia, and here they are present almost invariably.

Other conditions produce a similar picture and also have to be excluded: inflammatory myopathies, muscle involvement from an underactive thyroid, muscle pain caused by statins, and polyneuropathy. Worst of all is when the weakness and fatigue are put down to depression or chronic fatigue syndrome — that costs months of lost time on average.

How the diagnosis is confirmed

The work-up rests on three supports.

A blood test for antibodies against voltage-gated calcium channels confirms the diagnosis in the great majority. A negative result does not overturn it: in some people the antibodies are not detectable, and then the rest of the findings decide.

Nerve conduction studies with electromyography, in which the muscle is stimulated by gentle pulses through the skin and the response is recorded. What is being looked for is a characteristic pattern: an initially low response that rises sharply after a brief voluntary contraction of the muscle or after rapid stimulation. It is the most specific sign there is, and it is exactly what separates this syndrome from myasthenia gravis.

The search for a tumour — a CT scan of the chest, a PET scan where needed, and repeat imaging over about two years.

Thyroid function and other autoimmune markers are checked as well, since accompanying conditions are not unusual here.

How it is treated and what to expect

There is no complete cure, but treatment controls the symptoms well. There are four lines of approach.

Treating the tumour, if one has been found. This takes priority: with successful chemotherapy or surgery, muscle strength often recovers of its own accord, sometimes almost fully.

Drugs that increase acetylcholine release. The mainstay is amifampridine (3,4-diaminopyridine), a potassium channel blocker that prolongs the nerve impulse and increases the entry of calcium. It acts on the cause of the weakness and usually brings a marked improvement. Pyridostigmine is sometimes added, though on its own it does little in this syndrome. The dose is set by a neurologist, and exceeding it is dangerous.

Drugs that damp down the immune system — steroid tablets, along with medicines such as azathioprine that allow the steroid dose to be reduced gradually. They are used when the transmission-enhancing drugs alone are not enough. This treatment calls for regular blood tests and particular care around infections.

Intravenous immunoglobulin and plasma exchange work quickly but temporarily. They are used for severe weakness, for a deterioration, and while waiting for the other treatments to take effect.

The outlook depends above all on whether there is a tumour. Without one the syndrome does not shorten life, and with well-adjusted treatment most people keep their independence, though stamina usually stays reduced. With a small-cell cancer it is the tumour that determines the outlook. There is one encouraging observation, too: in people with that cancer who develop the syndrome, the tumour tends on average to behave less aggressively — apparently because the immune system is actively fighting it.

Medicines, anaesthesia and signs that need urgent help

This is worth knowing for both the patient and those close to them, because heading the problem off is easier than dealing with it.

Before any operation and any procedure under anaesthetic, always tell the anaesthetist about the diagnosis. People with this syndrome are extraordinarily sensitive to muscle relaxants, the drugs used to relax the muscles during anaesthesia. An ordinary dose can leave breathing unable to restart on its own, so that prolonged mechanical ventilation is needed. Knowing the diagnosis, the anaesthetist will take a different approach. The same applies to dental procedures and to endoscopy under sedation.

A number of everyday medicines also worsen the weakness: certain antibiotics (aminoglycosides above all, and also macrolides and quinolones), magnesium preparations, antiarrhythmic drugs, beta-blockers and calcium channel blockers. This is not a prohibition — many of them are prescribed where they are needed — but the doctor has to know the diagnosis in order to weigh the decision and warn about signs of deterioration. Carry a card or a note on your phone with the name of the condition and a list of your medicines.

Call an ambulance immediately (in Spain, Italy, Portugal, Poland and Ukraine on the single European number 112) if any of the following appears:

• increasing breathlessness, being unable to finish a sentence in one breath, needing to sit up in order to breathe;
• a weak cough, a feeling of being unable to clear the chest;
• choking, food or drink going into the airway, being unable to swallow;
• weakness building rapidly over hours, particularly during an infection or after a change of medication;
• slurred speech and weakness of the neck muscles, with the head no longer held up.

Serious breathing difficulty is rare in this syndrome, but it is precisely what threatens life, and there is no room for delay in that situation.

Online consultation

At an online appointment the doctor goes through your pattern of weakness using the features that genuinely tell the diagnoses apart: which muscles it started in, what happens to strength after exertion, whether there is a dry mouth and a drop in blood pressure on standing, and whether swallowing has changed. From that description it is already possible to see which specialist to refer to and how urgently, and which investigations to arrange first. If the diagnosis has already been made, the doctor will help you make sense of the treatment plan, explain which blood tests are needed and how often while you are on immunosuppression, remind you of the repeat lung imaging and its timing, and go through your regular medicines for anything capable of worsening the weakness. What to do at the first signs of deterioration, and how to prepare for planned surgery, are discussed separately.

This material is for information only and does not replace medical advice.