Myasthenia Gravis and Lambert Eaton Syndrome Flashcards
Myasthenia Gravis - Exacerbating Factors
The most common exacerbating factor is exertion resulting in fatigability, which is the hallmark feature of myasthenia gravis . Symptoms become more marked during the day
The following drugs may exacerbate myasthenia:
- penicillamine
- quinidine, procainamide
- beta-blockers
- lithium
- phenytoin
- ABx: gentamicin, macrolides, quinolones, tetracyclines
Myasthenic Crisis - Example Question
A 65-year-old man underwent an elective inguinal hernia repair. Due to the list running late into the evening, the patient was admitted for an overnight stay. During the night after the operation the patient was observed to have an increasing oxygen requirement and the following morning was referred to the oncall medical registrar.
The patient reported feeling progressively more short of breath since the operation, particularly when he had tried to lie down to sleep. He denied any cough, chest pain, leg swelling or palpitations. Prior to the operation the patient had been generally well although he had found that he frequently experienced double vision when reading especially in the evening. He also had noticed some difficulties when chewing tough foods in recent weeks. Past medical history was unremarkable and the patient took no regular medications.
Examination revealed a regular pulse, no elevation of jugular venous pressure and normal heart sounds. Both calves were soft and non-tender. The patient had a shallow respiratory effort and was unable to speak in full sentences. Chest expansion was reduced bilaterally, chest was resonant with vesicular breath sounds throughout. The patient had bilateral weakness of facial muscles and ptosis on prolonged upward gaze. Power of neck flexion and extension was reduced, graded as 4/5.
Basic observations: Blood pressure: 120 / 76 mmHg Heart rate: 115 beats / min Respiratory rate: 32 breaths / min Temperature: 36.8ºC
Portable CXR: technically poor film due to poor inspiratory effort; clear lung fields; no pleural effusion; no upper lobe blood diversion; no free air under diaphragm.
Arterial blood gas analysis (35 % O2)
pH 7.29 PaCO2 6.6 kPa PaO2 8.7 kPa Bicarbonate 18 mmol / L (reference 20.0-26.0) Lactate 2.1 mmol / L
Bedside forced vital capacity: 1.9 L
What is the most important next step in management?
> REFERRAL TO ITU
Pyridostigmine Referral to intensive care unit Reduce percentage of supplemental oxygen High-dose corticosteroids Intravenous immunoglobulin
The patient has symptoms and signs of previously unrecognised myasthenia gravis. The physiological stress of surgery has precipitated a myasthenic crisis associated with type 2 respiratory failure, tachycardia, tachypnoea and reduced forced vital capacity. The priority in management is to refer the patient to an intensive care unit for respiratory support.
Corticosteroids and pyridostigmine are mainstays of treatment of myasthenia gravis with intravenous immunoglobulin also used in severe cases. However, these treatments cannot be expected to restore respiratory muscle function rapidly in this emergency situation.
The patient has no history of obstructive lung disease with type 2 respiratory failure due instead to failure of ventilation due to respiratory muscle weakness. Therefore, reducing percentage of supplemental oxygen would not be beneficial and would cause additional hypoxia.
Myasthenia Gravis - Facial muscle weakness - Mx: Example Question
A 35 year old lady was referred to the neurology clinic for investigation of facial weakness. Over the past 2 months she noticed that her eyelids had tended to drop towards the end of the day, and she had occasional diplopia. She also felt that the corners of her mouth drooped a bit, and she reported some difficulty smiling. There was no limb weakness, and she had not had any difficulty swallowing.
On examination there was a bilateral facial droop, and bilateral partial ptosis. She was sitting with her head tilted up to compensate for this. She had almost complete ptosis after trying to keep her eyes in elevation for more than 15 seconds. Eye movements were otherwise normal. Palatal movement was equal on both sides, and there were no abnormalities in tongue movements. Tone, power, reflexes and sensation were normal in the upper and lower limbs.
What is the most appropriate initial management?
Mycophenolate mofetil Thymectomy Prednisolone Intravenous immunoglobulin > Pyridostigmine
This lady presents with weakness affecting her facial and extra-ocular muscles, demonstrating fatigueability. This is characteristic of myaesthenia gravis. Treatment choice depends on the severity of symptoms.
In mild disease such as in this case, acetylcholinesterase inhibitors such as pyridostigmine are useful in control of symptoms. In more severe disease, with limb weakness or bulbar dysfunction immunomodulatory agents are often required. Steroids are often employed, with the addition of steroid-sparing agents such as mycophenolate mofetil, ciclosporin or azathioprine if necessary.
Intravenous immunoglobulin and plasma exchange are useful in myaesthenic crises. Thymectomy improves symptoms in cases associated with thymoma, and may also be beneficial in young patients with recent onset of symptoms, but would not be used as an initial treatment option.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disorder resulting in insufficient functioning acetylcholine receptors. Antibodies to acetylcholine receptors are seen in 85-90% of cases*. Myasthenia is more common in women (2:1)
*antibodies are less commonly seen in disease limited to the ocular muscles
Myasthenia Gravis - Key features
The key feature is muscle fatigability - muscles become progressively weaker during periods of activity and slowly improve after periods of rest:
extraocular muscle weakness: diplopia
proximal muscle weakness: face, neck, limb girdle
ptosis
dysphagia
Myasthenia Gravis - Associations
Associations
thymomas in 15%
autoimmune disorders: pernicious anaemia, autoimmune thyroid disorders, rheumatoid, SLE
thymic hyperplasia in 50-70%
Myasthenia Gravis - Investigations
Investigations
single fibre electromyography: high sensitivity (92-100%)
CT thorax to exclude thymoma
CK normal
autoantibodies: around 85-90% of patients have antibodies to acetylcholine receptors. In the remaining patients, about about 40% are positive for anti-muscle-specific tyrosine kinase antibodies
Tensilon test: IV edrophonium reduces muscle weakness temporarily - not commonly used anymore due to the risk of cardiac arrhythmia
Myasthenia Gravis - Mx
Management
long-acting anti cholinesterase (acetylcholinesterase inhibitor) e.g. pyridostigmine
immunosuppression: prednisolone initially
thymectomy
Pyridostigmine is an acetylcholinesterase inhibitor in the cholinergic family of medications. It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.
Myasthenia Gravis - Myasthenic Crises Mx
Management of myasthenic crisis
plasmapheresis (usually quicker but involves more expensive equipment)
intravenous immunoglobulins
Myasthenia Gravis - Ix: Example Question
A 28 year-old woman presents with a two month history of double vision, which is worse at the end of each day. On examination, there is bilateral ptosis which is fatiguable. There is a complex ophthalmoplegia which does not conform to the pattern of one or more cranial nerves. Examination of the limbs is unremarkable.
Which of the following would be most suggestive of a diagnosis of myasthenia gravis?
Weakness confined to extraocular muscles > A decremental response to repetitive nerve stimulation An incremental response to repetitive nerve stimulation Thymic enlargement seen on chest imaging Internuclear ophthalmoplegia
In myasthenia gravis affected muscles show a decremental response to repetitive nerve stimulation (there is a progressive decline in the amplitude of the compound muscle action potential with repeated stimulation).
An incremental response to repetitive nerve stimulation is seen in the Lambert-Eaton myasthenic syndrome.
Weakness confined to extraocular muscles is certainly compatible with myasthenia gravis but is not diagnostic, and may be seen in thyroid eye disease, brainstem syndromes, and mitochondrial diseases. Ocular myasthenia is the mode of presentation of around half of patients with myasthenia gravis. A proportion may go on to develop generalised disease.
Thymic hyperplasia and thymoma are commonly seen in association with myasthenia gravis, as well as other autoimmune disease. Thymectomy is indicated in all patients with thymoma, due to the risk of malignant transformation. Thymectomy in the case of thymic hyperplasia is more controversial, and is generally reserved for younger patients with generalised disease and anti-AChR antibodies.
True internuclear ophthalmoplegia occurs in lesions of the medial longitudinal fasciculus in the brainstem, and as such is not a feature of neuromuscular junction disorders such as myasthenia gravis. However, the involvement of extraocular muscles (one or both medial recti) may on occasion mimic internuclear ophthalmoplegia.
Myasthenia Gravis and Thymectomy
Thymectomy is a well recognised treatment for myasthenia gravis and should also be considered in non-thymomatous generalised myasthenia in patients with antibodies to acetylcholine receptor who are aged under 50. Biopsy is not generally required prior to surgery.
However, thymectomy is not generally carried out in myasthenia gravis when patients have antibodies to MUSK, late onset disease or purely ocular disease.
Example Question:
A 80 year old woman is referred to neurology clinic after experiencing increasing diplopia, typically worsening during the course of the day. The patient reported no speech or swallowing problems and no limb weakness.
Past medical history included chronic obstructive pulmonary disease and ischaemic heart disease. The patient was able to mobilise around her flat with a frame but was required to use a wheelchair outside the home due to exertional breathlessness. Regular medications were inhaled salbutamol and tiotropium, aspirin, simvastatin, bisoprolol and ramipril. The patient lived with her husband and had once daily carers to assist with activities of daily living.
Examination in clinic was significant for the development of ptosis on prolonged upwards gaze. There was no significant weakness of facial muscles, palate or tongue. There was no evidence of fatiguable weakness in the arms or legs.
A summary of the patients investigations is given below.
Serum acetylcholine receptor antibodies negative
Serum muscle specific tyrosine kinase positive
Neurophysiology: no evidence of repetitive nerve stimulation
CT thorax: retro-sternal soft-tissue density mass equal in attenuation to muscle; mass demonstrates heterogeneous enhancement following contrast injection
What is the appropriate management of the retro-sternal mass?
Proceed to thymectomy Proceed to thymectomy if patient does not respond to first line treatment Surgical biopsy > No action required Trans-bronchial biopsy
Thymectomy is a well recognised treatment for myasthenia gravis and should also be considered in non-thymomatous generalised myasthenia in patients with antibodies to acetylcholine receptor who are aged under 50. Biopsy is not generally required prior to surgery.
However, thymectomy is not generally carried out in myasthenia gravis when patients have antibodies to MUSK, late onset disease or purely ocular disease as in this case. The patient’s poor performance status would also argue against surgical intervention.
Repetitive nerve stimulation is a specific test for myasthenia gravis but has a relatively low sensitivity, especially in ocular only disease.
Lambert-Eaton Syndrome and Lung Ca: Example Question
A 57 year old male presents with a three month history of unintentional weight loss (13kg over 3 months) and a chronic non-productive cough. He has just returned from a months holiday in India. He denies haemoptysis or chest pain. He is a lifelong non-smoker. He has no past medical history except a period of generalised limb weakness four years ago, when he was referred to outpatient neurology clinic and prescribed 3,4 diaminopyridine following investigations. His blood tests are unremarkable. However, his CXR demonstrates a rounded opacity in his right mid zone, about 2 cm from his right main bronchus. What is the diagnosis?
Tuberculosis Aspergilloma > Small cell lung carcinoma Non-small cell carcinoma Pneumocystitis Jirovecii infection
The patient was treated four years ago for Lambert-Eaton syndrome (LEMS), a neurological disorder characterised by limb weakness that improves with exercise, affecting proximal muscles more than distal muscle. It is caused by antibodies directed against voltage gated calcium channels and has a strong association with malignancy. Up to half of all LEMS patients has an underlying malignancy, the most common of which is small cell lung carcinoma. Neurological symptoms often precede malignancy diagnosis by around 5 years.
MG - Ix - Most specific/sensitive?
Single fibre electromyography: sensitivity 92-100 %
Repetitive nerve stimulation neurophysiology: sensitivity 70 %
Serum acetylcholine receptor antibodies: sensitivity 85 %
Serum muscle specific tyrosine kinase antibodies: sensitivity 40-70 %
MG - Diagnosis - Example Question
A 65-year-old man was referred to neurology outpatient clinic with a six month history of double vision. He had first noticed this when reading before going to bed but had more recently been occurring earlier during the day whenever the patient concentrated on an activity. The patients wife also reported that she had been struggling to hear the patient when he spoke to her and that on several occasions the patients eyelids had drooped during late in the day. The patient denied experiencing any weakness in his arms or legs but stated that his general mobility was normally very limited due to osteoarthritis of both his knees. Other past medical history included hypercholesterolaemia, hypertension and diverticular disease. Regular medications included bendroflumethiazide 2.5 mg OD, simvastatin 40 mg OD, co-dydramol as required. The patient was a retired builder and lived alone with his wife. He was an ex-smoker who rarely consumed alcohol.
Examination showed normal pupillary reflexes, visual acuity and visual fields. No ptosis was observed. Assessment of eye movements demonstrated a complex ophthalmoplegia with diplopia in all directions of gaze. There was significant weakness of bilateral facial muscles with bilateral involvement of the forehead. Examination of the tongue and palette was normal. Peripheral nerve examination was unremarkable except for evidence of fatiguable muscle weakness in the upper limbs.
Chest x-ray: clear lung fields with no effusion; no cardiomegaly; possible mediastinal widening
Haemoglobin 13.5 g / dL White cell count 8.9 * 109/l Platelets 409 * 109/l Urea 4.7 mmol / L Creatinine 95 micromol / L Sodium 137 mmol / L Potassium 4.8 mmol / L Calcium (adjusted) 2.5 mmol / L
What is the single most sensitive investigation for the likely diagnosis?
Repetitive nerve stimulation neurophysiology Serum acetylcholine receptor antibodies Serum muscle specific tyrosine kinase antibodies CT mediastinum > Single fibre electromyography
The patient is presenting with symptoms and signs consistent with myasthenia gravis. All of the above investigations would be appropriate in this context but have variable sensitivities for myasthenia gravis as listed below:
Single fibre electromyography: sensitivity 92-100 %
Repetitive nerve stimulation neurophysiology: sensitivity 70 %
Serum acetylcholine receptor antibodies: sensitivity 85 %
Serum muscle specific tyrosine kinase antibodies: sensitivity 40-70 %
The Edrophonium (Tensilon) test has a high sensitivity for myasthenia gravis but is no longer used due to risk of fatal cardiac arrhythmia. Around 10 % of patients with myasthenia gravis also have a thymoma and therefore CT scanning is an important part of assessment of these patients. However, this investigation will no yield a diagnosis.
Myasthenia Gravis - Patient symptomatic on max dose of Pyrostigmine: Example Question
You receive a call from a GP in the community. A 65 year old female patient who was diagnosed with generalised myasthenia gravis six years ago and last reviewed in neurology outpatients 6 weeks ago reports no improvements in her neck weakness, voice weakness and fatigue. In the neurology clinic, her dose of pyridostigmine was increased from 90mg QDS to 120mg QDS. She does not appear acutely unwell but complains that her life is significantly affected by her symptoms. She has no other past medical history. On examination by her GP, she has no respiratory distress and able to swallow salivary secretions normally. What is your advice?
Increase pyridostigmine to 150mg QDS Start prednisolone 60mg in community, neurology to follow up in 8 weeks as outpatient Start azathioprine in community, neurology to follow up in 8 weeks as outpatient > Admit to hospital, start oral prednisolone in hospital Admit to hospital, start intravenous immunoglobulin in hospital
The patient remains symptomatic despite being increased onto the maximum dose of pyridostigmine. The second decision is whether the patient is acutely, severely unwell, in which case rapid therapies such as IV Ig or plasmophoresis must be initiated, as per myasthenic crisis. In this case, she has no signs of respiratory distress or dysphagia, her symptoms are more of a case of not improved instead of rapid deterioration. Therefore, the patient does not require rapid therapy. However, she does require immunotherapy initiation. As a rule of thumb, patients who remain symptomatic despite 60mg QDS of pyridostigmine should be considered for immunotherapy.
The modality of immunotherapy must be individualised to the patient, as each drug has their own contraindications. In younger patients with no concerns regarding blood sugars, oral prednisolone is reasonable. Those with liver disease should avoid azathioprine, renal disease patients should avoid ciclosporin while those with haematological abnormalities should avoid mycophenolate and azathioprine.
However, starting of prednisolone, particularly at high doses, have been classically described to cause a paradoxical reaction in half of all patients, resulting in a transient deterioration before improvements are observed. Up to 10% of patients have been reported to have sufficiently severe respiratory failure requiring mechanical ventilation. Initiation of prednisolone should therefore take place in a monitored hospital setting.
