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A 52 year old lady presented with 15 day symptoms of fatigable bulbar weakness with proximal weakness of all our limbs with preserved reflexes and normal sensory examination. Evaluation revealed her to have myasthenia gravis. An approach to a case with bulbar and proximal limb weakness is discussed. Management issues in a patient with myasthenia are also included.
This 52 year old lady presented with the complaints of difficulty in swallowing with nasal intonation of voice for the last 15 days and weakness of all four limbs for the last 12 days. She became symptomatic about 15 days ago when she noticed food getting stuck in throat while swallowing. She also noticed that the difficulty in swallowing was to both solids and liquids and while attempting to swallow liquids there was nasal re.g.urgitation of fluids.
Analyze the symptom and how would you differentiate mechanical from neurogenic cause from dysphagia?
This patient has neurogenic dysphagia. The clues to presence of neurogenic dysphagia in a given patient include:
Presence of nasal re.g.urgitation and coughing while swallowing
Presence of voice change, nasal twang, hoarseness of voice
Dysphagia to solids and liquids from onset
She also gave history of nasal intonation of voice for the last 15 days which gradually increased and family members found it difficult to comprehend her speech. She could not converse for long and had to take pauses in between sentences. This symptom became worse at the end of day and at presentation to the hospital she could only produce sounds.
What would be the localization of the symptoms of neurogenic dysphagia and nasal intonation of voice?
The syndrome of bulbar palsy can be due to lesion at:
Brainstem involving lower cranial nerve nuclei
Nerve level: As part of multiple cranial and peripheral nerve palsy e.g. GBS
At the neuro muscular junction e.g. myasthenia gravis, botulism, cobra bite
At muscle level e.g. poly myositis/ dermatomyositis
Three days after the onset of the bulbar symptoms she developed symmetrical weakness of all four limbs in that she had difficulty in lifting arms up to the shoulder and also difficulty in getting up from squatting position. However she was able to button clothes and break chapattis and also there was no h/o slippers slipping off feet while walking.
Analyze her symptom and what can be the localization of this symptom?
She has now developed proximal weakness of all four limbs. Proximal weakness of all four limbs can occur due to lesions at:
Anterior horn cell e.g. SMA
Polyradiculoneuropathy e.g. GBS, CIDP
Neuro muscular junction e.g. myasthenia
All her symptoms became worse at the end of day. The symptoms improved following rest or sleep. They was progression of weakness over the last 12 days prior to presentation. At admission she could walk only 15m without support, was unable to get up from floor or lift arm above shoulder, was unable to swallow solids or liquids and chew hard food. No h/o diplopia, drooping of eyelids, neck falling forward, sensory symptoms, imbalance or incoordination, loss of consciousness, headache or vomiting or breathing difficulty. No h/o fever, cough sore throat or flu like symptoms, diarrhea, exposure to drug or toxin, vaccination, dog bite, recent surgery, rash over face or body or joint pains or swelling.
To summarize, at the end of history, this 52 years old lady has presented with fatigable proximal weakness of all limbs, nasal intonation of voice and dysphagia of 15 days duration with intermittent variability.
What is the differential diagnosis on history?
Difficulty in chewing solid food like chapattis, meat piece etc
Absence of ocular muscle involvement which is a usual feature even at onset in most patients with myasthenia
Acute onset progressive symptoms
Acute onset progressive symptoms
Absence of ocular muscle involvement
Difficulty in chewing food
Anterior horn cell involvement e.g. Motor neuron disease, secondary to malignancy
Rapid onset progressive symptoms
Absence of fasciculations on history
General examination was unremarkable and there was no sign of respiratory difficulty. Neurological examination revealed nasal intonation of voice with preserved gag reflex. Ocular movements were normal. There were no tongue wasting or fasciculations, neck muscle weakness was present. Motor system examination revealed proximal muscle weakness (4/5) with preserved reflexes. There were no fasciculations. Sensory examination was normal.
At the end of examination which condition can be safely be eliminated because of preserved reflexes?
Anterior horn cell involvement e.g. SMA (not ALS where reflexes will be brisk), secondary to malignancy
Can some bedside tests be done to establish fatigability?
Sustained up gaze to induce ptosis. The time to development of ptosis in which the upper eyelid covers at least the upper 1/3 rd of the cornea.
Rapid horizontal saccades. The time to development of diplopia.
Forward arm abduction time
Number of arm flaps before fatigue sets in
Investigations including hemogram, chemistries, x-ray chest, ECG, abdominal and pelvic ultrasound examination were all normal. HIV was negative. Nerve conduction studies and EMG were normal. Repetitive nerve stimulation test showed a significant decremental response. Neostigmine test and acetylcholine receptor antibody (AChR Ab) were positive. CECT chest was normal.
How is the neostigmine test done?
The neostigmine test is done in suspected patients with myasthenia gravis. The patient should not be on acetylcholine esterase inhibitor drugs. Baseline assessment of patient is done using definite clinical parameters including ptosis time, breath holding time, single breath count, voice, swallowing, forward arm abduction time, arm flaps and sit ups. Injection atropine 0.6 mg IM is given followed 30 minutes later by 1mg IM Injection neostigmine. After another 30 minutes assessment of the same clinical parameters is done to document improvement.
Is there any other drug which can be used other than neostigmine?
Edrophonium 2 mg IV followed by 8 mg IV if no definite improvement occurs can be used in dominantly ocular myasthenia. It is short acting drug with onset of action within 1-2 minutes which lasts for a few minutes only.
In what percentage of patients can AChR Ab be positive?
What is seronegative myasthenia?
AChR Ab negative myasthenia is seronegative myasthenia, 50% of these have Anti MuSK antibody positive.
She was diagnosed as myasthenia gravis and managed with pyridostigmine 60 mg TDS, prednisolone 20 mg OD, calcium supplements and proton pump inhibitors. Initially ryles tube feeds were given to prevent aspiration and once the swallowing improved these were discontinued. She showed significant improvement with this therapy.
When starting steroids what precautions should one take?
Nearly one third may have some worsening, the exact mechanism of which is unknown; hence steroids should be started at a lower dose and gradually built up. Patients who have swallowing difficulty or breathing difficulty and in whom steroids are being started may need to be admitted for observation for worsening in the initial period.
What is crisis and what are the types of crisis?
If a patient develops respiratory difficult which requires or has the potential to require mechanical ventilation the patient is said to be in crisis. There are two types of crisis: myasthenic and cholinergic.
How to differentiate the two?
Presence of cholinergic effects will predominate including queasiness, nausea, vomiting, cramps, loose stool, and diarrhea, increased oral and bronchial secretions. Theoretically, edrophonium 2 mg IV may be given to look for any worsening of symptoms in cholinergic crisis. However it is not routinely recommended.
How is myasthenic crisis treated?
In addition to ventilation patients need to be managed with either plasmapheresis or intravenous immunoglobulins.
What can precipitate a crisis?
Stress, infection, medications or surgery may precipitate crisis.
What are the indications and response to thymectomy?
Any patient with generalized myasthenia and in the age group of 10 to 60 years will benefit from thymectomy early in the course of the illness. Quality Standards Subcommittee of Americn Academy of Neurology conclude that myasthenia gravis patients undergoing thymectomy are twice as likely to achieve medication free remission, 1.7 times likely to show improvement in symptoms and 1.6 times likely to be symptom free.
Final Diagnosis: Myasthenia Gravis
Myasthenia Gravis is a common autoimmune condition affecting the neuromuscular junction. This is different from congenital myasthenia which is due to genetic abnormality of the neuromuscular junction. The usual age of onset in males is the fifth and sixth decade while in females it occurs earlier. Nearly two thirds of the patients present with ocular symptoms at onset which include diplopia and ptosis. Almost all of them will go on to develop these symptoms within the first two years of illness. Presentation with bulbar symptoms accounts for about one sixth of all patients. Our patient fell in the latter category. Myasthenia gravis is a treatable condition. Not only can the symptoms be relieved but the disease can be forced into remission using a combination of immunosuppression and thymectomy. Patient with myasthenia who are at high risk of dying include those with respiratory difficulty and/ or with bulbar weakness. Bulbar weakness may predispose them to aspiration. These are subsets of patients who should be identified and treated aggressively when following up patients with myasthenia gravis.
Take Home Message
Different diseases, some of them treatable can present with bulbar palsy with proximal muscle weakness.
Myasthenia may present with sparing of ocular muscles.
Outline of investigation and treatment of myasthenia gravis.
1. Drachman DB. Myasthenia Gravis and other diseases of the neuromuscular junction In: Fauci, Braunwald, Kasper Ed. Harissonâ€™s Principles of Internal Medicine 17 th edition. McGraw Hill 2008: 2672-2677.
2. Sanders DB, Howard Jr JF. Disorders of neuromuscular transmission In: Bradley WG, Daroff RB Ed. Neurology in Clinical Practice 5th edition. Butterworth Heinemann Elsevier 2008: 2383-2402.