Early onset myasthenia gravis in a Malawian woman: Challenges in managing myasthenia gravis in a low-resource setting

Case report

A 19-year old woman from Blantyre, Malawi was admitted to the medical department at Queen Elizabeth Central Hospital (QECH), with a three-week history of proximal limb weakness, difficulty with swallowing and chewing. She had been seen as an outpatient at two primary care facilities for dysphagia and was initially referred to the Ear, Nose and Throat (ENT) clinic before being seen at our facility. She had no significant medical history prior to this presentation. She had tested HIV-negative a week prior to presentation and had no prior history of thyroid or other autoimmune disease.

On examination, her vital signs were normal. She had dysphonia, a weak cough and her voice faded off after a few minutes of talking. Her chewing and swallowing were slow. She had bilateral ptosis which worsened over time and as the day progressed. She had normal ocular movements, and the rest of her cranial nerve examination was normal. She had marked proximal weakness in the upper and lower limbs and was unable to stand up from the sitting position. Her deep tendon reflexes and the rest of her neurological examination were normal. Cardiovascular, respiratory and gastrointestinal examinations were normal. Her weakness and ptosis improved after administration of neostigmine, and a clinical diagnosis of myasthenia gravis was made. She was started on prednisolone initially at a low dose (0.5 mg/kg), which was later doubled.

Blood tests showed a normal full blood count and renal function tests. Her chest radiograph and ECG were unremarkable. Electrophysiology and antibody tests were unavailable at our facility – thus, tests for acetylcholine receptor (AChR) and anti-muscle specific receptor tyrosine kinase (MusK) antibodies could not be done. A plain computed tomography (CT) scan of the chest showed a right superior mediastinal mass measuring 3.6 × 3.6 cm (Figure 1) posterior to the right sternal margin and ascending aorta. There were no hilar or mediastinal lymph nodes. The rest of the study was normal. OPEN IN VIEWER

Three weeks after admission, our patient underwent a thoracotomy where a thymic tumour measuring 5.5 × 3.5 × 2.5 cm was removed (Figure 1). Histology confirmed a B1 thymoma with no capsular invasion. A B1 thymoma histologically resembles normal thymic cortex and medulla. ¹

Pre-and post-operatively, our patient had frequent episodes of respiratory distress, and she therefore spent the majority of her hospital stay in the high dependency unit (HDU) and intensive care unit (ICU) of the hospital. Her medical management was complicated because of the non-availability of either pyridostigmine, a long acting anti-cholinesterase, nor a steroid-sparing agent, such as azathioprine, during the earlier part of her hospital stay. We were forced to use neostigmine initially until pyridostigmine became available. Owing to the former drug’s short-lived effect, the patient needed to be continuously monitored for signs of respiratory distress round the clock. The first two weeks were spent on ICU and she was stepped down to the high care unit when she was stable. Within a few days of being stepped down to the HDU, respiratory distress recurred and she was re-admitted to the ICU for mechanical ventilation, on account of respiratory failure. Treatment for a myasthenic crisis includes high-dose steroids. Intravenous methylprednisone was, however, not available. Plasmapheresis and gamma globulins may also be used in a crisis but neither treatment was available in our setting.

Two days subsequently, she had worsened respiratory symptoms. She had a cardiorespiratory arrest, and resuscitative efforts were unsuccessful. A post-mortem was not performed.

Discussion

QECH is a tertiary referral centre in the city of Blantyre, southern Malawi with a 1200-bed capacity. It is a government institution and caters for patients within Blantyre and those referred from 13 district hospitals in southern Malawi. As of the 2018 national census, Blantyre had a population of 1.2 million. ² The medical department at QECH has two six-bed HDUs housed within it catering for male and female medical patients, respectively. QECH has one four-bed ICU catering for all adult medical, surgical and obstetric patients. The hospital did not have a specialist neurologist at the time of our patient’s admission.

The correct diagnosis in our patient was delayed. Myasthenia gravis is a rare autoimmune disease caused by antibody-mediated destruction of nicotinic AChRs on the post-synaptic neuromuscular junction. Its typical presentation includes ocular symptoms with ptosis and diplopia which may occur when the patient stares up for a prolonged period. Some 20% of cases present with ocular symptoms alone. Generalised myasthenia gravis presents with fatigable and fluctuating skeletal muscle weakness predominantly involving the proximal limbs. Weakness may also involve the neck, bulbar and trunk muscles. Respiratory muscle weakness presenting with shortness of breath can be life-threatening. Tendon reflexes are usually preserved.^3,4

There are few publications on the prevalence of myasthenia gravis in African populations; the majority come from South Africa^5–9 where a 2007 study estimated the annual incidence rate of seropositive myasthenia gravis at 2.6 cases per million persons per year and 11.2 cases per million persons per year in Cape Town. ⁶ The worldwide annual incidence of myasthenia gravis is estimated at 10–20 new cases per million persons per year. ¹⁰

Racial differences in the presentation of myasthenia gravis have been described in South Africa – black patients presented with persistent ocular myasthenia gravis whilst the predominantly older white patients had severe generalised myasthenia gravis poorly responsive to therapy with frequent respiratory crises. Myasthenia gravis has a bimodal presentation with early presentation in the second and third decades predominantly in females and later presentation in the sixth and eighth decades. ¹¹

Confirmatory tests to clinch a diagnosis rest with electromyography and AChR and MusK antibody tests. Useful additional tests include imaging of the chest (chest radiograph or CT scan to exclude thymic tumours), nerve conduction tests, the tensilon and ice tests. The latter two are now rarely used. Myasthenia gravis may also present in association with other autoimmune diseases such as pernicious anaemia, thyroid disease, Type 1 diabetes mellitus and vitiligo.

Anti-cholinesterases, prednisolone and steroid-sparing agents are the mainstay of medical therapy. The onset of action of anti-cholinesterases may be delayed and so are started in combination with prednisolone at low dose. Pyridostigmine, a long acting anti-cholinesterase, prevents breakdown on acetylcholine in the neuromuscular junction making more acetylcholine available to reach the AChRs at the post-synaptic junctions. Steroid-sparing adjuncts such as azathioprine, mycophenolate mofetil, cyclophosphamide and methotrexate may be given in combination with steroids or as alternatives. Bulbar symptoms are a relative contraindication for administering high-dose corticosteroids.

Thymectomy is usually recommended where a thymoma is found and myasthenia is of early onset and related to AChR antibody positivity. A normal thymus may also be removed where AChR antibodies are found. Ideally thymectomy should be performed when symptoms are well controlled. Plasmapheresis, if available, should also be considered prior to surgery to stabilise the patient. Although thymectomy eliminates the future risk of the thymoma becoming malignant, there are conflicting reports as to whether it improves the severity or progression of symptoms in myasthenia gravis.^3,12

Challenges at each step of our patient’s management existed, beginning with diagnosis, the medical management and ready access to monitoring and cardiorespiratory support throughout the course of her admission. In the absence of other options for medical therapy and after a period of stability, a decision for thymectomy was made jointly by our surgical and medical teams. Monitoring in ICU pre-operatively and post-operatively did not prevent an unexpected deterioration.

A myasthenic crisis may be triggered by several factors including infection, drug therapy and surgery. Our patient deteriorated in the ward after being discharged from the ICU post-operatively. Although surgery in itself can trigger a myasthenic crisis, her final crisis started more than two weeks after surgical intervention. She did not have clinical symptoms or signs to suggest pneumonia, nor a new hospital acquired infection at that time. It was suspected that her respiratory distress had gradually worsened in the ward and her readmission to ICU was in terminal crisis.

Our patient’s death reflects both the severity of her illness and the lack of optimal facilities for care including round the clock respiratory care during her hospital stay. It was observed that her symptoms were worse particularly on weekends where nursing coverage on the wards was lower than on weekdays.

Conclusion

Myasthenia gravis is a rare, potentially fatal, but treatable disease. Limited resources pose a challenge to optimal management of the disease, but high clinical suspicion and good medical management, basic inpatient care and outpatient follow-up can make a substantial difference. In addition, in the event of sudden deterioration and respiratory failure, ventilating such a patient can be managed temporarily by hand to support the patient whilst awaiting definitive ICU care.