Ischaemic stroke in a patient with myasthaenic crisis and antiphospholipid antibody syndrome

Abstract

While autoimmune diseases have been frequently found to coexist in the same patients, the co-occurrence of myasthaeniagravis and antiphospholipid antibody syndrome (APAS) has only been reported in eight cases. We present a case of a 46-year-old Filipina who developed ischaemic stroke while admitted at the neurocritical unit for myasthaenic crisis. She was successfully thrombolysed with intravenous recombinant tissue plasminogen activator (rTPA), given a regimen of intravenous Ig and a dose of cyclophosphamide prior to discharge. Extensive workup revealed APAS to be the aetiology of her stroke. Twenty-one months into her follow-up, she is doing well with a modified Rankin Score of 0. Our case suggests that rTPA followed by immunomodulators may be given safely in myasthaenic crisis patients who develop ischaemic stroke. We emphasise the importance of doing a comprehensive neurological evaluation in agitated patients in the critical care unit.

Background

The in-hospital diagnosis of acute stroke may prove challenging, especially in the critically ill patients. In-hospital patients with ischaemic stroke compared with patients with community-onset stroke had longer time to from symptom recognition to thrombolysis.¹ The complexity of the medical conditions these patients come in with and their admission under physicians who lack familiarity with stroke quality measures may account for the worse outcomes with in-hospital stroke.²

Myasthaenia gravis (MG) is autoimmune condition characterised by weakness of bulbar and peripheral muscles.³ The disease is differentiated from other causes of weakness by its characteristic improvement with acetylcholinesterase inhibitors, and association with neuromuscular junction antibodies.⁴ Clinical scenarios involving muscle weakness can cause confusion between the diagnoses of MG and stroke.⁵ Antiphospholipid antibody syndrome (APAS) is an autoimmune syndrome causing a procoagulant state by binding β2-glycoprotein I (β2GPI) leading to thrombotic events.⁶ The diagnosis of APAS requires one clinical event and serological evidence of autoimmunity.⁷ Although the asymptomatic occurrence of antiphospholipid antibodies in patients with MG has been well documented⁸; thus far, there have only been eight reported cases of the co-occurrence of MG and APAS.^9–14 This report follows the ninth case of MG and APAS co-occurrence and presents a treatment strategy for ischaemic stroke in a patient with myasthaenic crisis, a condition that has not yet been described in literature.

Case presentation

We present a case of a 46-year-old Filipina who, in 2012, developed symptoms of diplopia and droopy eyelids that later progressed to generalised weakness. She was diagnosed with MG and subsequently started taking pyridostigmine. Despite the relief of some MG symptoms with pyridostigmine, she had three episodes of myasthaenic crises over the next 2 years. Her medical history, family medical history, personal social history and obstetric history are all unremarkable. In 2016, she developed difficulty of breathing and was rushed to a nearby hospital where she was intubated and placed on mechanical ventilation. Afterwards, she was transferred to our emergency department where we found her hypoxic with impaired air entry on auscultation. Immediately after our initial assessment, her cardiac monitor showed asystole and advanced cardiac life support for 2 min was done to revive her. Examination 30 min later demonstrated: intact ability to follow and communicate, bilateral ptosis, inability to sustain upward gaze, no facial asymmetry, generalised weakness (British Medical Research Council (BMRC) 3/5) on all extremities, normal reflexes, no extensor toe sign and no dysmetria. Coarse crackles were heard on both lower lung fields. Complete blood count was normal except for mildly elevated white blood cell count (11.80×10⁹/L) and an elevated neutrophil to lymphocyte ratio (NLR) of 6.16. Blood gases taken showed normal pH (7.35) with compensated respiratory alkalosis (pCO₂ 24.3 mm Hg) and coexisting metabolic acidosis (bicarbonate 14.4 mEq).

At 11:00 of the following day in the neurocritical care unit (NCCU), her neurological examination was similar to the day prior. She was intubated with ptotic eyelids and an inability to sustain upward gaze and arm raising. At 11:30, she started banging on her bed. After initially failing to determine the reason behind her agitation with the NCCU communication board, the attending neurologist noted the absence of movement (BMRC 0/5) on the patient’s right side 15 min later. The patient confirmed that this was the reason for her agitation. She had a National Institutes of Health Stroke Scale (NIHSS) of 18 on account of right-sided haemianopia, facial asymmetry, weakness and numbness. A non-contrast head CT scan showed no radiological evidence of ischaemia (see figure 1A–C). She was subsequently treated as a case of acute ischaemic stroke involving the left middle cerebral artery territory. At 14:15, intravenous recombinant tissue plasminogen activator (rTPA) was given at a dose of 0.9 mg/kg. The door-to-needle (DTN) time was 165 min. Twenty-four hours after thrombolysis, her NIHSS went down to 13. On the 4th day of hospitalisation, intravenous immunoglobulin (IVIG) was given. Cranial MRI done on the 16thday of hospitalisation showed a subacute infarct on the left subcortical parietal region (see figure 1D–F).

Figure 1.

Intracranial imaging. (A–C) Plain cranial CT scan done 70 min after ictus. (D–F) Fluid-attenuated inversion recovery (FLAIR) sequence of a cranial MRI done 14 days after ictus showing an infarct (white arrow) in the parietal subcortical region corresponding to the left middle cerebral artery territory. (G) Cranial magnetic resonance angiography showing normal cerebral vasculature.

Recurrent bouts of pneumonia prolonged her hospital stay. She underwent a cycle of cyclophosphamide prior to extubation on the 27th day. On the 28th day of hospitalisation, she was discharged with an NIHSS of 0 and a modified Rankin Scale (MRS) score of 0.

Outcome and follow-up

Three months after her discharge, she underwent another cycle of cyclophosphamide. Because she had none of the traditional risk factors for stroke, we considered hypercoagulable states such as APAS as the possible cause of her stroke. A year after her discharge, antiphospholipid antibody testing (lupus anticoagulant, dilute russel viper venom time) done twice, 20 weeks apart, yielded positive results thereby establishing the diagnosis APAS. Cardiac workup with transthoracic echocardiography, carotid Doppler ultrasound all yielded normal results. Workup for other stroke aetiologies (protein C, protein S, antithrombin III, homocysteine, anti-double stranded DNA) yielded normal findings as well. Still with an MRS of 0, she is on regular follow-up at the outpatient clinic, maintained on pyridostigmine and warfarin.

Discussion

Our case emphasises two important key points. First, a quick but comprehensive neurological assessment is necessary for acutely agitated patients in the NCCU. Second, work-up for other autoimmune conditions should be pursued in patients with MG who develop vascular events. At the time of the patient’s admission, a ‘Stroke Code’ protocol was not yet in place at our institution. Because of this, significant delay was apparent in our DTN time of 165 min. The difficulty in clinching the diagnosis of stroke in our patient in myasthaenic crisis who had generalised weakness and compromised ability to communicate by speech or writing also added to the delay in management.

She is the first reported patient in myasthaenic crisis to develop stroke in the critical care unit. Two small series that tackled ischaemic stroke in critically ill patients found the frequency of associated hemiparesis to be between 49% and 90%.^{15 16} The illnesses in these were mainly non-neurological illnesses such as infective endocarditis and malignancy. None of the patients had a primary neuromuscular condition. Hemiparesis was found to be independently associated with ischaemic stroke; conversely, patients presenting with seizures were more likely to have another condition.¹⁵ Besides APAS, our patient’s respiratory infection¹⁷ and increased NLR, a known marker of inflammation that has been shown to increase the risk of stroke even for healthy individuals¹⁸ may have contributed to the occurrence of ischaemic stroke. Deep sedation (Richmond Agitation Sedation Scale less than −2) should only be used when absolutely indicated (ie, tetanic spams) to allow for proper neurological assessment of patients in the NCCU.¹⁹ Had our patient’s agitation been mistaken to be from anxiety from being mechanically ventilated rather than from her acute hemiplegia, she would have been put under sedation and the window for reperfusion therapy would have passed.

Epidemiological data estimate the prevalence of MG to 5 per 100 000 individuals, while that of APAS is 40–50 per 100 000 persons.^{20 21} A systematic review found 13% of MG cases to be related to other autoimmune diseases.²² Predictors for these comorbid autoimmune conditions, seropositivity to MG autoantibodies and the female sex are both found in our patient.²² While the relationship of SLE with both MG and APAS has been established in several series,^{14 23} concurrent MG and APAS is much more uncommon.

After a thorough search of literature, we enumerate the rare instances when MG and APAS have been reported in the same patient (see table 1). Including our case, five cases of stroke associated with MG and APAS have been documented.9 11 12 14 Of these, only our case received thrombolysis with rTPA. Similar to large studies on polyautoimmunity,²⁴ female predominance is also seen in our review with only one male patient having APAS and MG.¹⁴ SLE was also found in three of the patients.^{14 25} A systematic review found that patients with MG who are seropositive are 3.68 times more likely to develop other autoimmune disease compared with those who are seronegative.²² This finding is supported in our review with 6 out of the 7 of the cases with available laboratory data,^{9 11–14} testing positive for the anti-acetylcholinesterase (anti-AChR) antibody. Four9 11 12 25 out of the five reviewed cases who underwent thymectomy developed APAS after the procedure. A study involving a small cohort of patients with patients with MG suggests that thymectomy may be related to the development of other autoimmune diseases²⁶ because of the loss of central tolerance and overproduction of antibodies.²³ The co-occurrence of MG and APAS gives further evidence for the ‘kaleidoscope of autoimmunity’, a concept pertaining to multiple autoimmune diseases existing in the same individual or family.²⁷ Genetic factors that lead to shared pathophysiological mechanisms are postulated to underlie this phenomenon.

Table 1.

Summary of cases with myasthaenia gravis (MG) and antiphospholipid antibody syndrome (APAS)

Study author and year Patient’s age and sex	Progression of symptoms	Diagnostics for APAS and MG	Medical management	Other therapeutics and comorbid autoimmune conditions
Shoenfeld et al 9 20/F (1997)	Initial: MG symptoms of extremity weakness Interim: 3 years APAS: two abortions, one stillbirth, ischaemic stroke left MCA territory, spleen artery obstruction	(+) Anticardiolipin antibody (moderate to high positive titers) (+) Repetitive nerve stimulation (+) Anti-AChR	Warfarin	(+) Thymectomy: onset of APAS symptoms is 2 years after the procedure (+) Thymus hyperplasia Maintained on an INR of 3.0–4.0: a lower target still resulted in spleen artery obstruction
Watanabe et al 10 40/F (1997) Article in Japanese Abstract retrieved	Initial: APAS symptoms of miscarriage and pulmonary embolism Interim: 13 years MG: diplopia, ptosis and fatigability	(+) Anticardiolipin (+) Lupus anticoagulant (+) Tensilon test	Aspirin (low dose)	(+) Thymectomy: Symptoms of APAS ameliorated after the procedure
Kaji et al 11 47/F (2002)	Initial: MG symptoms of generalised weakness Interim: 17 years APAS: phlebothrombosis of the left lower extremity and ischaemic stroke left and right MCA	(+) Anti-β2 glycoprotein-I antibody (IgG high titer) (+) Anti-AChR	Prednisolone Pyridostigmine Urokinase Heparin Warfarin	(+) Thymectomy: onset of APAS symptoms is 7 years after the procedure Urokinase and heparin were given 4 days after stroke onset and continued for 2 weeks Warfarin given for 1 month only because of bleeding
Bhinder et al 12 43/F (2005)	Initial: MG Interim: not specified APAS: ischaemic stroke and femoral artery thrombus	(+) Anticardiolipin (+) Anti-AChR (+) Repetitive nerve stimulation	Azathioprine Prednisone Warfarin Pyridostigmine	(+) Thymectomy: onset of APAS symptoms is after the procedure (+) SLE was the first disease diagnosed 10 year follow-up with well-controlled disease
Dan et al 13 42/F (2014)	Initial: APAS symptoms of three abortions Interim: not specified MG: diplopia, ptosis, dysphagia and fatigable chewing	(+) Anticardiolipin antibodies (IgG and IgM low positive titers) (+) Anti-β2 glycoprotein-I antibodies (IgG and IgM moderate to high) (−) Anti-AChR (+) Repetitive nerve stimulation (−) Anti-MuSK	Azathioprine Prednisone Pyridostigmine Aspirin (81 mg daily)	(−) Thymoma (+) Transient hypothyroidism
Miskovic et al 25 48/F (2015)	Initial: MG Interim: 28 years APAS: pulmonary embolism	(+) Anticardiolipin antibody (IgG and IgM moderate to high positive titers)	Unspecified anticoagulant Mycophenolate mofetil Prednisone	(+) Thymectomy: onset of APAS symptoms is 28 years after the procedure (+) SLE: diagnosed at the same time as APAS
Minchenberg et al 14 58/F (2018)	Initial: APAS presenting with stroke Interim: not specified MG: bilateral ptosis and diplopia	(+) Lupus anticoagulant (−) Anticardiolipin (−) Anti-β2 glycoprotein-I antibody (+) Anti-AChR	Treatment for APAS and MG not specified	(+) SLE diagnosed after APAS-related stroke (+) Hydroxycholoroquine for SLE
Minchenberg et al 14 57/M (2018)	Initial: APAS presenting with pulmonary embolisms Interim: not specified MG: symptoms of ptosis, diplopia fatigue and weakness	(+) Lupus anticoagulant (−) Anticardiolipin (−) Anti-β2 glycoprotein-I antibody (+) Anti-AChR	Mycophenolate mofetil Cholinesterase inhibitor	(+) SLE diagnosed at the same time as APAS Weakness responded to mycophenolate but not to cholinesterase inhibitor (+) Hydroxycholoroquine for SLE
Diestro et al 46/F (2019) Present case	Initial: MG ptosis, three episodes of crisis Interim: 4 years APAS: stroke, left MCA territory	(+) Lupus anticoagulant (−) Anticardiolipin (+) Anti-AChR (−) Anti-MuSK	Warfarin Alteplase	(−) Thymoma (+) Intrevenous thrombolysis done for ischaemic stroke while admitted for MG crisis

AChR, acetylcholine receptor; INR, international normalised ratio; MCA, middle cerebral artery; MuSK, anti-muscle-specific kinase; SLE, systemic lupus erythaematosus.

A comprehensive neurological examination should always be done for acutely agitated patients inside the NCCU. Future research should be geared towards improving stroke quality measures by profiling acute strokes occurring inside the NCCU. Our case report suggests that rTPA followed by IVIG and cyclophosphamide may be given safely to patients in myasthaenic crisis who develop acute ischaemic stroke. We also emphasise that the development of vascular events in patients with MG should prompt a thorough investigation into other autoimmune conditions and hypercoagulable states such as APAS.

Patient’s perspective.

It was the year 2012 when I first experienced double vision. We thought my eyes were the problem. Someone told us that I should see a neurologist because I had Bell’s palsy. When I saw a neurologist, I was diagnosed with myasthaenia gravis. In December 2012, I had difficulty with swallowing and breathing. I had my first crisis then. The doctor also advised me to undergo thymectomy, but I was unable to because of financial constraints and fear of undergoing surgery.

One month after discharge from my third myasthaenic crisis my husband had a massive heart attack. He died from the heart attack maybe because he kept on thinking about wanting to get me better. I had another crisis that came with a stroke. With the help of the doctors I was saved from certain death. I sometimes feel weak but I just rely on my son because he is the only one I have left. I try to be brave and to fight my disease because that is what my husband would want if he was still alive. I getting stronger everyday. My MG has been quiet for a while. Thank you to all the doctors who do not tire of helping me and my child.

Learning points.

• Antiphospholipid antibody syndrome should be an aetiologic consideration for patients with myasthaenia gravis who develop stroke.

• Intravenous recombinant tissue plasminogen activator followed by immunomodulators may be given safely for myasthaenic patients who develop acute ischaemic stroke.

• A comprehensive neurological examination should always be done for agitated patients in the critical care unit.