A 60-year-old right-handed male presented to a peripheral hospital with progressive weakness in August 2022. Past medical history included hypertension, dyslipidemia, type-2 diabetes and degenerative disc disease. Home medications included acetylsalicylic acid, ramipril, atorvastatin, metformin and gliclazide. For a visual timeline of clinical events and key investigations, see Figure 1 and Table 1, respectively. The patient experienced acute-onset left leg cramping pain and weakness. Over the following days, pain and weakness spread to his left arm and then right leg, and on day 4, he presented to the hospital. He denied chest pain, palpitations, vision changes, sensory loss, vertigo or oscillopsia. There was no preceding illness, sick contact, travel, immunization or exposure to toxins or spoiled food. He was an ex-smoker, drank alcohol rarely and denied drug use. There was a family history of myocardial infarction (father and paternal grandfather). On presentation, he was hypertensive (204/109 mmHg) but otherwise stable (heart rate 82/minute, respiratory rate 17/minute, SPO₂ 97% and temperature 36.7° C). The hospitalist identified left-sided face-sparing hemiparesis and admitted the patient for possible acute ischemic stroke. CT of the head and spine and CTA of the neck were unrevealing. The next day, he awoke with painful quadriparesis, dysarthria and dysphagia, orthopnea and urinary retention and constipation. He was transferred by air to the provincial neurology service overnight, during which he developed hypoxemia (PaO₂ 70 mmHg) and worsening hypertension (232/110 mmHg).

Figure 1. Timeline of clinical events and key investigations. Abbreviations: ABG = arterial blood gas; CK = creatinine kinase; CTA = computed tomography angiogram; CXR = chest X-ray; ECG = electrocardiogram; EMG/NCS = electromyography/nerve conduction studies; ER = emergency room; LVEF = left ventricular ejection fraction; MMI = medial medullary infarction; NMJ = neuromuscular junction; TTE = transthoracic echocardiogram; TA = tibialis anterior.

Table 1. Results of relevant investigations during clinical timeline

Note: key positive findings are indicated in bold text.

CMAP = compound muscle action potential; CTA = computed tomography angiogram; ECG = electrocardiogram; EMG = electromyography; FLAIR = fluid-attenuated inversion recovery; LV = left ventricle; LVEF = left ventricular ejection fraction; MRA = magnetic resonance angiogram; MUAP = motor unit action potential; NCS = nerve conduction studies; TTE = transthoracic echocardiogram.

When we received the patient the following morning, he was hypertensive (180/80 mmHg) on labetalol infusion (0.5 mg/min, heart rate 62/minute). He was distressed and could not tolerate lying flat. He required nasal oxygen (4 L/min, SPO₂ 98%) and demonstrated rapid, shallow respirations (24/min) with accessory muscle use, interspersed with gasps and brief apneic periods. Neurologic examination identified diminished eye abduction and horizontal gaze-evoked nystagmus bilaterally, bilateral eye and mouth closure weakness and hypophonic and dysarthric speech without tongue or palate asymmetry. There was neck flexion and extension weakness and flaccid quadriparesis (power was 0/5). Reflexes were normal (2+), and there were bilateral extensor plantar responses. Light touch, pinprick, vibration and proprioception were preserved. Routine investigations (complete blood count, creatinine, electrolytes, C-reactive protein, coagulation studies, creatine kinase, cardiac troponin and ECG) were unremarkable.

Because of acute-onset, painful and progressive quadriparesis with respiratory weakness and multiple cranial nerve involvement, our primary concern was acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Bilateral extensor plantar responses with preserved reflexes and dysautonomia were concerning for Guillain-Barré syndrome (GBS) subtypes like Bickerstaff brainstem encephalitis or acute pandysautonomia. We also considered acute disseminated encephalomyelitis, pontomedullary infarct, other neuromuscular conditions (e.g., botulism and myasthenia gravis) and neuroinfectious processes (e.g., West Nile virus). Lumbar puncture, performed for AIDP workup, revealed mild CSF albuminocytologic dissociation. Chest X-ray, bedside spirometry and arterial blood gas confirmed imminent risk of respiratory failure. We consulted ICU, who intubated the patient that afternoon. To assess for AIDP, we performed electrodiagnostic studies the next morning, after he was stabilized in the ICU. While sensory and motor nerve conduction studies revealed borderline conduction slowing, there was absent tibialis anterior voluntary activation on needle EMG, raising our concern for CNS insult. We requested an MRI of the brain, which revealed a “heart-shaped” region of T2/FLAIR hyperintensity and restricted diffusion in the bilateral medial medullae favoring subacute infarct (Figure 2).

Figure 2. Bilateral medial medulla infarction (MMI). On symptom day eight, an unenhanced MRI brain was performed on a Siemens 1.5 T MRI scanner (5 mm slice thickness), including sagittal T1 and axial T1, T2, Diffusion-Weighted Imaging (DWI)/Apparent Diffusion Coefficient (ADC), Fluid-Attenuated Inversion Recovery (FLAIR), Gradient-Echo (GRE), and Proton Density (PD) sequences. We did not request an MR angiogram. The brain MRI revealed a region of T2/FLAIR hyperintensity and restricted diffusion in the bilateral medial medullae, with a “heart-shaped” appearance, favoring subacute bilateral ventromedial medulla infarction. There was no evidence of pontine involvement. There were additional scattered punctate areas of subcortical white matter T2/FLAIR hyperintensity, representative of leukoaraiosis. (A) Fluid-attenuated inversion recovery, (B) diffusion-weighted imaging (DWI), and (C) ADC MRI sequences, showing evidence of bilateral MMI. Restricted diffusion in the bilateral ventromedial medulla has a pathognomonic heart-shaped appearance (“heart sign”) ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7} .

On day nine, cardiac monitoring demonstrated frequent premature ventricular complexes. Electrocardiogram (ECG) revealed inferior ST elevation and precordial ST depression, and cardiac enzymes suggested inferior myocardial infarction (MI), which was corroborated by transthoracic echocardiogram. Cardiology was consulted for inferior ST-segment elevation myocardial infarction (STEMI). They did not opine whether MI was the result of coronary artery plaque rupture (Type-1 MI) or demand ischemia (Type-2 MI), and the patient was not a candidate for cardiac catheterization. Conservative management, with dual antiplatelet therapy, beta-blockers, antihypertensives and IV nitroglycerin, was recommended. The patient was unable to breathe without ventilator support and was sedated with propofol for agitation caused by intubation. On day 10, propofol could be temporarily weaned with adjunctive dexmedetomidine, and the patient could communicate only using eyeblinks. To discuss goals of care with the patient and his family, sedation was again weaned the next day. The decision was made to withdraw care, and he died several hours later.

Bilateral medial medullary infarction (MMI) is a rare, heterogeneous and devastating stroke syndrome. Unilateral MMI was described by Dejerine (1914) as a triad of ipsilateral hypoglossal weakness, contralateral face-sparing hemiparesis and contralateral loss of deep sensation. ^{Reference Dejerine1} Features of “Dejerine syndrome” are attributed to involvement of the pyramidal tract and medial lemniscus above the medullary decussation, and the adjacent hypoglossal nucleus or fascicles, ^{Reference Gan and Noronha2} caused by occlusions of the anterior spinal artery or small perforating branches of the vertebral or proximal basilar arteries. ^{Reference Sciacca, Lynch, Davagnanam and Barker3} Bilateral MMI accounts for 0.02%–0.09% of ischemic strokes, ^{Reference Akimoto, Ogawa, Morita, Suzuki and Kamei4–Reference Toyoda, Imamura and Saku6} and prototypically involves acute-onset quadriparesis, loss of deep sensation, hypoglossal palsy and bulbar dysfunction, with or without respiratory failure. ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7} Acute-onset, painful and progressive quadriparesis, respiratory and bulbar weakness, bowel and bladder dysfunction and dysautonomia raised our concern for GBS. These findings are all among the clinical spectrum of bilateral MMI, which includes hemiparesis or quadriparesis, dysarthria, dysphagia, hypoglossal weakness, facial weakness, nystagmus, ophthalmoparesis, ataxia, Horner syndrome and respiratory failure. ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7} Two-thirds of cases have quadriparesis at onset, and another 20% develop quadriparesis within 72 hours. ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7} As with GBS, 25% develop respiratory failure. ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7}

Due to the heterogeneous clinical features of bilateral MMI, there is a broad differential diagnosis. There are cases describing bilateral MMI mimicking AIDP or acute motor axonal neuropathy. ^{Reference Ali, Amir and Akhtar8–Reference Gupta, Choudhary, Aggarwal and Sheoran12} After GBS, we considered acute disseminated encephalomyelitis, other neuromuscular conditions (e.g., botulism and myasthenia gravis) and neuroinfectious processes (e.g., West Nile virus). Others considered infectious or autoimmune rhombencephalitis, multiple sclerosis, myasthenia gravis, botulism or brainstem glioma. ^{Reference Ali, Amir and Akhtar8–Reference Lankapothu, Kumar, Dasi, Bhaskaran and Bathena13} GBS-acquired CNS demyelinating overlap syndrome should also be considered. ^{Reference Mao and Hu14} In a systematic review of bilateral MMI, MRI revealed T2/FLAIR hyperintensity or restricted diffusion of the bilateral medial medullae in all patients, despite 38% having normal angiography. ^{Reference Pongmoragot, Parthasarathy, Selchen and Saposnik7} Other authors required MRI with DWI to make a definitive diagnosis. ^{Reference Ali, Amir and Akhtar8–Reference Lankapothu, Kumar, Dasi, Bhaskaran and Bathena13}

To our knowledge, this is the first report of STEMI after bilateral MMI. Lateral medulla infarction with respiratory and cardiac complications has been described. ^{Reference Lassman and Mayer15} Respiratory failure may result from injury to the dorsal or ventral respiratory groups, while injury to the intermediate reticular group or nucleus tractus solitarius may cause dysautonomia leading to coronary vasospasm and Type-2 MI. ^{Reference Lassman and Mayer15} There is a relatively high incidence of myocardial injury after acute ischemic stroke: between 3% for MI, 27% for elevated troponin levels, and 50% for ECG changes. ^{Reference Nolte, von Rennenberg and Litmeier16 –Reference Mihalovic and Tousek18} In patients with elevated troponin after acute ischemic stroke, the incidence of acute MI is approximately 50%. ^{Reference Nolte, von Rennenberg and Litmeier16,Reference Mihalovic, Mikulenka and Linkova17} Literature suggests stroke is a risk factor for MI, independent of shared vascular risk factors. ^{Reference Mihalovic and Tousek18,Reference Sun, Zhang and Liu19} Myocardial injury after stroke is hypothesized to be caused by hypothalamic-pituitary-adrenal axis disruption causing excess catecholamine release, systemic inflammatory and immune activation and possibly gut-vascular translocation of microbiota and endotoxins – all leading to cardiomyocyte metabolic derangement and injury. ^{Reference Nolte, von Rennenberg and Litmeier16,Reference Mihalovic and Tousek18} Immune dysregulation after stroke may also increase the risk of atherosclerotic plaque rupture causing coronary occlusion. ^{Reference Mihalovic and Tousek18} In all cases, there is heightened risk of future major adverse cardiovascular events (recurrent stroke or MI), all-cause mortality and poor functional recovery. ^{Reference Mihalovic, Mikulenka and Linkova17,Reference Mihalovic and Tousek18}

Presently, we hypothesize the patient experienced small vessel atherosclerosis of the anterior spinal or basilar artery perforating branches, causing infarction of brainstem motor tracts and respiratory and autonomic centers. Acute-onset progressive quadriparesis; facial, bulbar and ocular weakness; respiratory failure and preserved reflexes with bilateral upgoing plantar responses suggested injury to the corticospinal and corticobulbar tracts and potentially respiratory centers. MI may have been secondary to coronary vasospasm due to involvement of brainstem autonomic centers. In future cases of suspected neuromuscular emergency with features atypical of neuromuscular disease (i.e., preserved reflexes, normal sensation and bilateral upgoing plantar responses), bilateral MMI should be considered and brain MRI performed.