Article

Reversible cerebral vasoconstriction syndrome after mRNA COVID vaccination (autopsy report)

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare neurological condition, characterized by recurrent thunderclap headaches with neuroimaging findings of multifocal vasoconstriction of cerebral arteries. In this study, the Japanese authors presented a patient who died of radiographically and pathologically confirmed reversible cerebral vasoconstriction syndrome (RCVS) one day after the third mRNA COVID (BNT162b2, Pfizer-BioNTech) vaccination.

RCVS is characterized by recurrent severe thunderclap headaches, with or without other acute neurological symptoms, and with multifocal segmental vasoconstriction of cerebral arteries that resolves spontaneously within 3 months. RCVS is typically a transient condition with a generally benign clinical course. However, certain patients may develop severe complications like an ischemic stroke and intracerebral hemorrhage. The diagnosis of RCVS requires a high clinical suspicion with recognition of typical signs and symptoms and common radiographic features. Brain scans of numerous patients diagnosed with RCVS look healthy despite the presence of diffuse vasoconstriction on concomitant cerebral angiograms. Lesions include reversible brain edema and three types of stroke: subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarction. To diagnose RCVS, cerebral angiography must demonstrate segmental narrowing and dilatation (a string of beads) of one or more arteries. Calabrese et al. established the diagnostic criteria for RCVS. (Calabrese LH, et al. Narrative review: reversible cerebral vasoconstriction syndrome. Ann Intern Med. 2007, 146:34-44.)

Endothelial dysfunction and a transient disturbance of the regulation of cerebral arterial tone are the two major pathophysiological mechanisms of RCVS currently under investigation. Sympathomimetic agents such as cannabinoids, selective serotonin reuptake inhibitors, and nasal decongestants have been identified as potential precipitants in many cases.

Approximately 50-70% of patients experience headaches after receiving the SARS-CoV-2 mRNA vaccination. The causes of headaches range from tension-type headaches to intracerebral bleeding, subarachnoid hemorrhage, or venous sinus thrombosis. There are several case reports of RCVS after mRNA vaccination; however, its pathophysiology remains poorly understood.

 

Case report

A 73-year-old man was hospitalized for acute exacerbations of chronic obstructive pulmonary disease. His medical history includes hypertension and osteoporosis, as well as giant cell arteritis. He was treated with salbutamol, ceftriaxone, and prednisolone. He developed hospital-acquired pneumonia on the 38th day of hospitalization and was treated with piperacillin and tazobactam. The patient received a third SARS-CoV-2 vaccination (BNT162b2, Pfizer-BioNTech, New York) on the 46th day after admission. The next morning, he experienced a moderate headache, tonic-clonic seizures, and a disturbance of consciousness. The neurological examination revealed a conjugate deviation of the eyes to the right.

Brain magnetic resonance imaging showed multiple vasoconstrictions of the middle and posterior cerebral arteries, without evidence of acute cerebral hemorrhage or infarction. Electroencephalography showed frequent spike activity, dominant in the right hemisphere, and diffuse high-voltage slow waves.

 

 

Original figure from the article of Shimura M et al. Head magnetic resonance angiography shows multiple vasoconstrictions involving the middle and posterior cerebral arteries (red arrows). T1-weighted (D-E), FLAIR (F-G), and diffusion-weighted (H-I) images show chronic ischemic changes without any acute intracranial hemorrhage or infarction.

 

The intravenous diazepam stopped the tonic-clonic seizures. Despite administering levetiracetam, intermittent convulsions of the left upper extremity and the left side of the face persisted. His family was opposed to any other treatment except diazepam and levetiracetam. His cognitive and cardiorespiratory conditions gradually deteriorated, and he died 40 hours after the vaccination.

 

Autopsy report

The brain autopsy revealed multiple fresh ischemic lesions in the cerebral cortices of the temporal and occipital lobes, as well as in the Ammons horns (CA1-3) on both sides of the brain.

No pathological changes were observed in the anterior lobe, basal ganglia, thalamus, brainstem, or cerebellum. There was no evidence of thrombus formation or inflammatory cell infiltration in the main cerebral arteries. Based on the findings of the autopsy, the scientists concluded that the patient had an acute ischemic brain injury, mainly in the cortex of the middle and posterior cerebral artery territories, caused by multiple vasospasms of the bilateral cortical branches of the middle and occipital cerebral arteries. RCVS has been diagnosed radiographically and pathologically.

 

Original figure from the article of Shimura M et al. Pathological examinations at autopsy (hematoxylin and eosin stain). Severe perineuronal space enlargement and many eosinophilic neurons were observed in the temporal cortex (A), CA1 (B), and CA2–3 (C) (black arrows). Conversely, no pathological changes were observed in the anterior lobe (D).

 

Possible differential diagnoses included status epilepticus, hypoxic-ischemic encephalopathy, and systemic circulatory disturbances. The hippocampal injury due to status epilepticus typically occurs in the CA1, 3, and 4 regions, whereas CA2 tends to be preserved, which is not consistent with the pathological findings in this case. There were no apparent lesions in the cerebellum or thalamus (dorsal medial nuclei), frequently affected by epilepsy. In addition, the cerebellar, visual, motor, and sensory cortices, easily affected by hypoxic-ischemic encephalopathies, remained intact in this patient.

The authors noted that they conducted a literature search in the PubMed database, and, found that their case report is the first autopsy case report of RCVS following a SARS-CoV-2 infection or vaccination. Although the underlying mechanism remains unknown, they assumed that vaccine-expressed SARS-CoV-2 spike protein interacts with angiotensin-converting enzyme 2 (ACE2), resulting in ACE2 down-regulation and an increase in the vasoconstrictive peptide angiotensin 2. This leads to vasoconstriction and RCVS.

 

Conclusion

In this study, the Japanese authors presented a patient who died of radiographically and pathologically confirmed reversible cerebral vasoconstriction syndrome (RCVS) one day after the third mRNA COVID (BNT162b2, Pfizer-BioNTech) vaccination. They recommended that imaging studies, including magnetic resonance imaging and magnetic resonance angiography, should be considered in individuals who experience headaches following the SARS-CoV2 vaccination. Future research is needed to better understand the underlying mechanism of headache and RCVS, and the adverse effects associated with the SARS-CoV-2 vaccination.

This article was published in Cureus.

 

Journal Reference

Shimura M, Fujikawa H, Yazawa M, et al. An Autopsy Case of Reversible Cerebral Vasoconstriction Syndrome After a Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination. Cureus 2024: 16(4): e59311. (April 29, 2024) (Open Access) https://www.cureus.com/articles/233306-an-autopsy-case-of-reversible-cerebral-vasoconstriction-syndrome-after-a-severe-acute-respiratory-syndrome-coronavirus-2-vaccination?score_article=true#!/

 

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