Splenic Hemorrhage and Cytotoxic Lesions Induced by SARS-CoV-2 Cytokine Storm: Pathophysiology, Imaging, Diagnosis, and Clinical Implications

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Introduction

Since the emergence of the coronavirus disease 2019 (COVID-19) pandemic, increasing evidence has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs beyond the respiratory tract. One of the most striking neurological complications observed is the occurrence of splenic hemorrhage cytotoxic lesions within the central nervous system (CNS), particularly involving the splenium of the corpus callosum. These lesions are thought to be mediated by a cytokine storm, a hyperinflammatory immune response driven by SARS-CoV-2 infection.

This article provides a comprehensive review of the pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, diagnostic approaches, treatment strategies, and prognosis of SARS-CoV-2-induced splenic hemorrhage cytotoxic lesions, supported by the latest global literature.

Case Review Summary

A 73-year-old male with no previous cardiovascular or respiratory disease presented to the emergency department with high fever (38°C), progressive dyspnea, and later, confusion. He was admitted to the intensive care unit for suspected COVID-19.

  • Initial CT scan revealed subtle hyperdense lesions in the splenium of the corpus callosum, suggestive of hemorrhage.

  • MRI studies further characterized the lesion, ruling out arterial occlusion and venous thrombosis.

  • Laboratory data revealed elevated ferritin, consistent with cytokine storm.

  • Differential diagnoses included splenial artery stroke, demyelinating lesions (ADEM), and SARS-CoV-2-induced cytotoxic lesions.

  • The patient received mechanical ventilation, antiviral therapy, anticoagulation prophylaxis, and supportive treatment.

Figures


Figure 1. CT Non-Contrast Scan; Findings: Subtle hyperdense lesion in the splenium, suspicious for hemorrhage.


Figure 2. MRI Scan; Findings: Cytotoxic lesion of the splenium with exclusion of arterial/venous occlusion using 2D TOF and post-contrast MP-RAGE sequences.

Pathophysiology

Cytotoxic lesions of the splenium are strongly associated with massive cytokine release in SARS-CoV-2 infection. Key mechanisms include:

  1. Cytokine storm: Elevated levels of IL-6, TNF-α, IL-1β, and ferritin trigger endothelial dysfunction, blood-brain barrier breakdown, and localized hemorrhage.

  2. ACE2 receptor-mediated invasion: SARS-CoV-2 enters neurons and endothelial cells via ACE2, facilitating direct CNS invasion.

  3. Neurotropic spread: Viral particles have been detected in the olfactory bulb, thalamus, and medulla, explaining anosmia, ageusia, and altered consciousness.

  4. Hypercoagulability: COVID-19-associated coagulopathy predisposes to microthrombi, ischemia, and hemorrhage.

  5. Metabolic & hypoxic stress: Severe hypoxia, fever, dehydration, and malnutrition exacerbate neuronal injury.

Epidemiology

  • Exact incidence is unknown; however, recent MRI-based studies show splenial involvement in 2–3% of hospitalized COVID-19 patients with neurological symptoms.

  • More common in elderly patients, males, and those with comorbidities such as diabetes, hypertension, or cardiovascular disease.

  • Associated with severe COVID-19 requiring ICU care.

Clinical Presentation

Patients typically present with:

  • Altered mental status (confusion, delirium, encephalopathy)

  • Fever and respiratory distress

  • Seizures (occasionally reported)

  • Neurological deficits (rare but possible, including weakness or ataxia)

Imaging Features

  • CT Scan: Subtle hyperdense lesions in the splenium; difficult to detect in early stages.

  • MRI:

    • Diffusion restriction on DWI/ADC sequences (hallmark cytotoxic lesion)

    • T2/FLAIR hyperintensity

    • Exclusion of vascular occlusion with TOF and MP-RAGE sequences

  • No mass effect (distinguishes from large hemorrhage or tumor).

Differential Diagnosis

  1. Splenial artery infarction

  2. ADEM (acute disseminated encephalomyelitis)

  3. Metabolic encephalopathy (e.g., hypoglycemia)

  4. Drug-related toxic encephalopathy

  5. Acute necrotizing encephalopathy (ANE)

Diagnosis

  • Combination of neuroimaging, laboratory markers (ferritin, CRP, IL-6), and clinical context of COVID-19.

  • Exclusion of other vascular or demyelinating conditions.

  • Confirmatory evidence: Positive RT-PCR for SARS-CoV-2 in respiratory or CSF samples.

Treatment

  • Supportive ICU care: Oxygenation, ventilation, sedation.

  • Antiviral therapy: e.g., remdesivir (in recent protocols; older regimens included hydroxychloroquine, lopinavir/ritonavir).

  • Immunomodulation: Corticosteroids, IL-6 inhibitors (tocilizumab) in cytokine storm.

  • Anticoagulation: Prophylactic LMWH to reduce thromboembolic risk.

  • Neuroprotective support: Fluids, nutrition, antipyretics, metabolic correction.

Prognosis

  • Generally favorable if recognized early; many splenial lesions are transient and reversible.

  • Severe cases with hemorrhage or multi-organ failure carry a poor prognosis.

  • Long-term neurological sequelae remain under investigation.

Quiz

Q1. What is the most common imaging feature of SARS-CoV-2-induced splenic cytotoxic lesion?

A. Mass effect in splenium

B. Diffusion restriction on MRI

C. Calcification

D. Ring-enhancing lesion

Q2. Which laboratory marker is most strongly associated with cytokine storm in COVID-19?

A. Lactate 

B. Ferritin

C. Bilirubin

D. Calcium

Q3. What is the primary receptor mediating SARS-CoV-2 entry into the CNS?

A. NMDA receptor

B. ACE2 receptor

C. GABA receptor

D. AMPA receptor

Q4. Which of the following is NOT a common differential diagnosis of splenial cytotoxic lesions?

A. ADEM

B. Hypoglycemia-induced encephalopathy

C. Glioblastoma multiforme

D. Splenial artery stroke

Q5. What is the expected prognosis of most COVID-19-related splenial cytotoxic lesions?

A. Fatal in majority

B. Permanent disability

C. Transient and reversible

D. Progressive deterioration

Answer & Explanation

1. Answer: B. Diffusion restriction on MRI. Explanation: Cytotoxic lesions typically show restricted diffusion, unlike mass effect or calcification.

2. Answer: B. Ferritin. Explanation: Hyperferritinemia is a hallmark of cytokine storm.

3. Answer: B. ACE2 receptor. Explanation: ACE2 receptors are expressed in endothelial and neuronal cells.

4. Answer: C. Glioblastoma multiforme. Explanation: Tumors typically present with mass effect, not isolated splenial cytotoxic lesions.

5. Answer: C. Transient and reversible. Explanation: Many cases resolve with supportive and immunomodulatory treatment.

References

[1] S. Ellul, et al., “Neurological associations of COVID-19,” Lancet Neurol., vol. 19, no. 9, pp. 767–783, 2020.
[2] P. Kremer, et al., “Brain MRI findings in severe COVID-19: A retrospective observational study,” Radiology, vol. 297, no. 2, pp. E242–E251, 2020.
[3] N. Radmanesh, et al., “Cytotoxic lesions of the corpus callosum in COVID-19 patients,” J. Neurol. Sci., vol. 418, 117103, 2020.
[4] J. Helms, et al., “Neurologic features in severe SARS-CoV-2 infection,” N Engl J Med., vol. 382, pp. 2268–2270, 2020.
[5] H. Kandemirli, et al., “Brain MRI findings in intensive care unit patients with COVID-19,” Radiology, vol. 297, pp. E232–E235, 2020.
[6] S. Toscano, et al., “Neurological complications of COVID-19,” BMJ Case Rep., 2020.
[7] T. Zanin, et al., “SARS-CoV-2 and the nervous system: From pathogenesis to clinical manifestations,” J. Neurol. Sci., vol. 414, 116884, 2020.

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