First Case Report: Acute Necrotizing Encephalopathy and Acute Fulminant Myocarditis

doi:10.21203/rs.3.rs-4737148/v1

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Case Report

First Case Report: Acute Necrotizing Encephalopathy and Acute Fulminant Myocarditis

https://doi.org/10.21203/rs.3.rs-4737148/v1

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Background: Acute necrotizing encephalopathy (ANE) is a rare condition characterized by multiple symmetrical brain lesions mainly involving the thalamus. Acute fulminant myocarditis is a diffuse inflammatory disease of the myocardium characterized by acute onset, rapid progression, and a high risk of death. Its pathogenesis involves excessive activation of the innate immune system and the formation of an inflammatory storm. Both conditions are thought to be caused by viral infections. We present a case of ANE with fulminant myocarditis. Reporting this case is important due to the rarity and the critical interplay of these two severe conditions occurring simultaneously.

Case presentation: A 16-year-old student presented with a 3-day history of high fever, cough, and expectoration, followed by multiple episodes of convulsive seizures. The patient was diagnosed with acute fulminant myocarditis. Despite high doses of vasoactive medications, the patient exhibited low blood pressure and elevated lactate levels. Portable echocardiography revealed diffuse decreased left ventricular motion with severe left ventricular dysfunction (ejection fraction < 30% by visual estimation). The patient remained comatosewith a Glasgow coma scale (GCS) score of 3 (E1V1M1).Brain CT and MRI revealed bilateral striatal, thalamic, and brainstem lesions, typical of ANE. Consequently, a diagnosis of ANE accompanied by fulminant myocarditis was considered. The treatment regimen included high doses of glucocorticoids, immunoglobulins, tocilizumab, and V-A ECMO (Veno-arterial extracorporeal membrane oxygenation) life support. The patient showed significant recovery of cardiac function and was discharged after approximately 24 days of rehabilitation.

Conclusion: This case report highlights the coexistence of ANE preceded by acute fulminant myocarditis. The underlying mechanisms remain unclear. Early recognition of these two conditions is crucial for prognosis, though challenging. This report underscores the need for heightened awareness and prompt, comprehensive treatment strategies to improve outcomes in such complex cases.

Acute necrotizing encephalitis

Acute fulminant myocarditis

Shock

Acute necrotizing encephalopathy(ANE)is a rare, acute, life-threatening condition characterized by symmetrical brain lesions affecting the thalami, putamina, cerebral and cerebellar white matter, and brain stem tegmentum following various viral illnesses [1, 2]. Acute fulminant myocarditis (FM) is a rapid progressing, acute diffuse inflammatory disease of the myocardium with a high risk of death [3]. Fulminant myocarditis can be caused by infections, toxins, drug toxicities, or autoimmune diseases [4]. Infection is the most common cause of the disease, and viruses are the predominant pathogens [2, 4]. Here, we report a case of ANE accompanied by fulminant myocarditis. To the best of our knowledge, this is the first reported case of FM complicated by ANE.

A 16‑year‑old student presented to the emergency department of a local hospital with a 3-day history of high-grade fever, cough, and expectoration, followed by multiple episodes of convulsive seizures. The patient had no underlying disease, significant family history, or current medications. Clinical examination revealed a comatose patient with a Glasgow Coma Scale (GCS) score of 6/15. She was intubated due to the low GCS and transferred to the intensive care unit. Simultaneously, the patient experienced a rapid decrease in blood pressure and an increase in lactate levels. Despite high doses of vasoactive medications, she maintained low blood pressure and elevated lactate levels. The doses of norepinephrine and dopamine administered were 1.5 ug/kg/min and 10 ug/kg/min, respectively. Consequently, her physician contacted us for extracorporeal membrane oxygenation (ECMO). The patient was then transported to our hospital on veno-arterial (V-A) ECMO.

Portable echocardiography revealed diffuse decreased left ventricular motion with severe left ventricular dysfunction (ejection fraction (EF) < 30% by visual estimation). Laboratory findings showed marked elevated cardiac troponin I (3.814c ng/ml), serum creatine phosphokinase isoenzyme (CK-MB) (26.54 ng/ml), N-terminal pro-brain type natriuretic peptide (>35000 pg/ml), and D-dimer (>20 ug/ml). Mycoplasma antibody was also positive. The patient had acute liver failure, acute kidney injury, and coagulation dysfunction. Laboratory test results are presented in Table 1.

Table 1

The evolution of the laboratory test results carried out at the local hospital (on 24 October 2023) versus our hospital (on 25 October 2023)
	24 October 2023	25 October 2023
TnI(ng/ml)	3.814	4.7
NT-proBNP (pg/ml)	>35000	20000
Leukocytes (10*10∧9/L)	10.82	6.53
Hemoglobin (g/L)	130	95
Platelets (10*10∧9/L)	75	37
CRP (mg/L)	ND	25.9
PCT (ng/ml)	9.76	6.39
Il-6 (pg/ml)	131	21.9
ALT (U/L)	2234	3219
AST (U/L)	5779	1532
Albumin (g/L)	31.8	25.3
BUN (mmol/L)	10.9	8.99
Cr (mmol/L)	129	104.4
NA+ (mmol/L)	148	144.8
LDH (U/L)	5851	3315
Glucose (mmol/L)	6	8.1
PT (s)	32	40.3
Fibrinogen (g/L)	0.346	0.4
D-dimer (ug/ml)	193	253
Lactate (mmol/L)	9.58	10.8
Tn: troponin I, NT-pro-BNP: N-terminal pro-brain natriuretic peptide, CRP: C-reactive protein, PCT: procalcitonin, ND: not performed, BUN: blood urea nitrogen; Cr: creatinine, LDH: Lactate dehydrogenase, PT: Prothrombin time.

[Insert Table 1 here]

On admission, vital signs were as follows: temperature: 36.9℃, heart rate: 114 bpm, respiratory rate: 13 cpm, blood pressure: 84/73 mmHg, SPO2: 98%. The GCS was graded 3 (E1V1M1). The pupils were symmetric in size but unreactive to light.

The treatment regimen included ECMO support, ventilatory support, azithromycin anti-infection therapy, methylprednisolone, and immunoglobulin. After treatment, cardiac function recovered up to 38% of EF on the sixth day of ECMO therapy, and the patient was weaned from ECMO 6 days after treatment initiation.

On the third day of admission, sedation and analgesia were discontinued, but the patient remained in a coma with a GCS score of 3. Lumbar puncture revealed an opening pressure of 130 mmH2O. Cerebrospinal fluid (CSF) analysis revealed an elevated erythrocyte count of 20×10⁶/L with a normal leukocyte count. CFS protein levels were elevated. CSF glucose, and chloride levels were normal, and the culture and cytology of the CSF were negative. Laboratory test results are presented in Table 2.

Table 2

Relevant serum and CSF studies in our patient
Infectious		Immunologic
HBV	Negative	Antinuclear antibody	Negative
HIV	Negative	C3 Complement
Syphilis	Negative	C4 Complement
EBV IgG/DNA	Negative	IgG
CMV DNA	Negative	IgM
SRSA-COV-2 PCR	Negative	IgA
Respiratory Viral PCR*	Negative	IgE
Respiratory Viral IgM**	Negative
Mycoplasma Pneumonia IgG/M	positive/weakly Positive
Genetics	RANBP2	Negative
CSF	Basic	Infectious
Glucose (mmol/L)	4.31	Bacterial and fungal culture	Negative
Protein (g/L)	0.81	Next Generation Sequencing	Negative
RBC (10*10⁹/L)	25	Ink stain	Negative
WBC (10*10⁹/L)	2	Acid-fast stain	Negative
HBV: Hepatitis B Virus, HIV: human immunodeficiency virus, EBV: Epstein–Barr virus, IgG: Immunoglobulin G, CMV: cytomegalovirus, IgM: Immunoglobulin M, SARS-COV-2: severe acute respiratory syndrome coronavirus disease 2019, IgA: Immunoglobulin A, PCR: polymerase chain reaction, IgE: Immunoglobulin E DNA: deoxyribonucleic acid, WNL: within normal limits, RANBP2: RAN-binding protein 2. Adenovirus, influenza A&B, respiratory syncytial virus (RSV), and Mycoplasma pneumoniae. * Echovirus, Coxsackievirus, adenovirus, respiratory syncytial virus (RSV), parainfluenza virus-1,2,3, and Chlamydia pneumoniae.

[Insert Table 2 here]

Brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed lesions involving the bilateral striatum, thalamus, and brainstem, typical for ANE (Fig. 1A, B.) A diagnosis of ANE accompanied by fulminant myocarditis was considered. Therefore, tocilizumab was included in the treatment regimen.

On the tenth day of admission, the patient began to regain consciousness. She was transferred to a general ward after 13 days. Echocardiography showed a significant improvement in left ventricular function (EF = 61%). The patient was discharged after approximately 24 days of rehabilitation. At the time of discharge, the patient could walk and speak clearly. She was discharged with a prescription for cardioprotective agents, including metoprolol, sacubitril/valsartan, spironolactone, furosemide, and dapagliflozin.

ANE is a rare encephalopathy more commonly seen in children. Most cases of ANE are sporadic, although familial ANE, caused by missense mutations in the RANBP2 gene, has been reported [5, 6]. ANE typically arises secondary to neurological complications of influenza or other viral infections and is characterized by altered mental status and seizures [1, 5, 7]. The disease progresses rapidly and often results in severe disability or death. It is usually preceded by fever and respiratory or gastrointestinal system symptoms. Characteristic neuro-radiologic findings include multifocal and symmetric lesions, mainly affecting the bilateral thalami, cerebral periventricular white matter, brainstem tegmentum, and cerebellum [1, 8].

The most common hypothesis for the pathogenesis of ANE is a "cytokine storm” involving interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-10, IL-15, and IL-1β, among others [7]. Treatment of ANE is mainly supportive, with early high-dose intravenous steroids (methylprednisolone) leading to better outcomes. Tocilizumab may also be beneficial in improving morbidity outcomes [7, 9–11]. Additionally, plasma exchange has been associated with increased survival in patients with ANE.

Fulminant myocarditis is mainly caused by a variety of viral infections and is characterized by the rapid onset of cardiogenic shock [3, 12]. In this case, the patient exhibited features such as sudden onset, rapid emergence of severe hemodynamic disorders, severe myocardial injury, and diffuse decreased ventricular wall movement, aligning with the diagnostic criteria of fulminant myocarditis [3]. Viral infection is considered a major cause of acute myocarditis [3, 12–15], Coxsackie B virus, adenovirus, and influenza virus being the most common pathogens. In fulminant myocarditis, indirect damage caused by abnormal immune system activation, excessive macrophage polarization, and aggregation in tissues and organs is an important pathophysiological mechanism leading to the rapid disease deterioration [3, 12]. The cellular and humoral immune response to viral infection stimulates infiltrative inflammatory and tissue cells to release a substantial cascade of cytokines, such as IL-1, IL-6, endothelial adhesion molecules, TNF-α [3, 15], which damages the myocardium. Active comprehensive treatment should be initiated as soon as possible for fulminant myocarditis, including anti-infection, antiviral therapy, glucocorticoids, gamma globulin, plasma and blood purification, life support measures, and general treatment to nourish the myocardium and reduce cardiac load, etc.) [3, 4, 15].

To the best of our knowledge, this is the first reported case of the coexistence of fulminant myocarditis and ANE. For this patient, we administered high doses of glucocorticoids, immunoglobulins, tocilizumab, and V-A-ECMO life support. Laboratory tests showed positive mycoplasma antibodies, and azithromycin was administered to treat the infection.

In conclusion, we report a case of ANE associated with fulminant myocarditis. Physicians should be aware of this uncommon but life-threatening complication when patients with fulminant myocarditis develop consciousness disturbances.

Patient perspective

I was afraid of such a serious illness all of a sudden. But I am also lucky that I am now fully back to my normal life with no after-effects.

ANE: Acute necrotizing encephalopathy; CK-MB: Creatine phosphokinase isoenzyme; CSF: Cerebrospinal fluid; CT: Computed tomography; ECMO: Extracorporeal membrane oxygenation; EF: Ejection fraction; FM: fulminant myocarditis; GCS: Glasgow Coma Scale; IL: Interleukin; MRI: Magnetic resonance imaging; SpO2: Peripheral Capillary Oxygen Saturation; TNF-α: Tumor necrosis factor-alpha; V-A ECMO: Veno-arterial extracorporeal membrane oxygenation

Ethics approval and consent to participate

The study is approved by ethics committee of the First Hospital of Lanzhou University.

Consent for publication

Written informed consent was obtained from the patient’s parent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

This research received no specific funding.

Authors' contributions

J.M.: initial manuscript preparing, patient managing;

C.L.P.: revising manuscript;

N.B.: literature review;

S.S.Z.: literature review;

P.L.M.: image editing;

Y.L.W.: table editing;

A.D.L.: reviewing and revising manuscript, final approval of the manuscript to be submitted

All authors have read and approved the final manuscript of “First case report: Acute Necrotiziing Encephalopathy and Acute Fulminant Myocarditis.”

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Authors' information

¹Department of Cardiovascular Medicine, the First Hospital of Lanzhou University, Chengguan District, 1 Donggang East Road, Lanzhou, Gansu, China

Declaration of the use of generative AI

Not applicable.

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No competing interests reported.

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First Case Report: Acute Necrotizing Encephalopathy and Acute Fulminant Myocarditis

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Patient perspective

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