
==== Front
BMC Neurol
BMC Neurol
BMC Neurology
1471-2377
BioMed Central London

3860
10.1186/s12883-024-03860-4
Case Report
Febrile neutropenia induced by adjuvant radiotherapy for a patient with breast cancer accompanied with reversible splenial lesion syndrome (RESLES, TypeI): a case report
Qi Xiao 123
Zou Dandan 123
Zhang Miao zhangmiao810208@126.com

123
Wang Huaqing huaqingw@163.com

123
1 https://ror.org/01y1kjr75 grid.216938.7 0000 0000 9878 7032 Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
2 Tianjin Cancer Institute of lntegrative Traditional Chinese and Western Medicine, Tianjin, China
3 https://ror.org/01y1kjr75 grid.216938.7 0000 0000 9878 7032 3The Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, China
19 9 2024
19 9 2024
2024
24 35318 5 2024
10 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Reversible splenial lesion syndrome (RESLES) is known as a neuro-imaging syndrome with recurrent but reversible lesion of the corpus callosum, characterized by nonspecific but usually mild encephalopathies and specific imaging manifestations.There are few published reports in the field of oncology.

Case presentation

A 33-year-old female with right breast cancer and with no particular family history was admitted to hospital with high fever and severe headache, after receiving adjuvant radiotherapy. Blood routine test upon admission suggested neutropenia, considering myelosuppression associated with radiotherapy. There were no definite findings of common pathogenic microorganism, and no imaging indication of certain infectious sites other than a likely reversible corpus callosum syndrome suggested by brain MRI, which was relieved after systemic antibiotic therapy and granulocyte colony-stimulating factor injection.

Conclusions

Reversible splenial lesion syndrome is a kind of clinical-imaging syndrome with multiple clinical manifestations and etiologies. This breast cancer patient after postoperative adjuvant radiotherapy develops a complication of RESLES that rings an alarm bell to the oncologists not to easily recognize the corpus callosum lesion as infarction or metastasis. Meanwhile, the potential pathogenic mechanisms need to be explored further.

Keywords

Febrile neutropenia
Reversible corpus callosum syndrome
Breast cancer
Radiotherapy
Infection
Tianjin Key Medical Discipline (Specialty) Construction ProjectTJYXZDXK-053B TJYXZDXK-053B TJYXZDXK-053B TJYXZDXK-053B Tianjin Health Research ProjectTJWJ2023MS013 http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82070206 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Reversible splenial lesion syndrome (RESLES) is known as a neuro-imaging syndrome with recurrent but reversible lesion of the corpus callosum, characterized by nonspecific but usually mild encephalopathies and specific imaging manifestations [1]. It usually occurs in children, with adult cases rarely reported [2]. RESLES was initially reported to be associated with anti-seizure medication (ASM) withdrawal [3], and infection was later reported to be a common precipitating factor, as well as encephalitis, epileptic seizures and certain metabolic disorders, such as hypoglycemia and hypernatremia [4]. The gold standard for the diagnosis of reversible splenial lesion syndrome is brain MRI which usually shows high signal in diffusion-weighted imaging (DWI) and T2-weighted imaging(T2WI ) sequence and low signal in apparent diffusion coefficient (ADC), which is caused by cytotoxic edema formation, with the mechanism of which not yet well understood, maybe due to the myelin cytotoxic edema, water-electrolyte imbalance, and transient inflammatory response [5]. There has been a gradual increase in the number of case reports on the occurrence of RESLES, which enriched the awareness of the disease [6]. However, there are few published reports in the field of oncology. By conducting this case report, we aim to draw attention to cancer patients accompanied with reversible corpus callosum syndrome to possibly avoid misdiagnosis and excessive medical care. This case is reported according to CARE guidelines.

Case presentation

The patient is a 33-year-old female who underwent a breast-conserving surgery and pathological diagnosis indicated invasive carcinoma, non-specific type, histological grade 2 with negative surgical margins. Immunohistochemistry: ER (3+), PR focal (+), HER-2(3+), Ki67 positive index 50%, Metastatic cancer was seen in 1 lymph node of the total 11 right axillary lymph nodes(1/11). Considering the diagnosis of right breast cancer, T2N1M0, stage IIB, the postoperative treatment plan was formulated as AC-TH regimen: chemotherapy (4 cycles of doxorubicin liposome + cyclophosphamide every 3 weeks, 4 cycles of paclitaxel combined with anti-HER2-targeted therapy every 3 weeks, and 1 year of anti-HER2-targeted maintenance therapy) with sequential radiotherapy and endocrine therapy. After radiotherapy, the patient suffered from high fever with a maximum temperature of 40℃, without obvious sore throat and runny nose, cough and sputum, chest tightness and chest pain, abdominal pain and diarrhea, urinary frequency or pain, or other infectious manifestations, but accompanied by a heavy headache, without dizziness, blurred vision. She was finally admitted to hospital 1 week after finishing the radiotherapy(Fig. 1). Physical examination showed no obvious positive signs, especially though the patient has fever and severe headache, the patient’s showed no abnormalities in neurological examination and exhibited no signs of meningeal irritation.

Fig. 1 Timeline of antitumor therapy

Laboratory examinations(Table 1): blood routine test revealed a neutropenia of 2.5 × 10^9/L, with rapid c-reactive protein(31.05 mg/L) and calcitoninogen(0.13 ng/mL) slightly elevated, liver and kidney function, blood sodium, blood chloride and other electrolyte levels are normal. Respiratory pathogens: Influenza A virus RNA, Influenza B virus RNA, respiratory syncytial virus RNA, adenovirus DNA, human rhinovirus RNA, Mycoplasma pneumoniae DNA, and COVID-19 RNA were all negative. Blood culture of aerobic and anaerobic bacteria was also negative; 1,3-beta-D Glucan and GalactoMannan tests were negative. Especially there was no obvious abnormity in intracranial pressure and cerebrospinal fluid test. Abdominopelvic CT scan: no significant abnormality. brain MRI: a patchy corpus callosum lesion with high signal in diffusion-weighted imaging (DWI) and low signal in apparent diffusion coefficient (ADC)(Fig. 2A1-E1).

Table 1 Indicators of laboratory tests

Peripheral blood analysis	Initials	Index	Normal range	
White blood cell count (/L)	WBC	2.50 × 10^9	3.5–9.5 × 10^9	
Red blood cell count (/L)	RBC	3.79 × 10^12	3.8–5.1 × 10^12	
Platelet (/L)	PLT	120 × 10^9	125–350 × 10^9	
C-reactive protein (mg/L)	CRP	31.05	0–10	
Procalcitonin (ng/mL)	PCT	0.13	< 0.05	
Creatine kinase (U/L)	CK	36	40–200	
Creatine kinase isoenzyme (ng/mL)	CKMB	0.8	< 5	
Aspartate aminotransferase (U/L)	AST	24.5	13–35	
Alanine aminotransferase (U/L)	ALT	31.8	7–40	
Serum creatinine (µmol/L)	SCR	51	41–73	
Blood urea nitrogen (mmol/L)	BUN	2	2.6–7.5	
Uric acid(µmol/L)	UA	129	142–340	
Blood sodium (mmol/L)	Na+	138.1	137–147	
Blood chlorine(mmol/L)	CI-	103	99–110	
Blood calcium(mmol/L)	Ca2+	2.17	2.11–2.52	
Tumor markers				
Carcino-embryonic antigen	CEA	(-)	(-)	
Cancer antigen 15 − 3	CA15-3	(-)	(-)	
Cancer antigen 125	CA125	(-)	(-)	
Thyroid antibodies				
Thyroid globulin antibodies	TG	(-)	(-)	
Thyroid peroxidase antibodies	TPO	(-)	(-)	
Microbiological exams				
Bacteria (blood culture)		(-)	(-)	
Influenza a virus	Inf A-RNA	(-)	(-)	
Influenza b virus	Inf B-RNA	(-)	(-)	
Respiratory syncytial virus	RSV-RNA	(-)	(-)	
Adenovirus	ADV-DNA			
Human rhinovirus	HRV-RNA	(-)	(-)	
Mycoplasma pneumoniae	MP-DNA	(-)	(-)	
Cerebrospinal fluid test				
Pressure		130	80-180mmH2O	
Color		colourless	colourless	
Clarity		transparent	transparent	
Protein	PRO	(-)	(-)	
Total cells	TC	(-)	(-)	

The patient suffered from febrile neutropenia accompanied by infectious indicators of hsCRP and PCT elevation, although no definite pathogens were detected, hyperpyrexia, poor response to antipyretic drug and freshly underwent radiotherapy were all risk factors of infection. Granulocyte-stimulating factor (G-CSF) 200 ug subcutaneous injection for 3 days and Biapenem 0.3 g intravenous infusion every 12 h(cephalosporins skin test is positive) were given. At the same time, non-steroidal anti-inflammatory drug Loxoprofen was given to relieve fever and analgesia, and the patient’s temperature did not recur with headache relieved simultaneously and the lesion in the corpus callosum disappeared on brain MRI examination(Fig. 2A2-E2).

Fig. 2 Brain MRI manifestation of RESLES: High signal in DWI sequence(A1);Slightly low signal in T1WI sequence(B1); High signal in T2WI sequence(C1-D1); Low signal in ADC(E1); The lesion in the corpus callosum disappeared on brain MRI examination after recovery(A2-E2). (A: DWI B: T1WI C: T2WI D: T2WI-FLAIR E: ADC)

Discussion

Evolution of the concept: Kim and colleagues first reported in 1999 that discrete and focal lesions of the corpus callosumon on magnetic resonance images in patients with epilepsy might be related to Anti-seizure medication(ASM), as the foci disappeared on follow-up after discontinuation of the drugs, indicating the possible mechanism being reversible demyelination associated with ASM toxicity [7]. The concept of mild encephalopathy/ encephalitis with reversible splenial lesion of the corpus callosum(MERS) was defined by Tada et al. in 2004 [8].This referred to a clinical imaging syndrome presenting with mild encephalopathic symptoms and imaging-defined lesions in the corpus callosum that were reversible on both clinical and imaging changes. Garcia ⁃ Monco et al. gave the name of Reversible splenial lesion syndrome (RESLES) in 2011 [1].The concept of Cytotoxic Lesions of the Corpus Callosum (CLCC or CLOCCs) was introduced in 2017 by Starkey J, indicating secondary lesions caused by infections or other underlying etiologies, as opposed to primary callosal lesions such as callosal ischemia or lymphoma [9]. RESLES is categorized into type I (involving the splenium of the corpus callosum, SCC, only) and type II [extending to the white matter areas on both sides of the brain and/or involving the entire corpus callosum] according to imaging, with type II being a very rare type [9].In this patient, only SCC was involved, considering to be RESLES Type I.

Pathogenesis: The etiology of RESLES has not yet been clarified, though often be regarded as cytotoxic edema. With the deepening of related research, a variety of factors have been revealed, mainly including infections [10], metabolic disorders [11], seizures [12] and the use of antiepileptic drugs [13] and chemotherapy [14]. RESLES caused by infection is often characterized by acute or subacute encephalitis or encephalopathy, which is common in children and adolescents, with viruses and bacteria being the main source of infection, not limited to Influenza viruses [10], Hantaviruses [15], Cytomegaloviruses [16],Rhinoviruses [17],Respiratory syncytial virus [18],Mycoplasma pneumoniae [19], Human Herpesvirus 6 [20], COVID−19 [21], Staphylococcus aureus [22], Streptococcus pneumoniae [23], Legionellae [24], Typhus [25]. The exact pathophysiologic mechanism of infection secondary to RESLES is unknown, and some studies have suggested that the likely mechanism is that acute infection activates the immune system, and the releasing antigen has a specific affinity for SCC neuronal axonal receptors, SCC can be easily induced reversible cytotoxic edema [26], for The corpus callosum itself has a variety of receptors including cytokine receptors, toxin receptors, glutamate receptors, and drug receptors. In particular, the density of receptors in SCC is more aggregated, making it more susceptible to cytotoxicity [27] [28]. Non-infectious factors such as metabolic disorder factors like hypoglycemia, hyponatremia or hypernatremia, seizures and use of antiepileptic drugs, especially abrupt withdrawal of antiepileptic drugs represented by carbamazepine and oxcarbazepine, could also induce RESLES. Carbamazepine and oxcarbazepine can act on cation channels in the cytosol membrane, and enhance the effect of antidiuretic hormone, thus causing osmotic pressure changes and finally lead to drug-induced cerebral edema [29]. Besides, several other mechanisms have been proposed for the pathogenesis of RESLES, including oxidative stress [30], neuroaxonal damage [31] and autoimmune processes. Cases of concomitant autoimmune Bickerstaff Brainstem Encephalitis(BBE) and autoimmune gliogenic fibrillary acidic protein (GFAP) astrocytosis have been reported [32–34], It is suggested that immune-related factors may also be potential causative factors. There have also been new developments at the molecular genetic level, with Kurahashi suggesting that the myelin regulatory factor (MYRF) gene may be associated with the development of RESLES [34]. Co-occurrence of RESLES and anti-N-methyl-D-aspartate receptor(anti-NMDAR) encephalitis was described in patients with or without teratoma [35, 36] Next-generation sequencing of a pair of 4-year-old twin sisters with RESLES reveals different CD36 shifted-code mutations that may be associated with pathogenesis [37]. Cases with a family history of RESLES have also been reported in Japan, The patient who was diagnosed with RESLES at the age of 8 had a recurrence at 26 years old, while the patient’s younger brother had also experienced recurrent episodes of RESLES between the age of 9 and 16, making genetic factors a potential etiologic factor that should not be ignored [38].

Diagnosis, treatment and prognosis: The clinical manifestations of RESLES varies with fever, headache, seizures, mental abnormalities and vomiting. Viral infections may present with fever, cough, diarrhea, and headache, depending on the pathogen, while bacterial infections are more likely to present with impaired consciousness and seizures with a longer disease duration. In recent years, there have also been case reports of transient blindness [39], elevated antithyroid antibodies [40], neurodeafness [41], language disorder [42],and transient ischemic attack(TIA)-like symptoms [43]as the only or main manifestations. Significant remission or disappearance of the corpus callosum lesion is necessary for diagnosis. In this case, the patient had bone marrow suppression after radiotherapy, neutropenia with fever, combining with the results of the patient’s blood routine and infection indexes, we considered her as of high infection risk. The complete remission after treatment verified our hypothesis. In addition, this patient suffered from a malignant tumor, the tumor microenvironment is considerably complex, she received a variety of anti-tumor treatments, such as surgery, chemotherapy, targeted therapy, radiotherapy and hormone therapy, since there have been few reports of RESLES accompanied with malignant tumors or specific diseases which need to receive chemotherapy [14].Maissa Thabet et al. have reported a case of RESLES due to the application of rituximab to treat IgG4-related disease [44]. Akiko Aoki et al. reported a case of methotrexate-treated elderly rheumatoid patient with diffuse large B-cell lymphoma of the paranasal sinuses who developed a transient corpus callosum lesion after 6 cycles of chemotherapy, which was initially diagnosed as RESLES, but a subsequent follow up showed enlargement of the corpus callosum lesion and new lesions emerged, which led to the final diagnosis of secondary central nervous system lymphoma. Therefore, secondary neoplastic lesions of the corpus callosum should also be excluded in diagnosing RESLES [45]. In this case, in addition to radiotherapy, the patient is still receiving uninterrupted anti-Her2-targeted maintenance therapy and endocrine therapy, which cannot be completely ruled out of the etiology, and the patient still needs to be vigilant for recurrent attacks of RESLES in the course of subsequent drug therapy.The treatment of RESLES is still based on etiological treatment, providing that SCC ischemic cerebral infarction, acute encephalomyelitis, multiple sclerosis, reversible posterior encephalopathy syndrome and the secondary neoplastic lesions mentioned above are excluded. Usually RESLES has a good prognosis, but it can recur. In this case, the lesion in the corpus callosum has completely disappeared.

Conclusions

RESLES is a unique clinical imaging syndrome, characterized by reversible brain MRI findings, good prognosis and a variety of infectious and non-infectious etiologies. Till now, the diagnosis is mainly based on MRI combined with clinical manifestations, lacking of standards for treatment strategy. In the last few years, several cases related to different disciplines but oncology have been reported. By conducting this case report, we aim to draw attention to cancer patients accompanied with reversible corpus callosum syndrome to possibly avoid misdiagnosis and excessive medical care. This breast cancer patient after postoperative adjuvant radiotherapy develops a complication of RESLES, with a prior consideration of radiotherapy-induced myelosuppression to cause the disease, so as to ring an alarm bell to the oncologists not to easily recognize the corpus callosum lesion as infarction or metastasis. Meanwhile, the reported incidence of RESLES in tumor patients, especially in patients receiving multiple antitumor therapies, is relatively low, although should not be ignored, and other potential pathogenic mechanisms need to be explored further.

Acknowledgements

The authors are thankful to the patient and to the healthcare professionals involved in his care.The authors are also thankful to Dr Kun Jiang for sharing his experience in treating RESLES in pediatrics.

Author contributions

Xiao Qi wrote the main manuscript text, Dandan Zou prepared the table. Huaqing Wang and Miao Zhang reviewed and edited the manuscript. All authors read and approved the final manuscript.

Funding

The work was funded by the National Natural Science Foundation of China(Grant No. 82070206); Tianjin Key Medical Discipline (Specialty) Construction Project (Grant No. TJYXZDXK-053B); Tianjin Health Research Project (Grant No. TJWJ2023MS013).

Data availability

No datasets were generated or analysed during the current study. All data relevant to the study are included in the article.

Declarations

Ethics approval and consent to participate

Written and signed consent to publish the information was obtained from the patient.

Consent for publication

Written and signed consent for publicaiton was obtained from all authors and the patient.

Competing interests

The authors declare no competing interests.

Abbreviations

RESLES Reversible splenial lesion syndrome

ASM Anti-seizure medication

DWI Diffusion-weighted imaging

ADC Apparent diffusion coefficient

G- CSF Granulocyte-stimulating factor

MERS Mild encephalitis with a reversible lesion in the splenium

CLCC or CLOCCs Cytotoxic Lesions of the Corpus Callosum

SCC Splenium of the corpus callosum

BBE Bickerstaff Brainstem Encephalitis

GFAP Gliogenic fibrillary acidic protein

MYRF Myelin regulatory factor

NMDAR N-methyl-D-aspartate receptor

TIA Transient ischemic attack

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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