Histiocytic necrotizing lymphadenitis with autoimmune encephalitis in a child: a case report

Introduction

Histiocytic necrotizing lymphadenitis (HNL), also known as Kikuchi-Fujimoto disease (1), is a rare, benign and self-limited inflammatory disease that primarily affects young adults (2-4). HNL is a non-neoplastic lymphadenitis, and in children, the main symptoms are fever and swollen lymph nodes (5,6). Several case reports suggest that HNL may lead to various complications, including meningitis, status epilepticus, interstitial lung disease, myocarditis, acute kidney failure, phagocytic syndromes, sickle cell anemia, and malignancy (7-16). However, the exact pathogenesis remains unknown (17). To date, only two cases of adult males with HNL combined with autoimmune encephalitis (AE) have been reported, both of whom showed improvement following immunotherapy; however, there have been no reports of HNL combined with AE in children (6,18).

Currently, there is no clear and well-established pathological logic to explain the pathogenesis of HNL, and laboratory tests lack specificity. Serology can detect antibodies to Epstein-Barr virus, human herpesvirus 6 and 8, and human parvovirus B19 (19). Similarly, imaging studies such as computed tomography and ultrasound also lack specificity. Therefore, the diagnosis of HNL currently relies on tissue biopsy with pathology diagnosis.

Additionally, there are no specific drugs for the treatment of HNL, and treatment is primarily symptomatic. Antibacterial drugs are typically ineffective. Oral hormone therapy is often the primary choice of treatment, but there is no specific guidelines for the therapeutic dosage (20). Hydroxychloroquine has been identified as an alternative treatment (21). Given its safety profile, hydroxychloroquine may be a better alternative to long-term, high-dose hormone therapy.

Recently, a 4-year-old child was diagnosed with HNL combined with contactin-associated protein-2 (CASPR2) antibody-associated encephalitis at Tongji Hospital of Huazhong University of Science and Technology. This case is exceedingly rare. This study sought to analyze the diagnostic and treatment records pertaining to this case to provide a reference for future research on the mechanism and clinical treatment of similar diseases. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-380/rc).

Case presentation

Description of the patient, case history, diagnostic assessments, therapeutic interventions, and outcome

The patient, a 4-year-old male, was initially admitted to the hospital on August 20, 2020, presenting with a neck mass persisting for more than 2 months and fever for 5 days. In the half year prior to this admission, the child had sought medical attention multiple times at external healthcare facilities and our outpatient clinic due to lymph node swelling and pain accompanied by fever with a peak temperature of 39.2 ℃. In March 2021, the patient also presented with abdominal pain and vomiting. The pre-admission ultrasound examination revealed enlarged lymph nodes but no necrosis, and the post-admission core needle biopsy indicated reactive hyperplasia of the left lymph node (Figure 1). No microbial/viral studies were conducted. Despite anti-infection treatment, his symptoms did not show significant improvement.

Figure 1 Pathological diagnosis shows that the left neck is in line with the characteristics of HNL. Immunohistochemistry: in the lesion area, CD3 (+), CD5 (+), CD8 (+), CD4 (scattered +), GrB (+), CD68 (+), CD123 (+), MPO (weak +), TIA-1 (a little weak +), CD30 (a little +, positive control +), LCA (+), GATA-3 (+), Mum-1 (scattered +), CD15 (−), PAX-5 (SP34) (−), CD20 (−, positive control +), CD19 (−), CD79a (−), OC-2 (−), BOb.1 (−), ALK1A4 (−), EMA (−), PCK (−), Ki-67:LI high. Molecular detection: EBER (CISH) (−), EBER (positive control +); TB qualitative RT-PCR (−). HNL, histiocytic necrotizing lymphadenitis; RT-PCR, real-time polymerase chain reaction.

Upon admission to the hospital, physical examination revealed multiple palpable and enlarged neck lymph nodes present bilaterally. The left lymph node, measuring approximately 1.5 by 1.0 cm, exhibited hardness, tenderness, and localized redness. Auxiliary examination revealed elevated C-reactive protein (CRP) at 13.78 mg/L (normal <5 mg/L), increased calcitonin levels at 1.40 ng/mL, and albumin at 36.7 g/L, fibrinogen at 4.25 g/L, and blood sedimentation at 24 mm/H. Other test results did not show any significant abnormalities.

Despite antibiotic treatment with teicoplanin, the patient showed no substantial improvement. A pathological analysis of the cervical lymph node biopsy indicated HNL of the left cervical tissue. The introduction of dexamethasone anti-inflammatory therapy notably reduced the inflammation (the redness and swelling of lymph nodes subsides). Following the resolution of the fever, the child was discharged from the hospital with maintenance treatment of oral prednisone for one week. However, after discharge, the child experienced low-grade fevers every month, which responded to antibiotic treatment, and his cervical lymph nodes remained enlarged.

After six months of intermittent fever, the child’s symptoms deteriorated, resulting in a high fever peaking at 39.1 ℃. The fever occurred frequently, approximately five times a day, and was accompanied by chills and abdominal pain. Oral cephalosporin was administered, but it proved to be ineffective.

On March 12, 2021, the child was readmitted to the hospital with a chief complaint of fever. Upon physical examination, multiple enlarged lymph nodes, each approximately the size of a soybean, were palpable in the neck, and similar-sized lymph nodes were also palpable in both groins, exhibiting hardness and mobility. Auxiliary examination revealed a CRP level of 39.04 ng/L, a procalcitonin level of 1.37 ng/mL, and a positive detection of respiratory syncytial virus nucleic acid. No other significant abnormalities were observed.

Five days after admission, the child displayed a diminished spirit, reduced voluntary activity, minimal speech, and poor appetite, which were indicative of neurological symptoms, prompting consideration of AE. The electroencephalogram showed bilateral posterior head background activity with an increased amount of delta slow-wave activity, particularly prominent on the right side (Figure 2). Simultaneously, a lumbar puncture was performed, revealing a total protein level of 116 mg/L, cerebrospinal fluid albumin level <95 mg/L, and no other abnormalities. The serum anti-CASPR2 antibody immunoglobulin G (IgG) was detected at a titer of 1:32. The report is from Wuhan Kindstar Diagnostics Co., Ltd., China. Additionally, enhanced magnetic resonance imaging (MRI) confirmed slight meningeal enhancement (Figure 3).

Figure 2 Representative electroencephalogram image showing bilateral posterior head background activity. This test shows that there is more δ slow wave activity in the bilateral posterior and anterior head regions of the patient, and it is more significant on the right side. The picture on the left is from this patient, and the picture on the right is from a healthy child. The right to use the relevant pictures has been agreed by the patients and their parents. They all signed the informed consent form.

Figure 3 Enhanced magnetic resonance imaging scan. This image shows that the bilateral cerebral hemispheres of this patient are symmetrical, and there is no obvious abnormal enhancement in the brain parenchyma. The ventricular system is not enlarged, the sulci and fissures of the brain are not widened, and the midline structure is not shifted. However, compared with the image of a normal person, this patient has slightly more leptomeningeal enhancement.

The patient received 7.5 g of gamma globulin (500 mg/kg). Following the definitive diagnosis, shock treatment consisting of methylprednisolone at a dose of 290 mg (once a day, 20 mg/kg, 290 mg each time, for a course of three days) was administered. Three days later, the child’s mood and appetite improved. The methylprednisolone dosage was then reduced by (once a day, 2 mg/kg, 30 mg each time). One week later, the child’s mood stabilized, his hand tremors subsided, and his speech and communication abilities were found to be essentially normal.

After being discharged from the hospital, the patient received maintenance therapy of methylprednisolone (2 mg/kg). Concurrently, the patient underwent monthly gamma globulin treatment. The symptoms were completely relieved after 2 weeks, and the subsequent treatment was maintenance treatment. In addition, a follow-up brain MRI was conducted after the second gamma globulin treatment. Subsequent to the third gamma globulin treatment, the serum CASPR2 antibody tested negative. Ultimately, the patient returned to the clinic after the complete remission of his symptoms. The serum biochemical indexes were within the normal limits; the cerebrospinal fluid anti-CASPR2 antibody (IgG) was negative; the cranial MRI scan did not reveal any significant abnormalities, and the patient’s mental state was normal.

Follow-up

One year later, following the discontinuation of prednisone, the child’s mental development was satisfactory, and no relapse had occurred. Subsequent follow-up examinations indicated the serum CASPR2 antibody remained negative. To date, the child’s intellectual development remains positive, his mental state is stable, and there have been no relapses. The patient and his parents are satisfied with the treatment outcome.

Ethics

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Chronic autoimmune system dysfunction can lead to neurological and visceral injuries (22,23). AE involves immune-mediated attacks on intracellular and neuronal surface antigens, resulting in various brain disorders (16,24). The previous view was that neuromyotonia, Morvan syndrome (MoS), and limbic encephalitis were caused by antibodies associated with the voltage-gated potassium channel (VGKC) complex. However, an enhanced understanding of autoimmune antibodies has revealed that the causative antibodies are primarily directed against the VGKC complex-associated proteins, specifically the leucine-rich glioma inactivation 1 protein and CASPR2.

The overexpression of anti-CASPR2 antibodies can lead to several age-related syndromes, including peripheral nerve hyperexcitability, limbic encephalitis, and MoS. Clinically, AE with anti-CASPR2 antibodies is rare. A study at Peking Union Medical College Hospital involving 279 cases of AE found that only 1.8% were CASPR2 antibody positive (25). However, the etiology of AE is currently unknown. Reports suggest that CASPR2-positive encephalitis may be secondary to viral infections, indicating the potential involvement of infections (26,27). Additionally, there has been a report of CASPR2-positive autoimmune limbic encephalitis secondary to pembrolizumab treatment, suggesting the possible involvement of immune system disorders (28).

In the early stages of the disease, the persistent lack of cure was attributed to the absence of detectable CASPR2 antibodies associated with AE, as all cerebrospinal fluid CASPR2 antibody tests returned negative results. Instead, serologic testing was employed, revealing an anti-CASPR2 IgG titer of 1:32. It was only after initiating the corresponding therapeutic regimen that the patient experienced significant remission, coinciding with the subsequent negativization of the antibodies. Similar test findings have been reported in previous studies, suggesting that the detection of serum anti-CASPR2 antibodies is more sensitive than that of cerebrospinal fluid (29,30). Additionally, studies have identified anti-CASPR2 antibodies in the serum of patients with MoS and neurogenic myasthenia gravis (29,31). Therefore, both serum and cerebrospinal fluid testing are essential for confirming the diagnosis.

It should be noted that on both times when the child was admitted to the hospital for exacerbations, gastrointestinal symptoms were present. Given that HNL and AE are both immune disorders, pediatric cases should be monitored for potential complications of other immune disorders, such as abdominal purpura and inflammatory bowel disease. Early management is crucial to improve the prognosis in the presence of symptoms.

This study had a number of limitations. First, the association between HNL and CASPR2 antibody-associated AE has not been fully elucidated. However, a clinical correlation between the two exists; autoimmune abnormalities may potentially contribute to the development of HNL, and HNL can also cause immune-related reactions, leading to CASPR2 antibody-associated AE. Second, there is still a lack of relevant diagnostic criteria. Early diagnosis and treatment can significantly improve patients’ symptoms, while delayed treatment may result in irreversible neurological damage or even death. These are all valuable avenues for future research.

Conclusions

In conclusion, HNL may lead to AE or neurologically-related symptoms, and relevant antibody tests should be conducted as early as possible. Early detection and treatment are vital for improving patient prognosis. This study offers a clinical diagnosis and treatment approach for managing HNL and its associated complications.

Acknowledgments

We appreciate the help of all our colleagues in the clinical departments.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-380/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-380/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-380/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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