Optic Neuritis in a Pediatric Patient with Kikuchi–Fujimoto Disease: A Case Report and Review of the Literature

Introduction

Kikuchi-Fujimoto disease (KFD), also referred to as histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limiting condition characterized by lymph node inflammation. However, the urgent intervention is required in systemic complications of the KFD, which involve generalized lymphadenopathy, arthralgia, rash, night sweats, weight loss, leucopenia, and neurological involvement, including aseptic meningitis, peripheral neuropathy, kinetic tremor and cerebellar ataxia.¹

While KFD is seldom associated with ocular manifestations, it has been found to present in various forms, including uveitis, retinal vein vasculitis, and optic neuritis (observed in 4 patients, including our case and another patient with neuromyelitis optica spectrum disorder, NMOSD).^2–4 Alongside the limited instances of optic neuritis associated with KFD in the existing literature, our case report adds to the knowledge by presenting a 13-year-old male patient with KFD and bilateral optic neuritis.

Case Report

A 13-year-old male patient presented with a recent complaint of fever and vision deficiency in his both eyes. Three months prior to his visit, he had undergone a neck lymph node biopsy, which led to a diagnosis of KFD. The lymph node biopsy revealed the paracortical necrosis without hematoxylin bodies, and the immunohistochemistry showed the positive lysozyme and CD68, consistent with KFD (Figure 1). There was no history of prior radiation treatment history. At the time of his complaint of fever and vision deficiency, he was undergoing treatment with 5 mg of prednisone per day. Except for the KFD, he was healthy previously and was of the Chinese Han ethnicity.

Figure 1 (A) Cervical lymph node biopsy section: areas of lymphocytic proliferation, apoptotic necrosis, and histiocytes infiltration. (Hematoxylin and Eosin staining). (B) CD68(+) histiocytes visualized on immunohistochemical staining.

The patient exhibited normal extraocular muscle motility. Funduscopic examination revealed no significant findings (Figure 2). There was no evidence of an afferent pupillary defect (APD). However, static automated perimetry revealed a loss in the visual field in the lower nasal areas of the right eye, and a loss of the upper visual field of the left eye. Compared with reference values,⁵ visual Evoked Potential (VEP) found that the P100 latency was prolonged (right: 125ms, left: 120ms), and there was a reduction in the P100 amplitude (right: 3.1 μV, left: 9.0 μV). The visual acuity and the rest of neurological and physical exam remained normal.

Figure 2 Fundus images of both eyes. The optic disc was not swollen in our case and the retrobulbar optic neuritis was considered.

Laboratory tests revealed elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin (IL)-6/-8/-10 and interferon (IFN)-γ levels, while the other blood parameters fell within normal ranges. The cerebrospinal fluid (CSF) analysis revealed the following parameters: white blood cell count within normal range at 0 × 10^6/L, chloride concentration of 122 mmol/L, glucose level of 3.2 mmol/L, lactate dehydrogenase (LDH) of 59 U/L, CSF protein concentration of 333 mg/L. The Pandy test result was negative.

We further ruled out the infection via the metagenomic next-generation sequencing (mNGS),⁶ an unbiased method for broad identification of pathogens by sequencing thousands of DNA fragments simultaneously and independently in both the blood and the CSF sample.

The method used for antibody testing was cell-based assay (CBA). Demyelinating antibody tests (AQP4, MOG, GFAP, MBP) and autoimmune encephalitis antibody tests (NMDAR, LGI1, GABABR, CASPR2, AMPAR1, AMPAR2) yielded negative results in both blood and CSF. Oligoclonal bands suggested disruption of the blood–brain barrier (Table 1).

Table 1 Characteristics and Manifestations of Cases with KFD and on/NMOSD

Autoantibodies were negative, including anti-double-stranded-DNA (dsDNA), anti-nucleosome, anti-histone, anti-ribosomal P protein, anti-Smith, anti-u1-ribonucleoprotein, anti-Sjögren’s syndrome antigen A (SSA)/Ro52, anti-SSA/Ro60, anti-SSB/La, anti-neutrophil cytoplasmic antibodies and rheumatoid factor.

Magnetic resonance imaging (MRI) scans of the brain and orbits with contrast revealed several findings. The imaging indicated a slight thickening and T2 enhancement of the orbital anterior segments of both optic nerves, consistent with optic neuritis (Figure 3). The brain parenchyma showed normal without evidence of mass, or hemorrhage. The MRI of the spinal cord was performed and negative. Malignancy screening, including chest CT and the ultrasound of the abdomen, the pelvis, and testicles, was negative as well.

Figure 3 (A) A slight thickening and T2 hyperintense signal of the orbital anterior segments of the both optic nerve. The yellow arrow indicates the slight thickening of the nerve. (B) T2WI of the optic nerve.

Normal visual field was restored within 2 days after intravenous immunoglobulin (IVIG) treatment. Although his visual symptoms improved, the fever persisted. Consequently, prednisone was administered at a dose of 2 mg/kg/day, leading to a relief of his fever.

A follow-up ophthalmology exam after one week demonstrated complete resolution with similar visual field in both eyes. Written informed consent was obtained from the patient’s parents.

Discussion

KFD, a rare condition characterized by the histiocytic necrotizing lymphadenitis, typically affects young East Asian females, with a male/female ratio of 1:1.3–4.¹ However, KFD in the pediatric population has a male predominance. A male/female ratio of 1.9:1 and a median age of 10 years in the childhood-onset KFD were previously reported in our hospital.⁷ KFD is rarely reported with ocular manifestations, including uveitis, retinal vein, optic neuritis, lacrimal gland involvement, oculomotor palsy, and etc.⁴ Our case of a 13-year-old male patient with the KFD and the bilateral optic neuritis illustrates the possibility of considering this association.

Optic neuritis, marked by the acute inflammation of the optic nerve, ranks among the common causes of optic neuropathy.⁸ Infection, neoplasm and systemic autoimmune disorders are suspected factors for optic neuritis. In our case, blood/CSF culture and mNGS were negative, so infectious factors were excluded. Bone marrow puncture was performed to rule out neoplastic causes. And three months ago, the lymph node biopsy suggested KFD rather than the tumor. Apart from the infection and the neoplasm, both optic neuritis and KFD have been reported to be associated with systemic autoimmune disorders, such as systemic lupus erythematosus (SLE).⁷ In our case, however, clinical presentation and laboratory assessments did not substantiate a diagnosis of SLE. Meanwhile, the optic neuritis occurred 3 months after the diagnose of the KFD in our case. Except for the case of Bouquet et al² that the optic neuritis and the KFD occurred simultaneously, the other two reported cases by Arslan et al⁴ and Kaku et al³ of the optic neuritis and the NMOSD occurred one year after the diagnosis of the KFD, respectively. Therefore, we suspected that the optic neuritis in our case might be associated with KFD, as reported in previous cases.^2–4 The basis for the potential association between KFD and optic neuritis lies in the similarity of their cytokine pathways, such as elevated levels of IFN-γ and IL-6.^9,10 Meanwhile, the elevation in cytokine levels might also be associated with the symptom of fever during the course of our case. However, the pathogenesis of the optic neuritis and the KFD still needs further investigation. The hypothesized mechanism is as follows. Following the onset of the KFD, lymphocytes may undergo hyperactivation, leading to the elevated production of inflammatory cytokines.⁹ This heightened cytokine activity subsequently triggers the activation of T cells, and consequently, CD8+ T cells or antibodies may target and attack neuron.⁹

In comparison to previous studies,^2,4 this case improves upon the differentiation of optic neuritis from other possibilities through comprehensive spinal magnetic resonance imaging (MRI) and antibody profiling in CSF. These measures help distinguish optic neuritis from conditions such as tumor, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and NMOSD. Notably, a case of NMOSD following optic neuritis in an adult with a history of KFD has been reported in the previous literature.³ In our case, MRI findings and CSF tests found no positive evidence. To be noticed, early identification of myelin oligodendrocyte glycoprotein-IgG associated disorders (MOGAD) and NMOSD is crucial because patients with these conditions are at risk of permanent vision loss and neurological disability resulting from relapses.¹¹

In the recommendation for optic neuritis treatment, intravenous methylprednisolone (IVMP) pulse therapy is recommended during the acute phase, especially those with bilateral eye involved.^12–14 Although high-dose intravenous corticosteroids do not significantly alter the long-term visual prognosis, they do accelerate initial recovery.¹⁴ However, in our case, the reason for not using IVMP initially was that this pediatric patient had been on steroids for a period during the treatment of KFD. Additionally, before initiating the IVMP therapy, time was required for completing procedures such as the bone puncture and the MRI for differential diagnosis. After the initial IVIG, the child’s visual field did indeed improve, but the body temperature did not subside. When infectious and neoplastic factors were ruled out, 2mg/kg IVMP was promptly added, and the fever was relieved very soon. IVMP was continued for 5 days and then changed to the oral administration.

Further studies are necessary to testify whether a combination of the IVIG and the prednisone might lead to good outcomes at the acute stage.^13,14 It remains controversial whether the IVIG therapy could exhibit promising outcomes in reducing relapse and delaying the progression from the optic neuritis to the MS.¹⁵ Surveying the limited case reports, one case of the simultaneous onset of KFD and optic neuritis exhibited spontaneous remission.² Furthermore, in another previous pediatric case report of the KFD with the optic neuritis by the Mayo Clinics,⁴ steroids and the anti-CD20 therapy were performed and achieved good results. In a case of the NMOSD in an adult patient following the KFD, plasma exchange was conducted.³ The choice of treatment method still depends.

The recurrence rates differed between adult patients (28% and 35% at 5 and 10 years of follow-up) and pediatric patients (only 5%).^16,17 Meanwhile, Optic Neuritis Treatment Trial (ONTT) reported 50% of adult optic neuritis patients, especially those with lesions on MRI develop MS after 15 years of follow-up.¹⁸ While in children, the meta-analysis reported that 9–32% developed MS after 6.3 years of the follow-up.^19,20 Even though the reported cases of the optic neuritis in the KFD were limited, there have been no documented instances of recurrence so far.^2–4 All in all, the ongoing monitoring is necessary for patients with optic neuritis. To be noticed, the only predictor of 1-year visual acuity was visual acuity at baseline. This may correlate with the mechanism of “point of no return”, which means crossing the line of damage leads to the permanent neurological disability.²¹

Limitation

The relationship between KFD and optic neuritis remains to be studied.

Conclusion

In summary, this case underscores the importance of paying more attention to the optic neuritis associated with the KFD. Vigilant monitoring and multidisciplinary evaluations, including specialized imaging, serological and CSF assessments, are crucial for the accurate diagnosis and the timely intervention. Further research and comprehensive studies are warranted to elucidate the intricate connections between KFD and optic neuritis, shedding more light on this rare association.