Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis

Brain & Development xxx (2017) xxx–xxx www.elsevier.com/locate/braindev

Case Report

Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis Joung-Hee Byun a,1, Su Eun Park a,b,1, Sang Ook Nam a,b, Young A Kim a,b, Young Mi Kim c, Gyu Min Yeon d, Yun-Jin Lee a,b,⇑ b

a Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan, South Korea Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea c Department of Pediatrics, Pusan National University Hospital, Busan, South Korea d Department of Pediatrics, Kosin University Gospel Hospital, Kosin University, Busan, South Korea

Received 15 July 2017; received in revised form 26 September 2017; accepted 27 September 2017

Abstract Background: Kikuchi necrotizing lymphadenitis (KNL) is a rare and benign cause of lymphadenopathy, most often cervical. The etiology of KNL remains unknown. Central nervous system (CNS) involvement, such as in meningoencephalitis, is a very rare clinical manifestation of KNL, especially in children. Case reports: A 12-year-old boy presented with unilateral cervical lymphadenopathy and fever. Histopathological findings led to the diagnosis of KNL. He revisited due to severe headache and vomiting one week later. Cerebrospinal fluid (CSF) analysis demonstrated pleocytosis (lymphocytic 57%), high protein (312 mg/dL) and low CSF/serum glucose ratio (52/121 mg/dL.) The next day, he had a seizure. Brain MRI revealed increased signal involving posterior area of both hemisphere. Another 17-year-old boy presented with headache for 7 days and behavioral and personality changes. He had a history of cervical lymphadenopathy two weeks ago. CSF analysis demonstrated lymphocytosis, high protein and low glucose ratio. MRI revealed the involvement of right cerebellum and posterior brainstem. A biopsy of one cervical lymphadenopathy demonstrated the findings of KNL. A 15-year-old girl presented with fever, headache, and cervical pain lasting 10 days. CSF analysis demonstrated pleocytosis (lymphocytic 95%), high protein and low CSF/serum glucose ratio. Histopathological findings of lymph node were suggestive of KNL. Above three patients were undertaken the steroid therapy and recovered fully without neurological dysfunction. Conclusions: Recognition of CNS involvement in KNL may help evaluate the patients of acute meningitis/encephalitis with regional lymphadenopathy, thereby avoiding unnecessary treatment. Ó 2017 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

Keywords: Histiocytic necrotizing lymphadenitis; Kikuchi disease; Encephalitis; Meningitis; Child

Abbreviations: KNL, Kikuchi necrotizing lymphadenitis; WBC, white blood cell; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; EBV, Epstein-Barr virus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; HSV, herpes simplex virus; EEG, electroencephalography; MRI, magnetic resonance imaging ⇑ Corresponding author at: Department of Pediatrics, Pusan National University Children’s Hospital, 20 Geumo-ro, Yangsan-si, Gyeongsangnamdo 50612, South Korea. E-mail address: [email protected] (Y.-J. Lee). 1 Joung-Hee Byun and Su Eun Park equally contributed to this work and are the first co-authors. https://doi.org/10.1016/j.braindev.2017.09.009 0387-7604/Ó 2017 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Byun J-H et al. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev (2017), https://doi.org/10.1016/j.braindev.2017.09.009

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Case 1 Case 2 Case 3 Jasti et al. [1]

Khishfe et al. [2] Gonc¸alves et al. [3] Gue´guen et al. [4] Komagamine et al. [5] Avkan-Oguz et al. [6] Shafqat et al. [7] Soman et al. [8]

CNS disease

MRI scan

Interval* (CNS symptoms)

CSF analysis

Treatment

Outcome

M/ 12 M/ 17 F/ 15 F/ 15

ME

HS in cerebellum & posterior aspect of bilateral occipital lobes

Good

HS in right cerebellum & posterior aspect of brainstem

Oral PD

Good

ME

Unremarkable (on CT) HS in dorsal midbrain & dorsal pons

IV MPD, IV acyclovir, IV IG IV Dexa, ceftriaxone

Good

BE

Pleocytosis, high protein Pleocytosis, high protein Pleocytosis, high protein Pleocytosis

IV Dexa,

BE

3 weeks (severe headache, meningeal sign, seizure) 2 week (behavior & personality change) 10 days (stupor mentality)

M/ 32 M/ 9 M/ 39 M/ 28 F/ 36 F/ 23 F/ 17

Meningitis

Diffuse leptomeningeal enhancement

IV MPD

Good

ME

HS in mesial temporal lobes, periaqueductal region, lateral wall of ventricle & mammillary bodies, & perivascular enhancement HS in internal temporal lobe, lenticular nuclei, left internal capsule & pons Unremarkable

Pleocytosis, high protein Pleocytosis, high protein Pleocytosis, high protein Pleocytosis

IV Dexa No

Neurocognitive sequelae Good

No

Good

Pleocytosis, upper limit of protein High protein

IV MPD, IV acyclovir IV Dexa,

Good

High protein

Oral PD, antituberculous agents

ME Recurrent meningitis ADEM

HS in medial temporal lobes & pons

BE

HS in pons, midbrain, middle & superior cerebellar peduncle

Encephalitis

Unremarkable (on CT) (Serologic-autoimmune abnormalities)

2 weeks (drowsy, nystagmus, blepharospasm) Not available (severe headache) Around 26 days (altered mentality) 22 years (headache, personality changes) 7 episodes over 7 years (headache, Kernig’s sign) 53 days (seizure, altered mentality) 36 days (drowsy, mild hemiparesis) Not available (headache, seizure)

Good

Good Good

ADEM: acute disseminated encephalomyelitis; BE: brainstem encephalitis; CNS: central nervous system; CSF: cerebrospinal fluid; Dexa: dexamethasone; F: female; HS: hyperintense signal; IG: immunoglobulin; IV: intravenous; M: male; ME: meningoencephalitis; MPD: methylprednisolone; MRI: magnetic resonance imaging; PD: prednisolone. * Interval between onset of lymphadenopathy and CNS symptoms.

J.-H. Byun et al. / Brain & Development xxx (2017) xxx–xxx

Please cite this article in press as: Byun J-H et al. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev (2017), https://doi.org/10.1016/j.braindev.2017.09.009

Table 1 The clinical and laboratory findings of the patients of meningitis or encephalitis associated with Kikuchi necrotizing lymphadenitis.

J.-H. Byun et al. / Brain & Development xxx (2017) xxx–xxx

1. Introduction Kikuchi necrotizing lymphadenitis (KNL), also known as histiocytic necrotizing lymphadenitis, is a rare regional lymphadenopathy with a benign self-limited course. It is often misdiagnosed as tuberculosis or lymphoma because of cervical lymphadenopathy and fever [1]. Neurological complications occur in approximately 11% of patients with some meningitis or encephalitis (Table 1) [1–8]. We report three children with meningoencephalitis associated with KNL. Additionally, we reviewed the literature of patients with KNL meningoencephalitis, for laboratory findings, neuroimaging, and management. 2. Case reports 2.1. Case 1 A 12-year-old boy with no significant medical history, presented to our emergency room with fever lasting 10

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days. He had high fever of 39 °C. A palpable lymph node 15 mm in size was present on the left posterior neck. White blood cell (WBC) count was 5020/mm3, C-reactive protein (CRP) level was 3.29 mg/dL (0–1.0 mg/dL), erythrocyte sedimentation rate (ESR) was 31 mm/h (0–16 mm/h), ferritin was 27 ng/mL (20–400 ng/ mL), and lactate dehydrogenase (LDH) was 380 IU/L. Epstein-Barr virus (EBV), cytomegalovirus, toxoplasma, and mycoplasma serology were negative. Antinuclear antibodies, rheumatoid factor and tuberculin skin test were negative. Excisional biopsy revealed a necrotic lymph node, which was consistent with the diagnosis of KNL (Fig. 1). His general condition improved with conservative management and he was discharged on the 4th day of hospitalization. The boy was readmitted 7 days later due to severe headache and vomiting. Neck stiffness and Kernig’s sign were present. On the next day, he had a generalized tonic-clonic seizure, and became lethargic state. Cerebrospinal fluid (CSF) analysis showed lymphocyticdominant pleocytosis (194/mm3, lymphocytes 57%),

Fig. 1. Histopathology of affected lymph node of case 1 (A) shows predominantly necrosis (H-E, X100). High magnification (B) mononucleated cells with irregular nuclei with marked karyorrhectic nuclear debris, and absence of neutrophils (H-E, X400). Histopathological findings of case 3 (C) showed scatter discreet areas of necrotic lymph node (H-E, X100, arrow). In a high-power field (D), the lesion demonstrated abundant karyorrhectic debris with apoptosis bodies and numerous histiocytes and large lymphoid cells (H-E, X400). (H-E = Hematoxilin-Eosin).

Please cite this article in press as: Byun J-H et al. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev (2017), https://doi.org/10.1016/j.braindev.2017.09.009

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Fig. 2. Axial fluid-attenuated inversion recovery images of case 1 (A-B) show hyperintense signals in the sulci in the superior cerebellum (circle) and posterior occipital lobe (arrows). T2-weighted magnetic resonance scans of case 2 (C-D) reveals hyperintense signals in the right cerebellum (circles) and posterior brainstem (arrows).

proteins 312 mg/dL, and glucose 52 mg/dL (blood glucose, 121 mg/dL). CSF culture was sterile, and PCR for viral agents were negative. CSF tuberculosis and herpes simplex virus (HSV) polymerase chain reaction (PCR) were negative. Electroencephalography (EEG) revealed continuous slow background activity. Magnetic resonance imaging (MRI) showed hyperintense signals in the superior cerebellum and the bilateral occipital lobes (Fig. 2). He was started on dexamethasone 45 mg (1 mg/kg/day) intravenously for 2 weeks to treat suspected meningoencephalitis. After 3 days, his mentality and lymphadenopathy improved significantly. He had no neurocognitive sequelae. 2.2. Case 2 A 17-year-old boy presented with headache lasting 7 days and acute behavioral disturbances and decreased

mentality. He had a history of cervical lymphadenopathy two weeks ago. He had mild fever of 37.5 °C, and bilateral cervical lymphadenopathy measuring 2  2 c m. WBC count was 6200/mm3, CRP 1.78 mg/dL, ESR 7 mm/h, ferritin 32 ng/mL, and LDH 351 IU/L. CSF analysis demonstrated lymphocytosis (168/mm3, lymphocytes 73%), high protein (333 mg/dL), and low CSF/serum glucose ratio (42/104 mg/dL). EEG demonstrated diffuse slow activity, and MRI revealed hyperintense signals in the right cerebellum and posterior brainstem (Fig. 2). He was started on anti-tuberculous agents (isoniazid, rifampin, ethambutol, and pyrazinamide) and oral prednisolone (60 mg/day) because of the possibility of tuberculous meningoencephalitis. Cervical lymph node biopsy showed necrotizing lymphadenitis without granuloma, suggestive of KNL. Tuberculin skin test and CSF tuberculosis PCR showed negative results. There was no evidence of other

Please cite this article in press as: Byun J-H et al. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev (2017), https://doi.org/10.1016/j.braindev.2017.09.009

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infectious agents. Anti-tuberculosis treatment was withdrawn. After 6 days, his mentality was prominently improved. The prednisolone was successfully tapered over 2 months. 2.3. Case 3 A 15-year-old girl presenting with fever, headache, and cervical pain lasting 10 days visited our hospital. A lymph node 2 cm in diameter was palpable on the left posterior cervical region. She developed stuporous behavior shortly after the visit. Routine laboratory findings were normal. EEG showed persistent slow background activity. CSF test results revealed WBC 87/ mm3 (lymphocyte 95%), protein 116 mg/dL, and glucose 43 mg/dL. MRI was not performed because she had dental braces. As meningoencephalitis was suspected, she was given IV acyclovir, immunoglobulin, and methylprednisolone 60 mg/day. Result of lymph node biopsy was suggestive of KNL (Fig. 1). CSF culture was sterile, and PCR for viral agents were negative. Acyclovir and immunoglobulin were discontinued. Her lymphadenopathy and mentality resolved over the subsequent 48 h. Methylprednisolone was tapered over one month. She followed up after 2 years without any neurological dysfunction.

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levels, which can lead to misdiagnosis as tuberculous meningitis due to similar CSF results and lymphadenopathy. Given the toxic effects of antituberculosis agents, it is important to distinguish between these diagnoses to avoid unnecessary harmful treatment [10]. Corticosteroids were administered to six of the eight patients, and most of them had favorable outcomes (except for one case). Our patients had no hepatosplenomegaly, normal levels of serum ferritin and LDH, and no restriction on diffusion-weighted MRI scan, which was not associated with the findings of hemophagocytic lymphohistiocytosis. We did not perform the bone marrow examination because they had no cytopenia in the peripheral blood. Our cases emphasize consideration of KNL as a differential diagnosis in children and adult patients of acute meningitis/encephalitis with regional lymphadenopathy. It can be diagnosed by lymph node biopsy, EEG, CSF analysis, and MRI, thereby avoiding unnecessary treatment.

Acknowledgement We have no financial relationships relevant to this article.

3. Discussion

References

KNL is explained as viral infection with autoimmune involvement and genetic susceptibility [4]. Various pathogens, including bacteria and viruses, are known to be associate with KNL. It is suggested that there may be causative substances produced after primary infection of unknown pathogen(s), and the substances may originate from not only the pathogens but also the injured host cells and/or activated immune cells caused by infectious insults [9]. These substances bind to specific cells of the target organs, such as specific target cells of the CNS in KNL meningoencephaltis. This leads to corresponding immune reactions against these substances, which induce inflammation in the pathologic lesions. Corticosteroids may act on hyperactive immune cells that are needed for disease control [9]. Early and adequate dose of corticosteroid treatment on KNL may be crucial. Aseptic meningitis is the most commonly reported neurological complication in KNL (2.8–9.8%) [2–5]. We searched eight published cases of KNL with meningitis/encephalitis in PubMed as English literature (Table 1). In the cases in the literature, the time between onset of lymphadenopathy and neurological symptoms were 10–53 days. Neuroimaging demonstrated hyperintense signals in the temporal lobes, brainstem, internal capsule, and cerebellum. CSF analysis showed lymphocyte-dominant pleocytosis with high protein

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Please cite this article in press as: Byun J-H et al. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev (2017), https://doi.org/10.1016/j.braindev.2017.09.009