Encephalopathy With a Reversible Splenial Lesion

Accepted Manuscript Subclinical neuroaxonal damage in patients with clinically mild encephalitis/ encephalopathy with a reversible splenial lesion Mitsuo Motobayashi, Tetsuhiro Fukuyama, Jiu Okuno-Yuguchi, Keiko Tsukahara, Sachiko Nagaharu, Rokuro Hagimoto, Tatsuya Kinoshita, Yozo Nakazawa, Yuji Inaba PII:

S0887-8994(17)30556-8

DOI:

10.1016/j.pediatrneurol.2017.05.026

Reference:

PNU 9167

To appear in:

Pediatric Neurology

Received Date: 26 May 2017 Accepted Date: 28 May 2017

Please cite this article as: Motobayashi M, Fukuyama T, Okuno-Yuguchi J, Tsukahara K, Nagaharu S, Hagimoto R, Kinoshita T, Nakazawa Y, Inaba Y, Subclinical neuroaxonal damage in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion, Pediatric Neurology (2017), doi: 10.1016/j.pediatrneurol.2017.05.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

Letter to the editor Subclinical neuroaxonal damage in patients with clinically mild

RI PT

encephalitis/encephalopathy with a reversible splenial lesion

Mitsuo Motobayashia,b, Tetsuhiro Fukuyamac, Jiu Okuno-Yuguchic, Keiko Tsukaharad,

SC

Sachiko Nagaharue, Rokuro Hagimotof, Tatsuya Kinoshitae, Yozo Nakazawab and Yuji

M AN U

Inabab

Affiliations:

Division of Neonatology, Department of Pediatrics, Shinshu University School of

TE D

a

Medicine, Matsumoto, Japan

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

c

Department of Neurology, Nagano Children's Hospital, Azumino, Japan

d

Department of Pediatrics, Kofu Municipal Hospital, Kofu, Japan

e

Department of Pediatrics, Ina Central Hospital, Ina, Japan

f

Department of Pediatrics, Iida Municipal Hospital, Iida, Japan

AC C

EP

b

Address correspondence to: Mitsuo Motobayashi, MD, PhD

1

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

Department of Pediatrics, Shinshu University School of Medicine Address: 3-1-1 Asahi, Matsumoto 390-8621, Japan

SC

Short title: CSF levels of pNf-H in MERS patients

RI PT

Phone: +81-263-37-2642; Fax: +81-263-37-3089; E-mail: [email protected]

M AN U

Key Words: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS); reversible splenial lesion syndrome (RESLES); phosphorylated form of

TE D

neurofilament heavy chain (pNf-H); neuroaxonal damage; biomarker.

Financial Disclosure: The authors have indicated they have no financial relationships

EP

relevant to this study to disclose.

AC C

Conflict of Interest: The authors have indicated they have no potential conflicts of interest to disclose.

2

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

To the editor: Reversible isolated lesions in the splenium of the corpus callosum, as detected by

RI PT

magnetic resonance imaging (MRI), are associated with various disorders1, and have been termed reversible splenial lesion syndrome (RESLES).1 Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) has been

SC

considered as a form of RESLES.2 To evaluate neuroaxonal damage in patients with

M AN U

MERS, we analyzed cerebrospinal fluid (CSF) concentrations of the phosphorylated form of neurofilament heavy chain (pNf-H), which is a specific neuroaxonal biomarker.3

TE D

Four children with MERS and 14 age-matched disease control subjects who were seen at our hospitals and whose parents gave written informed consent were

EP

retrospectively analyzed in this study. The diagnosis of MERS was made based on the reported criteria.4 The significance of differences between 2 groups was calculated

AC C

using the Mann-Whitney’s U test. Undetectable pNf-H levels were defined as 0.010 ng/mL for statistical analyses. All statistical analyses were conducted using PASW statistics, version 18 (SPSS, Inc., Chicago, USA). The level of significance was established as a p-value of less than 0.05. This study was approved by the Ethics

3

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

Committee of Shinshu University School of Medicine and performed in accordance with the 1964 Declaration of Helsinki and its later amendments.

RI PT

As shown in Table 1, no significant differences in age or gender were observed between the patients with MERS and control subjects. All 4 patients with MERS had disturbance of consciousness, although no subjects in the control group did. Two

SC

patients and 14 controls showed seizures. All 18 patients enrolled in this study had no

M AN U

sequelae and fully recovered. There were no significant differences in peripheral white blood cell counts, CSF cell counts, or CSF levels of glucose and protein between the 2 groups. Serum C-reactive protein levels were significantly higher in patients with

TE D

MERS than in controls, and serum sodium concentrations in patients with MERS were significantly lower than in controls. All 4 patients with MERS had abnormal MRI

EP

findings specific for MERS. No patients in the control group showed abnormal brain MRI or computed tomographic findings. CSF levels of pNf-H were significantly higher

AC C

in patients with MERS (median, 0.093 ng/mL; range, 0.010-2.336) than in controls (0.010 ng/mL; P = 0.006) (Table 1). Neurofilament is a major structural component of neurons and is composed of 3 subunits, including a light, medium, and heavy chain.3 Increases in pNf-H levels in CSF have been reported in both pediatric and adult patients with cerebro-spinal disorders.3

4

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

Therefore, the CSF value of pNf-H can be used as a specific biomarker for neuroaxonal injury or degeneration;3 however, there have been no reports in patients with MERS to

RI PT

date. In this study, there was a significant increase in the CSF concentration of pNf-H in patients with MERS compared with control subjects, although all these patients fully recovered and had no clinically evident sequelae as with the previous report. This

SC

suggested that these MERS patients had subclinical neuroaxonal damage, which is

M AN U

consistent with previous reports of cases of MERS that had clinically evident sequelae.4,5 However, the pathophysiological mechanism of neuroaxonal damage in

References 1.

TE D

patients with MERS has been unclear, and further analyses are warranted.

Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion

Azuma J, Nabatame S, Katsura T, et al. Marked elevation of urinary

AC C

2.

EP

syndrome (RESLES): what's in a name? J. Neuroimaging. 2011;21:e1-14.

beta2-microglobulin in patients with reversible splenial lesions: A small case series. J. Neurol. Sci. 2016;368:109-12.

3.

Petzold A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J. Neurol. Sci. 2005;233:183-98.

4.

Hoshino A, Saitoh M, Oka A, et al. Epidemiology of acute encephalopathy in

5

MOTOBAYASHI et al.

ACCEPTED MANUSCRIPT

Japan, with emphasis on the association of viruses and syndromes. Brain Dev. 2012;34:337-43.

RI PT

Takanashi J, Miyamoto T, Ando N, et al. Clinical and radiological features of

EP

TE D

M AN U

SC

rotavirus cerebellitis. AJNR. Am. J. Neuroradiol. 2010;31:1591-5.

AC C

5.

6

ACCEPTED MANUSCRIPT

Table 1. Clinical and laboratory findings of children with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) and age-matched control subjects. Controls (n = 14) Median (range) or number

Age (years)

5.4 (2.0 to 8.0)

5.4 (0.2 to 15.8)

Male : female

3:1

6:8

Fever (≥38.0 degree C)

4

2

Disturbance of consciousness

4

0

Seizure

14

Sequela

2 0

Causative pathogens or diagnosis

Rotavirus enteritis

2

Epilepsy

Acute pharyngitis

1

CwG

MCLS

1

SC 12 2

M AN U

0

RI PT

Patients with MERS (n = 4) Median (range) or number

Blood exam Peripheral WBC (/µL)

16,490 (9,100 to 23,630)

10,080 (5,300 to 20,910)

Serum CRP (mg/dL)

5.94 (2.30 to 20.31)

0.01 (0.00 to 7.82)*

Serum sodium (mEq/L)

133 (130 to 134)

140 (133 to 144) †

Cell counts (/µL)

4 (1 to 5)

Glucose (mg/dL)

72 (58 to 86)

Protein (mg/dL)

17 (11 to 21)

TE D

CSF exam‡

1 (0 to 13)

56 (47 to 126) 23 (12 to 72)

4

CSF levels of pNf-H (ng/mL) §

0.093 (0.010 to 2.336)

AC C

EP

Abnormal brain imaging test finding

0 N.D¶

CRP, C-reactive protein; CSF, cerebrospinal fluid; CwG, benign convulsions with mild gastroenteritis; MCLS, mucocutaneous lymph node syndrome; N.D, all samples were below the detectable limit; pNf-H, phosphorylated form of neurofilament heavy chain; WBC, white blood cell. * Significant difference between patients with MERS and controls (p = 0.005). † Significant difference between patients with MERS and controls (p = 0.006). ‡ Lumbar punctures were performed atraumatically without red blood cells contamination for routine diagnostic evaluation. All CSF samples were collected within 24 hours after admission with no immunosuppressive therapies or antiviral agents, and stored at -30 °C until later testing. § CSF levels of pNf-H were measured by enzyme-linked immunosorbent assay using sandwich-type commercial kits (pNf-H Sandwich ELISA Kit, Merck Millipore, Billerica, Massachusetts, USA) according to the manufacturer’s instructions. Samples were assayed in duplicate. The Lower detection limits of pNf-H were 0.029 ng/mL. ¶ Significant difference between patients with MERS and controls (p = 0.006).