European Review for Medical and Pharmacological Sciences

2014; 18: 2148-2151

An infant with steroid-refractory
cytomegalovirus-associated ADEM who
responded to immunoglobulin therapy
G. IMATAKA, O. ARISAKA
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, JapanA b s t r a c t . – Acute disseminated encephalomyelitis (ADEM) develops via an immunological mechanism. We encountered a 10month-old infant with a rare pathogenesis of cytomegalovirus (CMV)-related ADEM. The patientscomplaints were; protracted fever; counsciousness disorder; and affected cervical stability.
Cerebral magnetic resonance imaging (MRI) 9days after onset, revealed a disseminated lesion,suggesting ADEM. Pulse therapy with methylprednisolone at 30 mg/kg was performed for 3days. However, its clinical efficacy was notmarked. Therapy with immunoglobulin (IVIg) at
400 mg/kg/day was started 15 days after onset,
and continued for 5 days. This markedly improved the consciousness level and muscle
strength, and the infant was discharged without
neurological sequelae . ADEM showed amonophasic course, and the infant’s subsequent
growth has been favorable. Altough the numberof case reports is small, massive-IVIg therapy
should be considered in patients with steriod-refractory ADEM, as demonstrated in this casestudy.
Key Words:
Cytomegalovirus, Acute disseminated encephalomyelitis, Immunoglobulin.

Introduction
Acute disseminated encephalomyelitis(ADEM) represents monophasic allergic encephalomyelitis with a disseminated white matterlesion. Autoimmune disorders with inflammatory
demyelination in response to myelin antigen in
the central nervous system may be involved in
the various pathogenesis1,2. We herein report theclinical course of an infant with a rare pathogenesis of cytomegalovirus (CMV)-related ADEM.
Steroid therapy is usually effective for conventional cases of ADEM 3. However, methylpredonisolone pulse therapy was not effective in thepresent case, and this infant responded better to2148

immunoglobulin (IVIg) therapy. We discuss theclinical course of this infant who was diagnosed
with neuroradiological method using MRI, MRS,
99m
Tc-ECD SPECT analysis.
Case Study
The infant was a 10-month-old boy. His development was normal, and neither the medical nor
family history was contributory. The infant wasadmitted for fever and poor sucking at 6 days after onset. Consciousness on admission consistedof repeated excitation with crying and somnolence. On consultation, pharyngeal flare was observed. The eyes were frequently fixed on the
median line, and sometimes, there was no pursuit
eye movement. The light reflex was normal.
General muscle strength was reduced, and neckstabilization was impossible. The deep tendon reflex of the upper limbs was normal, but that of
the lower limbs was enhanced. Neither brain CTon day 7 after onset revealed any abnormal densities. Hematology showed a WBC of 19,600, aCRP level of 0.6, an AST level of 117, and ALTlevel of 224. The electrolyte, glucose and blood
gas levels were normal. The infant was positive
for serum CMV-specific IgM antibody. CSF wasnegative for myelin basic protein and oligoclonalbands, with a cell count of 5/3 and a protein levelof 22 mg/dl. Concerning the consciousness level
at 8 days after onset, the infant’s eyes opened
when his body was shaken, and Jouvet Coma
Scale JCS) was evaluated as 20. On EEG, a 2-Hz
slow wave was predominant as the backgroundactivity. At nine days after onset, brain MRI revealed an abnormal disseminated intensity, thus,
suggesting ADEM (Figure 1A). Steroid pulse
therapy (30 mg/kg/day) was performed for 3days. A respiratory disorder related to a submerged tongue root occurred 10 days after onset,
and intubation was, thus, performed. In the Magnetic Resonance Spetroscopy (MRS) findings on
the 12th day, abnormal signals remained in theCorresponding Author: George Imataka, MD; e-mail: geo@dokkyomed.ac.jp

Cytomegalovirus-associated ADEM

Figure 1. A, The MRI findings of the day 9: Multiple high intensity areas were observed in the T2WI, almost symmetrically,
on both sides of the thalamus, periaqueductal gray matter, on the right side of the pons, both sides of the cerebral hemisphere’s
white matter and the cerebellar dentate nucleus. These signals presented as high signals in the diffusion-weighted images(DWI) and low signals in the ADC-map, thus representing a finding of cellulous edema. B, In the MRI findings of day 17: Although abnormal signals were observed at multiple areas on both sides of the subcortical white matter in the DWI, there wasmore of a tendency toward contraction than previously observed. In the T2WI findings, abnormal signals remained almost
symmetrical at the thalamus and in the temporal lobe subcortical white matter and the long T2 lesion in the brain stem disappeared. C, The MRI from 6 months after onset showed normal findings.

thalamus and elsewhere, and a lactic acid peak
was detected at both echo times of 135 and 30(Figure 2A). In the 99mTc-ECD SPECT findingsof the same day, uneven images of cerebral hypoperfusion were observed at both sides of thebasal ganglion, thalamus brain stem and in thecerebellum region (Figure 3A). To treat convulsion, continuous intravenous injection of midazolam at 0.3 mg/kg/hr was performed. The neckstability remained low 15 days after onset, andthere was no improvement in the consciousness
levels from 20 days after onset. Subsequent treatment, massive doses of immunoglobulin therapy

at 400 mg/kg were administered for 5 days fromthe 15th to 19th day. MRI scans were taken on the17th day. Although abnormal signals in the T2
weighted images remained, when looking at thediffusion-weighted image, the abnormal signals,
including the subcortical white matter, demonstrated a contractive tendency (Figure 1B). In theMRS findings on the 19th day, both echo times of
135 and 30 tended to improve with respect to thelactic acid levels (Figure 2B). Head shaking
movements gradually occurred from 21 days after onset, and the eyes became persistently open
in the absence of stimulation. Neck stabilization

Figure 2. The MRS from day 12 (A) and day 19 (B). The measurement site was a long T2 lesion of the left thalamus. At TE =135, the Lac/NAA rate was observed to have decreased from 0.21 to 0.1. At TE = 30, the Lac/NAA reduced from 0.31 to 0.14
and the peak of lactic acid decreased by half.

2149

G. Imataka, O. Arisaka

became possible at 28 days after onset. In theSPECT findings on the 35th day, the cerebral hypoperfusion image on both sides of the basal
ganglion showed no improvement (Figure 3B).
Rehabilitation treatment was started, and it became possible to maintain the sitting position by
41 days after onset. The infant could stand while
grasping something at 43 days after onset, and he
was discharged 44 days after onset. Six months
later, brain the MRI findings have also normalized (Figure 1C) and a cerebral perfusion image
in both basal ganglion and thalamus were improved (Figure 3C). Currently, the boy is 4 years
old, no neurological sequelae have been observed, and his motor and intellectual development was normal.

Discussion
Acute disseminated encephalomyelitis(ADEM) presents as a monophasic clinical course
characterized by allergic encephalomyelitis with adisseminated white matter lesion. In the pathogenesis, autoimmune disorders with inflammatory demyelination in response to myelin antigen in thecentral nervous system may be involved. ADEM isclassified into 3 types by etiological factors: postinfection ADEM4,5, post-prophylactic vaccination
ADEM6, and idiopathic ADEM1,2. Various etiological factors for ADEM have been reported but inpost-viral infection CMV-related ADEM is considered to be rare7-11. There have been few reports

of ADEM occurring due to a cytomegalovirus infection and there have only been a few cases of infant patients with a related background of immunosuppressive condition bone marrow transplant or renal transplantation 11. In our infant,methylpredonisolone steroid pulse therapy wasinitially performed, but its clinical efficacy was
found to be insufficient. Thereafter, massive dosesof immunoglobulin therapy were administrated
which successfully, improved the consciousness
level and general muscle strength. There were noadverse reactions to the immunoglobulin therapy.
The subsequent development was, thus, normal
without any neurological sequelae. In this infant,
ADEM showed a monophasic clinical course. Recent studies have reported the efficacy of immunoglobulin therapy not only for the treatmentof ADEM but also for the treatment of various autoimmune disorders12. Unfortunately, the detailed
pharmacological mechanism of immunoglobulin
for ADEM remains unclear. However, massive
doses of immunoglobulin therapy should be considered in the early stages of the disease to treat
steroid-refractory ADEM, as demonstrated in ourinfant, although the number of such clinically reported patients is still small. As a result, further
clinical studies of a larger number of patients are,thus, called for before any definitive conclusions
can be made.
–––––––––––––––––-––––

Conflict of Interest

The Authors declare that there are no conflicts of interest.

Figure 3. SPECT findings using 99mTc-ECD on day 12 (A) shows uneven images of cerebral hypoperfusion on both sides ofthe basal ganglion, thalamus brain stem and cerebellum region. In the SPECT findings on day 35, the cerebral hypoperfusion
image was particularly well observed on both sides of the thalamus. C, The 99mTc-ECD SPECT findings on the 6 months after
onset showed improvement of cerebral perfusion in both side of basal ganglia and thalamus.

2150

Cytomegalovirus-associated ADEM

References
1) G UPTE G, S TONEHOUSE M, WASSMER E, C OAD NA,W H I T E H O U S E WP. Acute disseminated encephalomyelitis: a review of 18 cases in childhood. J Paediatr Child Health 2003; 39: 336-342.
2) INCECIK F, HERGUNER MO, ALTUNBASAK S. Acute disseminated encephalomyelitis: an evaluation of 15
cases in childhood. Turk J Pediatr 2013; 55: 253259.
3) MONDEN Y, YAMAGATA T, KUROIWA Y, TAKAHASHI T, MORI M,FUKUDA T, SUGIE H, MOMOI MY. A case of ADEM withatypical MRI findings of a centrally-located longspinal cord lesion. Brain Dev 2012; 34: 380-383.
4) M OHSEN H, A BU Z EINAH GF, E LSOTOUHY AH, M O HAMED K. Acute disseminated encephalomyelitis
following infectious mononucleosis in a toddler.
BMJ Case Rep 2013 Jul 10; 2013. Pii:
bcr2013010048. Doi: 10.1136/bcr-2013-010048.
5) BUDAN B, EKICI B, TATLI B, SOMER A. Acute disseminated encephalomyelitis (ADEM) after pertussis infection. Ann Trop Paediatr 2011; 31: 269-272.
6) FUJII K, SUYAMA M, CHIBA K, OKUNUSHI T, OIKAWA J,
KOHNO Y. Acute disseminated encephalomyelitis
following 2009 H1N1 influenza vaccine. Pediatr
Int 2012; 54: 539-541.

7) Z AGURI R, S HELEF I, I FERGAN G, A LMOG Y. Fetal
acute disseminated encephalomyelitis associated with cytomegalovirus infection. BMJ Case
Rep 2009; 2009. Pii: bcr07.2008.0443. doi:
10.1136/bcr.07.2008.0443.
8) K ANZAKI A, Y ABUKI S. Acute disseminated encephalomyelitis (ADEM) associated with cytomegalovirus infection—a case report. Rinsho
Shinkeigaku 1994; 34: 511-513.
9) TAKETANI T, KIMURA M, KISHI K, SEJIMA H, TAKUSA Y, YAMAGUCHI S. Acute disseminated encephalomyelitis
in a 3-month-old infant. No To Hattatsu 2001; 33:172-177.
10) TOMONARI A, TOJO A, ADACHI D, ISEKI T, OOI J, SHIRAFUJI N, TANI K, ASANO S. Acute disseminated encephalomyelitis (ADEM) after allogenic bone marrow transplantation for acute myeloid leukemia.
Ann Hematol 2003; 82: 37-40.
11) I WANAGA T, O OBOSHI H, I MAMURA T, M IZUMASA T,IBAYASHI S, HIRAKATA H, FUJISHIMA M. A case of acutedisseminated encephalomyelitis after renal transplantation. Rinsho Shinkeigaku 2001; 41: 792796.
12) IMATAKA G, ARISAKA O. Long-term, high-dose intravenous immunoglobulin therapy in a patient withbanker-type juvenile der matomyositis. Cell
Biochem Biophysn 2014; 69: 747-748.

2151