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Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination
Journal of the Neurological Sciences 349 (2015) 226–228
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination Jun-ichi Takanashi a,⁎, Takashi Shiihara b, Takeshi Hasegawa c, Masaru Takayanagi d, Munetsugu Hara e, Akihisa Okumura f, Masashi Mizuguchi g a
Department of Pediatrics, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan Department of Neurology, Gunma Children's Medical Center, Shibukawa, Japan Department of Pediatrics, Soka Municipal Hospital, Soka, Japan d Division of Pediatrics, Sendai City Hospital, Sendai, Japan e Department of Pediatrics & Child Health, Kurume University School of Medicine, Kurume, Japan f Department of Pediatrics, Aichi Medical University, Nagakute, Japan g Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 8 October 2014 Received in revised form 18 November 2014 Accepted 12 December 2014 Available online 18 December 2014 Keywords: Mumps vaccination Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) Hyponatremia MRI Diffusion Splenium
a b s t r a c t We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7–15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Natural mumps infection causes symptomatic aseptic meningitis in 1– 10%, and encephalitis in 0.1% [1]. The central nervous system (CNS) complications are much less common in mumps monovalent vaccine recipients, aseptic meningitis and encephalitis being observed in 0.05% and 0.0004% in Japan [2,3]. A reversible lesion with transiently reduced diffusion in the splenium of the corpus callosum has been reported in patients with clinically mild encephalitis/encephalopathy, leading to a new clinical–radiological syndrome, clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS) [4,5]. The reason for the transiently reduced diffusion is unknown, however, transient
Abbreviations: ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalography; MERS, clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MRI, magnetic resonance imaging. ⁎ Corresponding author at: Department of Pediatrics, Tokyo Women's Medical University, Yachiyo Medical Center, 477-96 Owadashinden, Yachiyo-shi 276-8524, Japan. Tel.: +81 47 450 6000; fax: +81 47 458 7047. E-mail address: [email protected] (J. Takanashi).
http://dx.doi.org/10.1016/j.jns.2014.12.019 0022-510X/© 2014 Elsevier B.V. All rights reserved.
intramyelinic edema has been postulated as a possible mechanism [4,5]. Recently, Japanese children with MERS after mumps vaccination have been reported [6,7]. In order to better understand this condition, we evaluated the clinical and radiological features of three patients with MERS after mumps vaccination in addition to the two reported ones.
2. Methods Information on patients with MERS after mumps vaccination was retrospectively collected by sending out a questionnaire to the members of the Annual Zao Conference on Pediatric Neurology in addition to the corresponding authors of previous reports [6,7], after approval by the institutional review board of Tokyo Women's Medical University. The diagnosis of MERS was established according to diagnostic criteria [4,8]. We reviewed the clinical charts of the patients in order to accrue information on symptoms, medication, treatment, outcome, and results of cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), and electroencephalography (EEG). Mumps virus and its strain were confirmed by RT-PCR and/or isolation from CSF and sequencing of SH gene. The day of the initial symptoms, such as fever, was defined as day 0.
J. Takanashi et al. / Journal of the Neurological Sciences 349 (2015) 226–228
227
3. Case series and literature review Three previously healthy Japanese patients (3 males, aged from 2 to 9 years) were enrolled in this study. Patient 3 was reported in an annual hospital report, written in Japanese [9]. The clinical and radiological records, including those of two patients previously reported (patients 4 and 5, both males aged 8 and 1), are summarized in Table 1. The five patients presented with fever (5 patients), vomiting (4), and headache (2) as the initial symptoms (day 0) at 13 to 21 days after mumps vaccination. Consciousness disturbance (Glasgow Coma Scale ≤ 13, 3 patients), delirious behavior (2), seizures (2), or dysarthria (1) was observed on days 1 to 3, which had completely resolved on days 2 to 11. A CSF study revealed pleocytosis, and confirmed mumps vaccine virus (Hoshino strain in 4 patients, Torii strain in 1). MRI revealed reduced diffusion and mild T2 prolongation in the splenium of the corpus callosum (5 patients) with the genu of the corpus callosum (1) and the symmetric white matter (3) on days 2 to 4 (Fig. 1), which had completely disappeared on follow-up scanning on days 7–15. EEG showed high voltage slow waves in 3 patients (diffuse in 1, O dominant in 2), which later normalized. Hyponatremia was observed in all patients on days 2 to 3, which normalized on days 5 to 10. Hyponatremia was due to the syndrome of inappropriate secretion of antidiuretic hormone in 4 patients. 3 patients were given steroids (3) or δ-globulin (1) as specific therapy for encephalopathy. The clinical, laboratory and radiological findings led to a diagnosis of MERS after mumps vaccination. 4. Discussion Encephalitis is an extremely rare CNS manifestation in mumps vaccine recipients, the frequency is estimated to be 0.0004% (4/1,000,000) [3], which is much lower than that in natural mumps (0.1%) [1]. Encephalitis after mumps vaccination may include acute disseminated encephalomyelitis (ADEM) [10]. The exact frequency of ADEM is uncertain, however, it should be very rare according to the fact that possible ADEM after mumps vaccine was only reported in one patient among 1.53 million doses of mumps vaccine in Japan [11]. As far as we know, there have been five Japanese patients with MERS after mumps vaccination (Table 1) [6,7],
Fig. 1. MRI of patient 2. On day 3, diffusion-weighted images reveal lesions in the splenium of the corpus callosum and symmetric white matter. These lesions disappear completely on day 8, which is compatible with MERS type 2.
including the present three patients, suggesting that this condition may be a more frequent adverse event after mumps vaccination than previously considered. MERS is the mildest and the second most common infectious encephalitis/encephalopathy syndrome in Japanese children, and is characterized by mild neurological symptoms (delirious behavior in 54%, consciousness disturbance in 35%, and seizures in 33%) with complete clinical recovery, and the MRI finding of a reversible splenial lesion (type 1 MERS), sometimes associated with symmetrical white matter lesions (MERS type 2) [4,5,8]. Hyponatremia is often observed in patients with MERS [12], thus, hyponatremic cerebral edema is postulated to be a contributing factor for MERS, though the exact pathophysiology is still uncertain. The five patients with MERS after mumps vaccination showed an interval from vaccination to clinical symptoms ranging from
Table 1 Data for MERS after mumps vaccination. Pt.
Age/sex
Initial symptoms (day 0)
Mumps vaccination
Neurological symptoms
CSF CC Mumps strain
Lowest/normalized Na mechanism
1
9/M
Fever, vomiting
D-13
Con (D2–4)
2
5/M
Fever, vomiting, headache
D-20
Del (D1–2), seizure (D2)
3
2/M
Fever
D-21
Con (D2), dysarthria (D2–11)
117 (D2)/137 (D10) SIADH 124 (D3)/137 (D7) SIADH 131 (D2)/137 (D5)
4
8/M
Fever, vomiting, headache
D-20
Del (D1–6)
5
1/M
Fever, vomiting
D-17
Con (D3–6), seizure (D3)
277 (M 157, P 120) (D2) Hoshino 280 (M 276, P 4) (D2) Hoshino 490 (M 490, P 0) (D2) Hoshino 624 (M 618, P 6) (D4) Torii 868 (M 854, P 14) (D3) Hoshino
128 (D2)/137 (D6) SIADH 125 (D3)/134 (D6) SIADH
DWI lesion
EEG results
Prognosis
Sp, genu, WM (D3) None (9) Sp, WM (D3) None (D8) Sp (D3) None (D11) Sp, WM (D2) None (D15) Sp (D4) None (D7)
HVS in O (D2)
CR
Reference
HVS in P,O (D2) Normal (D8) Normal (D4)
CR CR
9
Normal (D6)
CR
6
Diffuse HVS (D4) Normal (D11)
CR
7
Abbreviations Pt, patient; CSF, cerebrospinal fluid; CC, cell counts; DWI, diffusion-weighted image; EEG, electroencephalography; M, male; D, day; Con, consciousness disturbance; Del, delirium; M, mononuclear leukocyte; P, polymorphonuclear leukocyte; SIADH, syndrome of inappropriate; DEX, dexamethasone; mPSL, methylprednisolone; Glo, δ-globulin; Sp, splenium; WM, white matter; HVS, high voltage slow; O, occipital; P, parietal; CR, complete recovery.
228
J. Takanashi et al. / Journal of the Neurological Sciences 349 (2015) 226–228
13 to 21 days (equal to the incubation time of mumps infection); initial symptoms of fever, headache, and vomiting (suggesting meningitis), followed by CNS symptoms within 3 days; hyponatremia; and positive vaccine strain in CSF (Table 1). These findings strongly suggest that live attenuated mumps virus directly causes aseptic meningitis first, then possibly progressing to MERS under hyponatremic conditions. It has been reported that males more frequently present with mumps meningitis than females [1]. Actually, the male/female ratio of natural mumps meningitis in Japan between 2009 and 2011 was 2.32 (1764/ 759) [13]. Meningitis after mumps vaccination also occurs more predominantly in males than in females, i.e., nine of 10 patients with meningitis after mumps vaccination were males [2]. Interestingly, the five patients with MERS after mumps vaccination were all males. The number of MERS after mumps vaccination is too small to estimate the statistical significance; male might be a risk factor for developing MERS after mumps vaccination. In Japan, methylprednisolone pulse therapy and intravenous immunoglobulin are recommended for patients with infectious encephalopathy regardless of the pathogen or the clinicoradiological syndromes [14]. These treatments suppress inflammatory cytokines, and may be effective for those caused by cytokine storm, such as acute necrotizing encephalopathy (ANE) [14]. However, there is no evidence of their efficacy in MERS. As a treatment, steroids and intravenous immunoglobulin were given in 16 and 8 of the 54 patients with MERS in Japan [4], respectively. On the other hand, 19 patients received no such treatment. All 54 patients with MERS clinically recovered completely, irrespective of the treatments, suggesting that steroids or intravenous immunoglobulin is not always necessary. This is also the case for MERS after mumps vaccination, the five patients recovering completely, irrespective of the treatment, which might be related with normalization of sodium. In any case, MERS after mumps vaccination is expected to recover completely. Unlike ANE or acute encephalopathy with biphasic seizures and late reduced diffusion, which are by far more common in East Asia than in the rest of the world [4,14], MERS has been reported all over the world [15]. MERS after mumps vaccination, however, has never been reported in a country other than Japan. Because of the relatively high incidence of influenza encephalopathy in Japan, we usually perform brain MRI in children with relatively mild CNS symptoms. This may explain why MERS after mumps vaccination has been reported only in Japan, that is, this might be underestimated. This study has some limitations, mainly based on retrospective nature. Because we had no protocol for MRI, there might be some patients whose splenial lesion had already disappeared before MRI studies, which may lead to underestimation of this condition. The number of patient is too small to make statistical analysis, including whether there is male predominance. Further study with MRI protocol may lead to a better understanding of this condition. In conclusion, it should be emphasized that MERS after mumps vaccination may be more common than previously considered, and
the prognosis is excellent. One should suspect MERS when a male patient after mumps vaccination presents with neurological symptoms (delirious behavior, consciousness disturbance, and seizures) with hyponatremia, following symptoms of aseptic meningitis (fever, headache and vomiting), and MRI should be performed to evaluate the splenium of the corpus callosum.
Conflict of interest All authors declare no conflict of interest.
Acknowledgments This study was supported by the Grant-in-Aid for Scientific Research (B24390258) from the Japan Society for the Promotion of Science to J.T. and M.M.
References [1] Hviid A, Rubin S, Mühlemann K. Mumps. Lancet 2008;371:932–44. [2] Nagai T, Okafuji T, Miyazaki C, Ito Y, Kamada M, Kumagai T, et al. A comparative study of the incidence of aseptic meningitis in symptomatic natural mumps patients and monovalent mumps vaccine recipients in Japan. Vaccine 2007;25:2742–7. [3] Ihara T. Mumps vaccine: present and future situations. In Japanese. Rinsho To Uirusu 2010;38:386–92. [4] Takanashi J. Two newly proposed encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521–8. [5] Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63:1854–8. [6] Hara M, Mizuochi T, Kawano G, Koike T, Shibuya I, Ohya T, et al. A case of clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. Brain Dev 2011;33:842–4. [7] Oikawa N, Okumura A, Oyama S, Baba H, Shimizu T, Kato A. A 15-month-old-boy with reduced consciousness and convulsion. J Clin Virol 2012;53:276–9. [8] Hoshino A, Saitoh M, Oka A, Okumura A, Kubota M, Saito Y, et al. Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndrome. Brain Dev 2012;34:337–43. [9] Sasaki K, Uchida T, Takayanagi M, Nakamura H, Takahashi T, Sato D, et al. Case report; clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination. In Japanese. J Sendai City Hosp 2014;34:46–9. [10] Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. Post-vaccination encephalomyelitis: literature review and illustrative case. J Clin Neurosci 2008;15:1315–22. [11] Nakayama T, Onoda K. Vaccine adverse events reported in post-marketing study of the Kitasato Institute from 1994 to 2004. Vaccine 2007;25:570–6. [12] Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ. Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev 2009;31:217–20. [13] Hosaka S, Komori T, Hoshina K, Mine M, Hosoya M, Igarashi T. Evaluation of severe patients with mumps and varicella zoster. In Japanese. Nihon Shounika Ikaihou 2012;44:182–6. [14] Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 2007;115:45–56. [15] Garcia-Monco JC, Cortina IE, Ferreira E, Martínez A, Ruiz L, Cabrera A, et al. Reversible splenial lesion syndrome (RESLES): what's in a name? J Neuroimaging 2011;21:e1-14.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination Jun-ichi Takanashi a,⁎, Takashi Shiihara b, Takeshi Hasegawa c, Masaru Takayanagi d, Munetsugu Hara e, Akihisa Okumura f, Masashi Mizuguchi g a
Department of Pediatrics, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan Department of Neurology, Gunma Children's Medical Center, Shibukawa, Japan Department of Pediatrics, Soka Municipal Hospital, Soka, Japan d Division of Pediatrics, Sendai City Hospital, Sendai, Japan e Department of Pediatrics & Child Health, Kurume University School of Medicine, Kurume, Japan f Department of Pediatrics, Aichi Medical University, Nagakute, Japan g Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 8 October 2014 Received in revised form 18 November 2014 Accepted 12 December 2014 Available online 18 December 2014 Keywords: Mumps vaccination Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) Hyponatremia MRI Diffusion Splenium
a b s t r a c t We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7–15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Natural mumps infection causes symptomatic aseptic meningitis in 1– 10%, and encephalitis in 0.1% [1]. The central nervous system (CNS) complications are much less common in mumps monovalent vaccine recipients, aseptic meningitis and encephalitis being observed in 0.05% and 0.0004% in Japan [2,3]. A reversible lesion with transiently reduced diffusion in the splenium of the corpus callosum has been reported in patients with clinically mild encephalitis/encephalopathy, leading to a new clinical–radiological syndrome, clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS) [4,5]. The reason for the transiently reduced diffusion is unknown, however, transient
Abbreviations: ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalography; MERS, clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MRI, magnetic resonance imaging. ⁎ Corresponding author at: Department of Pediatrics, Tokyo Women's Medical University, Yachiyo Medical Center, 477-96 Owadashinden, Yachiyo-shi 276-8524, Japan. Tel.: +81 47 450 6000; fax: +81 47 458 7047. E-mail address: [email protected] (J. Takanashi).
http://dx.doi.org/10.1016/j.jns.2014.12.019 0022-510X/© 2014 Elsevier B.V. All rights reserved.
intramyelinic edema has been postulated as a possible mechanism [4,5]. Recently, Japanese children with MERS after mumps vaccination have been reported [6,7]. In order to better understand this condition, we evaluated the clinical and radiological features of three patients with MERS after mumps vaccination in addition to the two reported ones.
2. Methods Information on patients with MERS after mumps vaccination was retrospectively collected by sending out a questionnaire to the members of the Annual Zao Conference on Pediatric Neurology in addition to the corresponding authors of previous reports [6,7], after approval by the institutional review board of Tokyo Women's Medical University. The diagnosis of MERS was established according to diagnostic criteria [4,8]. We reviewed the clinical charts of the patients in order to accrue information on symptoms, medication, treatment, outcome, and results of cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), and electroencephalography (EEG). Mumps virus and its strain were confirmed by RT-PCR and/or isolation from CSF and sequencing of SH gene. The day of the initial symptoms, such as fever, was defined as day 0.
J. Takanashi et al. / Journal of the Neurological Sciences 349 (2015) 226–228
227
3. Case series and literature review Three previously healthy Japanese patients (3 males, aged from 2 to 9 years) were enrolled in this study. Patient 3 was reported in an annual hospital report, written in Japanese [9]. The clinical and radiological records, including those of two patients previously reported (patients 4 and 5, both males aged 8 and 1), are summarized in Table 1. The five patients presented with fever (5 patients), vomiting (4), and headache (2) as the initial symptoms (day 0) at 13 to 21 days after mumps vaccination. Consciousness disturbance (Glasgow Coma Scale ≤ 13, 3 patients), delirious behavior (2), seizures (2), or dysarthria (1) was observed on days 1 to 3, which had completely resolved on days 2 to 11. A CSF study revealed pleocytosis, and confirmed mumps vaccine virus (Hoshino strain in 4 patients, Torii strain in 1). MRI revealed reduced diffusion and mild T2 prolongation in the splenium of the corpus callosum (5 patients) with the genu of the corpus callosum (1) and the symmetric white matter (3) on days 2 to 4 (Fig. 1), which had completely disappeared on follow-up scanning on days 7–15. EEG showed high voltage slow waves in 3 patients (diffuse in 1, O dominant in 2), which later normalized. Hyponatremia was observed in all patients on days 2 to 3, which normalized on days 5 to 10. Hyponatremia was due to the syndrome of inappropriate secretion of antidiuretic hormone in 4 patients. 3 patients were given steroids (3) or δ-globulin (1) as specific therapy for encephalopathy. The clinical, laboratory and radiological findings led to a diagnosis of MERS after mumps vaccination. 4. Discussion Encephalitis is an extremely rare CNS manifestation in mumps vaccine recipients, the frequency is estimated to be 0.0004% (4/1,000,000) [3], which is much lower than that in natural mumps (0.1%) [1]. Encephalitis after mumps vaccination may include acute disseminated encephalomyelitis (ADEM) [10]. The exact frequency of ADEM is uncertain, however, it should be very rare according to the fact that possible ADEM after mumps vaccine was only reported in one patient among 1.53 million doses of mumps vaccine in Japan [11]. As far as we know, there have been five Japanese patients with MERS after mumps vaccination (Table 1) [6,7],
Fig. 1. MRI of patient 2. On day 3, diffusion-weighted images reveal lesions in the splenium of the corpus callosum and symmetric white matter. These lesions disappear completely on day 8, which is compatible with MERS type 2.
including the present three patients, suggesting that this condition may be a more frequent adverse event after mumps vaccination than previously considered. MERS is the mildest and the second most common infectious encephalitis/encephalopathy syndrome in Japanese children, and is characterized by mild neurological symptoms (delirious behavior in 54%, consciousness disturbance in 35%, and seizures in 33%) with complete clinical recovery, and the MRI finding of a reversible splenial lesion (type 1 MERS), sometimes associated with symmetrical white matter lesions (MERS type 2) [4,5,8]. Hyponatremia is often observed in patients with MERS [12], thus, hyponatremic cerebral edema is postulated to be a contributing factor for MERS, though the exact pathophysiology is still uncertain. The five patients with MERS after mumps vaccination showed an interval from vaccination to clinical symptoms ranging from
Table 1 Data for MERS after mumps vaccination. Pt.
Age/sex
Initial symptoms (day 0)
Mumps vaccination
Neurological symptoms
CSF CC Mumps strain
Lowest/normalized Na mechanism
1
9/M
Fever, vomiting
D-13
Con (D2–4)
2
5/M
Fever, vomiting, headache
D-20
Del (D1–2), seizure (D2)
3
2/M
Fever
D-21
Con (D2), dysarthria (D2–11)
117 (D2)/137 (D10) SIADH 124 (D3)/137 (D7) SIADH 131 (D2)/137 (D5)
4
8/M
Fever, vomiting, headache
D-20
Del (D1–6)
5
1/M
Fever, vomiting
D-17
Con (D3–6), seizure (D3)
277 (M 157, P 120) (D2) Hoshino 280 (M 276, P 4) (D2) Hoshino 490 (M 490, P 0) (D2) Hoshino 624 (M 618, P 6) (D4) Torii 868 (M 854, P 14) (D3) Hoshino
128 (D2)/137 (D6) SIADH 125 (D3)/134 (D6) SIADH
DWI lesion
EEG results
Prognosis
Sp, genu, WM (D3) None (9) Sp, WM (D3) None (D8) Sp (D3) None (D11) Sp, WM (D2) None (D15) Sp (D4) None (D7)
HVS in O (D2)
CR
Reference
HVS in P,O (D2) Normal (D8) Normal (D4)
CR CR
9
Normal (D6)
CR
6
Diffuse HVS (D4) Normal (D11)
CR
7
Abbreviations Pt, patient; CSF, cerebrospinal fluid; CC, cell counts; DWI, diffusion-weighted image; EEG, electroencephalography; M, male; D, day; Con, consciousness disturbance; Del, delirium; M, mononuclear leukocyte; P, polymorphonuclear leukocyte; SIADH, syndrome of inappropriate; DEX, dexamethasone; mPSL, methylprednisolone; Glo, δ-globulin; Sp, splenium; WM, white matter; HVS, high voltage slow; O, occipital; P, parietal; CR, complete recovery.
228
J. Takanashi et al. / Journal of the Neurological Sciences 349 (2015) 226–228
13 to 21 days (equal to the incubation time of mumps infection); initial symptoms of fever, headache, and vomiting (suggesting meningitis), followed by CNS symptoms within 3 days; hyponatremia; and positive vaccine strain in CSF (Table 1). These findings strongly suggest that live attenuated mumps virus directly causes aseptic meningitis first, then possibly progressing to MERS under hyponatremic conditions. It has been reported that males more frequently present with mumps meningitis than females [1]. Actually, the male/female ratio of natural mumps meningitis in Japan between 2009 and 2011 was 2.32 (1764/ 759) [13]. Meningitis after mumps vaccination also occurs more predominantly in males than in females, i.e., nine of 10 patients with meningitis after mumps vaccination were males [2]. Interestingly, the five patients with MERS after mumps vaccination were all males. The number of MERS after mumps vaccination is too small to estimate the statistical significance; male might be a risk factor for developing MERS after mumps vaccination. In Japan, methylprednisolone pulse therapy and intravenous immunoglobulin are recommended for patients with infectious encephalopathy regardless of the pathogen or the clinicoradiological syndromes [14]. These treatments suppress inflammatory cytokines, and may be effective for those caused by cytokine storm, such as acute necrotizing encephalopathy (ANE) [14]. However, there is no evidence of their efficacy in MERS. As a treatment, steroids and intravenous immunoglobulin were given in 16 and 8 of the 54 patients with MERS in Japan [4], respectively. On the other hand, 19 patients received no such treatment. All 54 patients with MERS clinically recovered completely, irrespective of the treatments, suggesting that steroids or intravenous immunoglobulin is not always necessary. This is also the case for MERS after mumps vaccination, the five patients recovering completely, irrespective of the treatment, which might be related with normalization of sodium. In any case, MERS after mumps vaccination is expected to recover completely. Unlike ANE or acute encephalopathy with biphasic seizures and late reduced diffusion, which are by far more common in East Asia than in the rest of the world [4,14], MERS has been reported all over the world [15]. MERS after mumps vaccination, however, has never been reported in a country other than Japan. Because of the relatively high incidence of influenza encephalopathy in Japan, we usually perform brain MRI in children with relatively mild CNS symptoms. This may explain why MERS after mumps vaccination has been reported only in Japan, that is, this might be underestimated. This study has some limitations, mainly based on retrospective nature. Because we had no protocol for MRI, there might be some patients whose splenial lesion had already disappeared before MRI studies, which may lead to underestimation of this condition. The number of patient is too small to make statistical analysis, including whether there is male predominance. Further study with MRI protocol may lead to a better understanding of this condition. In conclusion, it should be emphasized that MERS after mumps vaccination may be more common than previously considered, and
the prognosis is excellent. One should suspect MERS when a male patient after mumps vaccination presents with neurological symptoms (delirious behavior, consciousness disturbance, and seizures) with hyponatremia, following symptoms of aseptic meningitis (fever, headache and vomiting), and MRI should be performed to evaluate the splenium of the corpus callosum.
Conflict of interest All authors declare no conflict of interest.
Acknowledgments This study was supported by the Grant-in-Aid for Scientific Research (B24390258) from the Japan Society for the Promotion of Science to J.T. and M.M.
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