Brain & Development xxx (2015) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis Yoriko Matsui a, Toshiki Takenouchi a,⇑, Atsushi Narabayashi b, Kentaro Ohara c, Tadaki Nakahara d, Takao Takahashi a a
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan Department of Pediatrics, Kawasaki Municipal Hospital, Kanagawa, Japan c Department of Pathology, Keio University School of Medicine, Tokyo, Japan d Department of Radiology, Keio University School of Medicine, Tokyo, Japan b
Received 11 March 2015; received in revised form 27 April 2015; accepted 11 May 2015
Abstract Sjo¨gren syndrome is an autoimmune disease characterized by dry mouth and eyes, known as sicca symptoms. The exact spectrum of neurological involvement, especially of the central nervous system, in childhood Sjo¨gren syndrome has not been well defined. We report a girl who presented with acute febrile brainstem encephalitis. In retrospect, she had exhibited a preceding history of recurrent conjunctivitis and strong halitosis that could be considered as sicca symptoms. The histopathology results of a minor salivary biopsy, the presence of anti-SSA/Ro antibody, and keratoconjunctivitis confirmed the diagnosis of Sjo¨gren syndrome. Commonly observed features in previously reported patients with childhood Sjo¨gren syndrome and central nervous system complications have included fever at the time of neurologic presentation, cerebrospinal fluid pleocytosis, abnormal neuroimaging, and positivity for several specific antibodies. In children presenting with unknown acute febrile encephalopathy, Sjo¨gren syndrome should be included in the differential diagnosis, especially when sicca symptoms are present. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Sjo¨gren syndrome; Central nervous system; Sicca symptoms; Encephalitis; Children
1. Background Sjo¨gren syndrome is an autoimmune disease that is characterized by dry eyes and mouth, so-called sicca symptoms. Besides these ocular and oral symptoms, this condition occasionally involves the peripheral and central nervous systems. In the central nervous system (CNS), it manifests as focal and multifocal neurological
⇑ Corresponding author at: Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 3816; fax: +81 3 5379 1978. E-mail address: [email protected] (T. Takenouchi).
deficits that can extend to optic and spinal involvement. In rare cases, diffuse brain involvement, i.e., encephalitis, can occur [1]. The presentations of childhood Sjo¨gren syndrome differ from those of adulthood Sjo¨gren syndrome in that the former often presents with recurrent parotitis, as opposed to classic sicca syndrome. Neurological involvement has been reported in several childhood cases. However, because of the low incidence of Sjo¨gren syndrome in children, the exact spectrum of CNS complications associated with primary childhood Sjo¨gren syndrome has not been well defined.
http://dx.doi.org/10.1016/j.braindev.2015.05.005 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
2
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
2. Case report A 9-year and 9-month-old girl presented at a local hospital with acute changes in her mental status. Two days prior to her presentation, she developed a fever of 38 °C. Although she became afebrile on the following day, she started to exhibit confusion and to speak unintelligible words. She also became lethargic, had difficulty with ambulation, and experienced several episodes of emesis. Upon admission, she was afebrile but lethargic. She opened her eyes intermittently to speak, but she did not follow any commands. She required support for ambulation. Her physical examination revealed bilateral conjunctivitis and strong halitosis. Lymphadenopathy or nuchal rigidity was not observed. A neurological examination revealed an upper gaze deviation of the left eye without regular nystagmus and an absent light reflex in the right eye. The deep tendon reflexes were increased, with a positive Babinski reflex observed on the right side. A caloric test revealed an abnormality on the right side, with nystagmus towards the opposite direction. A cerebrospinal fluid (CSF) analysis showed an increased cell count of 48 cells/lL and a protein level of 76 mg/dL. An electroencephalogram showed generalized slow waves mainly in the delta range, without epileptogenic activity. On the fifth day of admission, she experienced a tonic-clonic seizure that lasted for 30 s. On an electrocardiogram, she was noted as having paroxysmal ventricular contractions with bradycardia (heart rate in the 60 s per min). Based on the multifocal cranial nerve deficits and autonomic involvement in the setting of a seizure and encephalopathy, she was clinically diagnosed as having brainstem encephalitis. She was treated with intravenous methylprednisolone 30 mg/kg/day for 3 days and immunoglobulin 1 g/kg/day for 2 days, followed by oral prednisolone at 2 mg/kg/day with gradual tapering over the course of 4 weeks. A further history obtained from her mother revealed that the patient had experienced recurrent episodes of “red eyes,” particularly when she had a cold. She had hyperviscous saliva and had multiple dental caries, despite regular brushing of her teeth. Laboratory testing revealed normal complete blood counts, mild elevations in serum IgG (1808 mg/dL; normal, 608–1572 mg/dL) and IgM (303 mg/dL; 52– 242 mg/dL), and an erythrocyte sedimentation rate of 21 mm (0–10 mm/h). She tested positive for anti-nuclear antibody (1:80), her anti-SSA/Ro level was markedly elevated at 1:>1200, and she tested positive for rheumatoid factor (1:64). She tested negative for anti-SSB/La, anti-Sm, anti-dsDNA, anti-RNP, ani-Scl70, antiphospholipid, anti-Jo-1, anti-GQ1b, and anti-aquaporin-4 antibodies. Brain magnetic resonance imaging on the eighth day of admission showed cerebellar hyperintensity, which was suggestive of brain
parenchymal inflammation (Fig. 1). Schirmer’s test was negative, but corneal fluorescein staining showed keratoconjunctivitis. A minor salivary gland biopsy showed chronic sialadenitis with one lymphocytic focus, consistent with Greenspan grade III (Fig. 2). These findings met the diagnostic criteria for primary Sjo¨gren syndrome as defined by the American College of Rheumatology. Salivary gland scintigraphy showed a significantly decreased uptake of the radiotracer in both the parotid and submandibular glands with a lack of tracer excretion after lemon juice stimulation (Fig. 3). These findings further supported a diagnosis of primary Sjo¨gren syndrome. Her hospital course was complicated by a persistent fluctuating mental status, a neurogenic bladder with resultant anuria, syndrome of inappropriate secretion of antidiuretic hormone, renal tubular acidosis, and transient oral dyskinesia. Seven months after her initial presentation, she was fully communicative but had residual upper gaze deviation of the left eye and an ataxic gait. Because of residual dysphagia, she continued to consume only soft food in a paste form. 3. Discussion Herein we document a young girl who first presented with an acute altered mental status, seizure, focal neurologic deficits, and autonomic dysfunction. In retrospect, she had preceding sicca symptoms, including halitosis, hyperviscous saliva, dental caries despite regular teeth brushing, and a history of recurrent conjunctivitis. The histopathology results for a minor salivary gland, the presence of keratoconjunctivitis, and the specific
Fig. 1. Brain magnetic resonance imaging findings. A fluid-attenuated inversion recovery image obtained on the eighth day of admission shows diffuse hyperintensity in the cerebellar hemispheres, suggesting brain parenchymal inflammation.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
3
Fig. 2. Biopsy findings of minor salivary glands. A microscopic investigation of the minor salivary glands (4, A) and a magnification (B) show a small lymphocytic focus with relative preservation of the acinar and ductal structures. Scale bar in B, 100 lm.
Fig. 3. Salivary gland scintigraphic results for the patient, compared with normal findings. The green curves represent the right gland, the red curves represent the left gland, and the white curves show the baseline. The time-activity curves of the parotid (A) and submandibular (B) glands in the present patient showed slowly increasing uptakes with no apparent radioisotope washout at 15 min. (i.e., the time of lemon juice oral administration, represented by the vertical yellow bars). The salivary gland uptake values at 15 min were 0.19% (right parotid), 0.17% (left parotid), 0.18% (right submandibular), and 0.23% (left submandibular) of the total injected dose. (C) and (D) are examples of the time-activity curves for normal salivary gland function. These curves show quickly increasing uptakes followed by clear tracer excretions in response to the oral administration of lemon juice. The salivary gland uptake values at 15 min were 0.38% (right parotid), 0.35% (left parotid), 0.18% (right submandibular), and 0.17% (left submandibular) of the total injected dose. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
serologic findings confirmed a diagnosis of Sjo¨gren syndrome as the underlying cause of her acute brainstem encephalitis. We reviewed reported cases of childhood Sjo¨gren syndrome with CNS complications and reported the results in a tabular form (Table 1) [2–10]. The review revealed that only 1/10 (10%) children had been diagnosed as having Sjo¨gren syndrome prior to the neurologic manifestation. This finding was consistent with that of a report describing adulthood Sjo¨gren syndrome, in which more than 80% of the cases with neurologic involvement exhibited such involvement prior to a diagnosis of Sjo¨gren syndrome [11]. The review also revealed that the range of neurological symptoms was diverse, from headache to focal neurological deficits and seizures, but several features were frequently observed: fever at the time of neurologic presentation (observed
at least in 6/10 cases), CSF pleocytosis (8/10), abnormal neuroimaging (10/10), anti-SSA/Ro (10/10), anti-SSB/La (7/10), anti-nuclear antibody (9/10), and rheumatoid factor (5/10). In children presenting with unknown acute febrile encephalopathy, these specific serologic screening tests should be added to routine laboratory testing, especially if any sicca symptoms are present. Whether the diagnostic criteria for Sjo¨gren syndrome proposed for adults are directly applicable to pediatric patients has long been a controversial topic. This controversy arose because a minor salivary gland biopsy, which is the diagnostic gold standard for adult patients, tends to show mild changes in children, often failing to fulfill the histopathological criterion (i.e., at least one lymphocytic focus per 4 mm2) [12]. Indeed, the presently reported patient barely met this histopathology criterion; instead,
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
4
Case #
1
3
3
4
5
6
7
8
9
10
Age of onset (years)/sex Prior diagnosis of Sjo¨gren syndrome Fever at presentation Neurologic manifestation
10/Female
9/Female
9/Female
14/Male
10/Female
9/Female
16/Female
11/Female
16/Female
9/Female
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Present
Absent
Present
Present
Present
Present
ND
ND
ND
ND
Present
Present
Weakness, paresthesia, headache, dizziness, and vomiting
Nausea then right hemiparesis
Severe headache and fever
Seizure
Polyradiculoneuritis and meningoencephalitis, which resulted in quadriparesis
Headache, leg numbness, dysarthria and ataxia
Somnolence and seizure
Present
Present
Present
Present
Optic neuritis, urinary incontinence, bilateral lower extremity paresis and a sensory deficit below T8 Present
Headache and vomiting
Present
Facial diplegia, headache, dizziness, vertical diplopia, and “walking sideways” Present
Present
Present
+ + +
+
+
+
ND
Neuroimaging abnormalities Cerebrum Cerebellum Brainstem Spine Cerebrospinal fluid pleocytosis Anti-SSA/Ro Anti-SSB/La Anti-nuclear antibody Rheumatoid factor Microscopic findings of salivary gland biopsy Immunomodulatory treatment Residual neurological deficits at follow-up Reference
+
Present
+ + +
+
+
Present
+ Present
Present
Present
ND
ND
Present
+ Present
+ Present
Present
Positive Positive Positive
Positive Positive Positive
Positive Positive Positive
Positive Negative Negative
Positive Positive Positive
Positive Negative Positive
Positive Positive Positive
Positive Positive Positive
Positive Positive Positive
Positive Negative Positive
Positive Periductal lymphocytic infiltrate Steroids CPA
Positive ND
Positive ND
ND ND
Steroids
Negative Two discrete lymphocytic foci Steroids
Negative Mild inflammatory infiltrate Steroids
Steroids tacrolimus
Positive Periductal lymphocytic infiltrate Steroids IVIG
Present
Present
ND (stable)
ND (stable)
Present
Absent
Positive Periductal lymphocytic inflammation Steroids CPA plasmapheresis Present
ND ND
Steroids
ND One lymphocytic focus Steroids CPA chrolambucil Present
Present
Present
Berman et al. [2]
Ohtsuka et al. [3]
Kobayashi et al. [9]
Bartunkova et al. [6]
Gottfried et al. [5]
Wong et al. [7]
Arabshahi et al. [8]
Hoshina et al. [4]
Present patient
DeGuzman et al. [10]
CPA, cyclophosphamide; IVIG, intravenous immunoglobulin; ND, not documented.
Steroids CPA
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
Table 1 Central nervous system complications in childhood Sjo¨gren syndrome.
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
her scintigraphy showed typical severe salivary dysfunction, as shown in Fig. 3, strongly supporting a diagnosis of Sjo¨gren syndrome. Because of its lower degree of invasiveness, salivary gland scintigraphy may still have a role as an adjunctive test in children with possible Sjo¨gren syndrome. In conclusion, neurological manifestation often precedes a diagnosis of childhood Sjo¨gren syndrome. In children with acute febrile encephalopathy, Sjo¨gren syndrome should be included in the differential diagnosis, especially if the patient’s history and physical findings suggest that sicca symptoms might be present. For diagnostic confirmation, salivary gland scintigraphy may be helpful as an adjunct to specific serologic tests. Funding The authors disclosed no financial support for the research or authorship of this article. Ethical approval Parental informed consent was obtained for the publication of this article. References [1] Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, et al. The wide spectrum of clinical manifestations in Sjogren’s syndrome-associated neuropathy. Brain 2005;128:2518–34.
5
[2] Berman JL, Kashii S, Trachtman MS, Burde RM. Optic neuropathy and central nervous system disease secondary to Sjogren’s syndrome in a child. Ophthalmology 1990;97:1606–9. [3] Ohtsuka T, Saito Y, Hasegawa M, Tatsuno M, Takita S, Arita M, et al. Central nervous system disease in a child with primary Sjogren syndrome. J Pediatr 1995;127:961–3. [4] Hoshina T, Yamaguchi Y, Ohga S, Kira R, Ishimura M, Takada H, et al. Sjogren’s syndrome-associated meningoencephalomyelitis: cerebrospinal fluid cytokine levels and therapeutic utility of tacrolimus. J Neurol Sci 2008;267:182–6. [5] Gottfried JA, Finkel TH, Hunter JV, Carpentieri DF, Finkel RS. Central nervous system Sjogren’s syndrome in a child: case report and review of the literature. J Child Neurol 2001;16:683–5. [6] Bartunkova J, Sediva A, Vencovsky J, Tesar V. Primary Sjogren’s syndrome in children and adolescents: proposal for diagnostic criteria. Clin Exp Rheumatol 1999;17:381–6. [7] Wong S, Pollock AN, Burnham JM, Sherry DD, Dlugos DJ. Acute cerebellar ataxia due to Sjogren syndrome. Neurology 2004;62:2332–3. [8] Arabshahi B, Pollock AN, Sherry DD, Albert DA, Kreiger PA, Pessler F. Devic disease in a child with primary Sjogren syndrome. J Child Neurol 2006;21:285–6. [9] Kobayashi I, Furuta H, Tame A, Kawamura N, Kojima K, Endoh M, et al. Complications of childhood Sjogren syndrome. Eur J Pediatr 1996;155:890–4. [10] DeGuzman M, Fishman MA, Lewis RA, McCluggage C, Warren RW, Finegold MJ. Chronic neurologic disease with visual, gait, and bladder problems in a male teenager. J Pediatr 1998;132:742–7. [11] Delalande S, de Seze J, Fauchais AL, Hachulla E, Stojkovic T, Ferriby D, et al. Neurologic manifestations in primary Sjogren syndrome: a study of 82 patients. Medicine 2004;83:280–91. [12] Lieberman SM. Childhood Sjogren syndrome: insights from adults and animal models. Curr Opin Rheumatol 2013;25:651–7.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
Case Report
Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis Yoriko Matsui a, Toshiki Takenouchi a,⇑, Atsushi Narabayashi b, Kentaro Ohara c, Tadaki Nakahara d, Takao Takahashi a a
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan Department of Pediatrics, Kawasaki Municipal Hospital, Kanagawa, Japan c Department of Pathology, Keio University School of Medicine, Tokyo, Japan d Department of Radiology, Keio University School of Medicine, Tokyo, Japan b
Received 11 March 2015; received in revised form 27 April 2015; accepted 11 May 2015
Abstract Sjo¨gren syndrome is an autoimmune disease characterized by dry mouth and eyes, known as sicca symptoms. The exact spectrum of neurological involvement, especially of the central nervous system, in childhood Sjo¨gren syndrome has not been well defined. We report a girl who presented with acute febrile brainstem encephalitis. In retrospect, she had exhibited a preceding history of recurrent conjunctivitis and strong halitosis that could be considered as sicca symptoms. The histopathology results of a minor salivary biopsy, the presence of anti-SSA/Ro antibody, and keratoconjunctivitis confirmed the diagnosis of Sjo¨gren syndrome. Commonly observed features in previously reported patients with childhood Sjo¨gren syndrome and central nervous system complications have included fever at the time of neurologic presentation, cerebrospinal fluid pleocytosis, abnormal neuroimaging, and positivity for several specific antibodies. In children presenting with unknown acute febrile encephalopathy, Sjo¨gren syndrome should be included in the differential diagnosis, especially when sicca symptoms are present. Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Sjo¨gren syndrome; Central nervous system; Sicca symptoms; Encephalitis; Children
1. Background Sjo¨gren syndrome is an autoimmune disease that is characterized by dry eyes and mouth, so-called sicca symptoms. Besides these ocular and oral symptoms, this condition occasionally involves the peripheral and central nervous systems. In the central nervous system (CNS), it manifests as focal and multifocal neurological
⇑ Corresponding author at: Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 3816; fax: +81 3 5379 1978. E-mail address: [email protected] (T. Takenouchi).
deficits that can extend to optic and spinal involvement. In rare cases, diffuse brain involvement, i.e., encephalitis, can occur [1]. The presentations of childhood Sjo¨gren syndrome differ from those of adulthood Sjo¨gren syndrome in that the former often presents with recurrent parotitis, as opposed to classic sicca syndrome. Neurological involvement has been reported in several childhood cases. However, because of the low incidence of Sjo¨gren syndrome in children, the exact spectrum of CNS complications associated with primary childhood Sjo¨gren syndrome has not been well defined.
http://dx.doi.org/10.1016/j.braindev.2015.05.005 0387-7604/Ó 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
2
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
2. Case report A 9-year and 9-month-old girl presented at a local hospital with acute changes in her mental status. Two days prior to her presentation, she developed a fever of 38 °C. Although she became afebrile on the following day, she started to exhibit confusion and to speak unintelligible words. She also became lethargic, had difficulty with ambulation, and experienced several episodes of emesis. Upon admission, she was afebrile but lethargic. She opened her eyes intermittently to speak, but she did not follow any commands. She required support for ambulation. Her physical examination revealed bilateral conjunctivitis and strong halitosis. Lymphadenopathy or nuchal rigidity was not observed. A neurological examination revealed an upper gaze deviation of the left eye without regular nystagmus and an absent light reflex in the right eye. The deep tendon reflexes were increased, with a positive Babinski reflex observed on the right side. A caloric test revealed an abnormality on the right side, with nystagmus towards the opposite direction. A cerebrospinal fluid (CSF) analysis showed an increased cell count of 48 cells/lL and a protein level of 76 mg/dL. An electroencephalogram showed generalized slow waves mainly in the delta range, without epileptogenic activity. On the fifth day of admission, she experienced a tonic-clonic seizure that lasted for 30 s. On an electrocardiogram, she was noted as having paroxysmal ventricular contractions with bradycardia (heart rate in the 60 s per min). Based on the multifocal cranial nerve deficits and autonomic involvement in the setting of a seizure and encephalopathy, she was clinically diagnosed as having brainstem encephalitis. She was treated with intravenous methylprednisolone 30 mg/kg/day for 3 days and immunoglobulin 1 g/kg/day for 2 days, followed by oral prednisolone at 2 mg/kg/day with gradual tapering over the course of 4 weeks. A further history obtained from her mother revealed that the patient had experienced recurrent episodes of “red eyes,” particularly when she had a cold. She had hyperviscous saliva and had multiple dental caries, despite regular brushing of her teeth. Laboratory testing revealed normal complete blood counts, mild elevations in serum IgG (1808 mg/dL; normal, 608–1572 mg/dL) and IgM (303 mg/dL; 52– 242 mg/dL), and an erythrocyte sedimentation rate of 21 mm (0–10 mm/h). She tested positive for anti-nuclear antibody (1:80), her anti-SSA/Ro level was markedly elevated at 1:>1200, and she tested positive for rheumatoid factor (1:64). She tested negative for anti-SSB/La, anti-Sm, anti-dsDNA, anti-RNP, ani-Scl70, antiphospholipid, anti-Jo-1, anti-GQ1b, and anti-aquaporin-4 antibodies. Brain magnetic resonance imaging on the eighth day of admission showed cerebellar hyperintensity, which was suggestive of brain
parenchymal inflammation (Fig. 1). Schirmer’s test was negative, but corneal fluorescein staining showed keratoconjunctivitis. A minor salivary gland biopsy showed chronic sialadenitis with one lymphocytic focus, consistent with Greenspan grade III (Fig. 2). These findings met the diagnostic criteria for primary Sjo¨gren syndrome as defined by the American College of Rheumatology. Salivary gland scintigraphy showed a significantly decreased uptake of the radiotracer in both the parotid and submandibular glands with a lack of tracer excretion after lemon juice stimulation (Fig. 3). These findings further supported a diagnosis of primary Sjo¨gren syndrome. Her hospital course was complicated by a persistent fluctuating mental status, a neurogenic bladder with resultant anuria, syndrome of inappropriate secretion of antidiuretic hormone, renal tubular acidosis, and transient oral dyskinesia. Seven months after her initial presentation, she was fully communicative but had residual upper gaze deviation of the left eye and an ataxic gait. Because of residual dysphagia, she continued to consume only soft food in a paste form. 3. Discussion Herein we document a young girl who first presented with an acute altered mental status, seizure, focal neurologic deficits, and autonomic dysfunction. In retrospect, she had preceding sicca symptoms, including halitosis, hyperviscous saliva, dental caries despite regular teeth brushing, and a history of recurrent conjunctivitis. The histopathology results for a minor salivary gland, the presence of keratoconjunctivitis, and the specific
Fig. 1. Brain magnetic resonance imaging findings. A fluid-attenuated inversion recovery image obtained on the eighth day of admission shows diffuse hyperintensity in the cerebellar hemispheres, suggesting brain parenchymal inflammation.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
3
Fig. 2. Biopsy findings of minor salivary glands. A microscopic investigation of the minor salivary glands (4, A) and a magnification (B) show a small lymphocytic focus with relative preservation of the acinar and ductal structures. Scale bar in B, 100 lm.
Fig. 3. Salivary gland scintigraphic results for the patient, compared with normal findings. The green curves represent the right gland, the red curves represent the left gland, and the white curves show the baseline. The time-activity curves of the parotid (A) and submandibular (B) glands in the present patient showed slowly increasing uptakes with no apparent radioisotope washout at 15 min. (i.e., the time of lemon juice oral administration, represented by the vertical yellow bars). The salivary gland uptake values at 15 min were 0.19% (right parotid), 0.17% (left parotid), 0.18% (right submandibular), and 0.23% (left submandibular) of the total injected dose. (C) and (D) are examples of the time-activity curves for normal salivary gland function. These curves show quickly increasing uptakes followed by clear tracer excretions in response to the oral administration of lemon juice. The salivary gland uptake values at 15 min were 0.38% (right parotid), 0.35% (left parotid), 0.18% (right submandibular), and 0.17% (left submandibular) of the total injected dose. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
serologic findings confirmed a diagnosis of Sjo¨gren syndrome as the underlying cause of her acute brainstem encephalitis. We reviewed reported cases of childhood Sjo¨gren syndrome with CNS complications and reported the results in a tabular form (Table 1) [2–10]. The review revealed that only 1/10 (10%) children had been diagnosed as having Sjo¨gren syndrome prior to the neurologic manifestation. This finding was consistent with that of a report describing adulthood Sjo¨gren syndrome, in which more than 80% of the cases with neurologic involvement exhibited such involvement prior to a diagnosis of Sjo¨gren syndrome [11]. The review also revealed that the range of neurological symptoms was diverse, from headache to focal neurological deficits and seizures, but several features were frequently observed: fever at the time of neurologic presentation (observed
at least in 6/10 cases), CSF pleocytosis (8/10), abnormal neuroimaging (10/10), anti-SSA/Ro (10/10), anti-SSB/La (7/10), anti-nuclear antibody (9/10), and rheumatoid factor (5/10). In children presenting with unknown acute febrile encephalopathy, these specific serologic screening tests should be added to routine laboratory testing, especially if any sicca symptoms are present. Whether the diagnostic criteria for Sjo¨gren syndrome proposed for adults are directly applicable to pediatric patients has long been a controversial topic. This controversy arose because a minor salivary gland biopsy, which is the diagnostic gold standard for adult patients, tends to show mild changes in children, often failing to fulfill the histopathological criterion (i.e., at least one lymphocytic focus per 4 mm2) [12]. Indeed, the presently reported patient barely met this histopathology criterion; instead,
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
4
Case #
1
3
3
4
5
6
7
8
9
10
Age of onset (years)/sex Prior diagnosis of Sjo¨gren syndrome Fever at presentation Neurologic manifestation
10/Female
9/Female
9/Female
14/Male
10/Female
9/Female
16/Female
11/Female
16/Female
9/Female
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Present
Absent
Present
Present
Present
Present
ND
ND
ND
ND
Present
Present
Weakness, paresthesia, headache, dizziness, and vomiting
Nausea then right hemiparesis
Severe headache and fever
Seizure
Polyradiculoneuritis and meningoencephalitis, which resulted in quadriparesis
Headache, leg numbness, dysarthria and ataxia
Somnolence and seizure
Present
Present
Present
Present
Optic neuritis, urinary incontinence, bilateral lower extremity paresis and a sensory deficit below T8 Present
Headache and vomiting
Present
Facial diplegia, headache, dizziness, vertical diplopia, and “walking sideways” Present
Present
Present
+ + +
+
+
+
ND
Neuroimaging abnormalities Cerebrum Cerebellum Brainstem Spine Cerebrospinal fluid pleocytosis Anti-SSA/Ro Anti-SSB/La Anti-nuclear antibody Rheumatoid factor Microscopic findings of salivary gland biopsy Immunomodulatory treatment Residual neurological deficits at follow-up Reference
+
Present
+ + +
+
+
Present
+ Present
Present
Present
ND
ND
Present
+ Present
+ Present
Present
Positive Positive Positive
Positive Positive Positive
Positive Positive Positive
Positive Negative Negative
Positive Positive Positive
Positive Negative Positive
Positive Positive Positive
Positive Positive Positive
Positive Positive Positive
Positive Negative Positive
Positive Periductal lymphocytic infiltrate Steroids CPA
Positive ND
Positive ND
ND ND
Steroids
Negative Two discrete lymphocytic foci Steroids
Negative Mild inflammatory infiltrate Steroids
Steroids tacrolimus
Positive Periductal lymphocytic infiltrate Steroids IVIG
Present
Present
ND (stable)
ND (stable)
Present
Absent
Positive Periductal lymphocytic inflammation Steroids CPA plasmapheresis Present
ND ND
Steroids
ND One lymphocytic focus Steroids CPA chrolambucil Present
Present
Present
Berman et al. [2]
Ohtsuka et al. [3]
Kobayashi et al. [9]
Bartunkova et al. [6]
Gottfried et al. [5]
Wong et al. [7]
Arabshahi et al. [8]
Hoshina et al. [4]
Present patient
DeGuzman et al. [10]
CPA, cyclophosphamide; IVIG, intravenous immunoglobulin; ND, not documented.
Steroids CPA
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
Table 1 Central nervous system complications in childhood Sjo¨gren syndrome.
Y. Matsui et al. / Brain & Development xxx (2015) xxx–xxx
her scintigraphy showed typical severe salivary dysfunction, as shown in Fig. 3, strongly supporting a diagnosis of Sjo¨gren syndrome. Because of its lower degree of invasiveness, salivary gland scintigraphy may still have a role as an adjunctive test in children with possible Sjo¨gren syndrome. In conclusion, neurological manifestation often precedes a diagnosis of childhood Sjo¨gren syndrome. In children with acute febrile encephalopathy, Sjo¨gren syndrome should be included in the differential diagnosis, especially if the patient’s history and physical findings suggest that sicca symptoms might be present. For diagnostic confirmation, salivary gland scintigraphy may be helpful as an adjunct to specific serologic tests. Funding The authors disclosed no financial support for the research or authorship of this article. Ethical approval Parental informed consent was obtained for the publication of this article. References [1] Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, et al. The wide spectrum of clinical manifestations in Sjogren’s syndrome-associated neuropathy. Brain 2005;128:2518–34.
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[2] Berman JL, Kashii S, Trachtman MS, Burde RM. Optic neuropathy and central nervous system disease secondary to Sjogren’s syndrome in a child. Ophthalmology 1990;97:1606–9. [3] Ohtsuka T, Saito Y, Hasegawa M, Tatsuno M, Takita S, Arita M, et al. Central nervous system disease in a child with primary Sjogren syndrome. J Pediatr 1995;127:961–3. [4] Hoshina T, Yamaguchi Y, Ohga S, Kira R, Ishimura M, Takada H, et al. Sjogren’s syndrome-associated meningoencephalomyelitis: cerebrospinal fluid cytokine levels and therapeutic utility of tacrolimus. J Neurol Sci 2008;267:182–6. [5] Gottfried JA, Finkel TH, Hunter JV, Carpentieri DF, Finkel RS. Central nervous system Sjogren’s syndrome in a child: case report and review of the literature. J Child Neurol 2001;16:683–5. [6] Bartunkova J, Sediva A, Vencovsky J, Tesar V. Primary Sjogren’s syndrome in children and adolescents: proposal for diagnostic criteria. Clin Exp Rheumatol 1999;17:381–6. [7] Wong S, Pollock AN, Burnham JM, Sherry DD, Dlugos DJ. Acute cerebellar ataxia due to Sjogren syndrome. Neurology 2004;62:2332–3. [8] Arabshahi B, Pollock AN, Sherry DD, Albert DA, Kreiger PA, Pessler F. Devic disease in a child with primary Sjogren syndrome. J Child Neurol 2006;21:285–6. [9] Kobayashi I, Furuta H, Tame A, Kawamura N, Kojima K, Endoh M, et al. Complications of childhood Sjogren syndrome. Eur J Pediatr 1996;155:890–4. [10] DeGuzman M, Fishman MA, Lewis RA, McCluggage C, Warren RW, Finegold MJ. Chronic neurologic disease with visual, gait, and bladder problems in a male teenager. J Pediatr 1998;132:742–7. [11] Delalande S, de Seze J, Fauchais AL, Hachulla E, Stojkovic T, Ferriby D, et al. Neurologic manifestations in primary Sjogren syndrome: a study of 82 patients. Medicine 2004;83:280–91. [12] Lieberman SM. Childhood Sjogren syndrome: insights from adults and animal models. Curr Opin Rheumatol 2013;25:651–7.
Please cite this article in press as: Matsui Y et al. Childhood Sjo¨gren syndrome presenting as acute brainstem encephalitis. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.05.005
