Accepted Manuscript Encephalitis lethargica with isolated substantia nigra lesions on MRI followed by a second encephalitis in a boy with humoral immunity deficiency Lu Yang, Guijuan Jia, Baomin Li, Gefei Lei, Ruopeng Sun PII: S0887-8994(15)00178-2 DOI: 10.1016/j.pediatrneurol.2015.03.030 Reference: PNU 8645 To appear in: Pediatric Neurology Received Date: 21 March 2015 Accepted Date: 21 March 2015 Please cite this article as: Yang L, Jia G, Li B, Lei G, Sun R, Encephalitis lethargica with isolated substantia nigra lesions on MRI followed by a second encephalitis in a boy with humoral immunity deficiency, Pediatric Neurology (2015), doi: 10.1016/j.pediatrneurol.2015.03.030. 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. ACCEPTED MANUSCRIPT 1.Title Encephalitis lethargica with isolated substantia nigra lesions on MRI followed by a second encephalitis in a boy with humoral immunity deficiency 2.Running title RI PT Encephalitis lethargic followed by a second encephalitis 3.Author names and affiliations(Authors’ names were arranged in order of given names followed by family names.) Lu Yang(first author) SC Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012. M AN U email: yanglukitty2002@sina.com.cn Guijuan Jia Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012 Baomin Li TE D Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012 Gefei Lei EP Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012 Ruopeng Sun(corresponding author) AC C Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012 email: srpyl2008@sina.com.cn 4.Corresponding author: Ruopeng Sun(corresponding author) Pediatric department of Shandong University Qilu Hospital, Jinan city, Shandong Province, China, 250012 email: srpyl2008@sina.com.cn 5. The manuscript has 1457 words. ACCEPTED MANUSCRIPT Encephalitis lethargica with isolated substantia nigra lesions on MRI followed by a second encephalitis in a boy with humoral immunity deficiency Abstract Background: Encephalitis lethargica is an encephalitic illness with combination of multiple nervous system symptoms. Lesion only involving substantia nigra on magnetic resonance imaging is scarce, especial- RI PT ly in children. A second encephalitis after encephalitis lethargica has never been reported before. Patient description: We report a 7-year-old boy, with a history of humoral immunity deficiency, developed encephalitis lethargica with bilateral substantia nigra lesions on magnetic resonance imaging. After nearly full recovery, he developed encephalitis once again. Results: The boy was diagnosed as having humoral immunity de- SC ficiency 3 years ago. After excluding possible viral encephalitis, he was diagnosed as having encephalitis lethargica with the symptoms of somnolence, akinetic mutism and ophthalmoplegia after intermittent fever. Cerebrospinal fluid tests revealed pleocytosis and positive oligoclonal band. Symmetrical substantia nigra M AN U high intensity on magentic resonance imaging gradually resolved into liquid signal. The boy got nearly full recovery in short time. However, he suffered from fatigue and hypersomnia and diagnosed with encephalitis again which was supported by mild pleocytosis in cerebrospinal fluid and subcortical white matter lesions in bilateral frontal lobe. Corticosteroid and immunoglobulin successfully relieved his symptoms. Conclusion: This is the first case report of an immune deficient child suffering from encephalitis lethargica with isolated substantia nigra lesions on magnetic resonance imaging and a second encephalitis after recovery from en- TE D cephalitis lethargica. Introduction EP Encephalitis lethargica was a mysterious, epidemic disease that occurred between 1917-1927. It is defined as an acute or subacute encephalitic illness highlighted by sleep disorder, movement disorder and neuropsychiatric sequelae. Clinical criteria for diagnosis of encephalitis lethargica should exclude all other toxic, AC C metabolic and infectious etiologies and include at least three of the following: 1) signs of basal ganglia involvement; 2) oculogyric crises; 3) ophthalmoplegia; 4) obsessive-compulsive behavior; 5) akinetic mutism; 6) central respiratory irregularities; and 7) somnolence or sleep inversion or both.1 Encephalitis lethargica cases have been sporadically reported in children and adult after that epidemic.2,3 Imaging studies have suggested variable structural involvement of the basal ganglia, substantia nigra, midbrain, thalamus, etc. or generalized atrophy or no abnormality at all.2,3 Here we reported a boy suffering from encephalitis lethargica with lesions predominantly in substantia nigra and a second encephalitis involving subcortical white matter after recovery from encephalitis lethargica. Patient description ACCEPTED MANUSCRIPT A 7-year-old boy suffered from intermittent fever, vomiting and lethargy for 13 days before admission. He has been treated with cephalosporin and immunoglobulin 10g/day for 5 days. He was diagnosed with humoral immunity deficiency(serum IgG<1.31g/L,IgA<0.24g/L,IgM<0.17g/L) when treated for suppurative arthritis 3 years ago and received immunoglobulin several times thereafter. However, the nature of humoral immunity deficiency was not further determined. On admission, he was somnolent and reticent. Neurological examination revealed nuchal rigidity, muscle weakness(upper extremities grading III, lower ex- RI PT tremities grading IV), hyperactive patellar tendon reflex with predominance in the left side and bilateral Babinski signs. Treatment with methylprednisolone was initiated at dosage of 2mg/kg/d. Brain magnetic resonance imaging(MRI) on the fourth day of admission showed symmetric T2 hyperintense lesions confined to substantia nigra, which were hypointense on T1-weighted image(Figure 1A,B). There was no lesion elsewhere in the brain. Cerebrospinal fluid(CSF) examination revealed SC 20cells/mm3( lymphocytes 88%, neutrophil 8%, monocyte 4%), 3.4mmol/L glucose, 0.38g/L protein, 129mmol/L chloride, 1.5mmol/L lactate. CSF PCR for Ebstein-Barr(EB) virus, cytomegalovirus, herpes simplex virus-1(HSV-1), mycoplasma tuberculosis and mycoplasma pneumoniae were all negative. CSF M AN U myelin basic protein was within normal range. CSF and serum Anti-NMDAR antibody was negative Oligoclonal band was positive both in CSF and serum. Serum antibodies against mycoplasma pneumoniae, mycoplasma tuberculosis, Japanese encephalitis(JE) virus were all negative. On the fourth hospital day, his condition deteriorated and he had mask-like face, reduced blinking reflex, hypokinesia and akinetic mutism. Examination revealed restricted vertical eye movement, horizontal nystagmus and limited movement due to lead-pipe rigidity in all four limbs. The boy was diagnosed as hav- TE D ing EL. The dosage of methylprednisolone was adjusted to 10mg/kg/d for 3 days and slowly tapered off. On the eighth hospital day, tremors of lips and left hand developed. Eighteen days after admission, his mental state returned to normal and he started on rehabilitation training. Electroencephalographic study at this time showed unsymmetrical slow background. Twenty one days after admission, tremor and nystagmus disap- EP peared. He still had generalized rigidity. After that, he gradually improved. He could speak slowly, sit and walk with support. The second MRI scan at 1 month after admission showed bilateral substantia nigra le- AC C sions which were isotense to cerebrospinal fluid on the T2-weighted image(Figure1C,D). He was discharged with hypomimia and slow gait at 35 days after admission without reexamination of CSF. He recovered gradually after dischargement and the third MRI two weeks later showed the same lesions as the last MRI scanning. Telephone followup reported normal daily life with little residual hypomimia and bradykinesia. However, the boy was readmitted for fatigue and hypersomnia 85 days after dischargement. Physical examination revealed only hyperreflexia. MRI scanning indicated new lesions in bilateral frontal lobe subcortical white matter(Figure 2C,D) which were not seen in previous scanning(Figure 2A,B) . CSF examination revealed 14cells/mm3. Oligoclonal band was positive in serum but negative in CSF. He was considered to suffer from encephalitis again. Intravenous methylprednisolone 10mg/kg/d for 3 days followed by immunoglobulin 2g/kg delivered over 3 days totally relieved the boy’s discomfort. Lumbar puncture was not repeated. The boy was maintained on oral prednisone at dosage of 1.5mg/kg/d after discharge- ACCEPTED MANUSCRIPT ment. Two months later, outpatient followup reported no abnormality of his mental state and motor function. Prednisone was gradually withdrawn. Discussion Isolated bilateral substantia nigra lesions during first admission in our patient is an interesting imaging manifestation. Literature search about exclusive substantia nigra lesion in acute encephalitis revealed that it could occur in encephalitis related to JE virus, St.Louis virus, EB virus, influenza A virus, HSV-1 virus and measles virus.4-9 However our etiologic tests did not support any viral encephalitis mentioned above. There RI PT were three case reports about encephalitis lethargica with MRI lesions exclusively in substantia nigra in adult patients.10-12 Our boy presented with somnolence, parkinson like syndrome(mask like face, akinetic mutism, tremor, rigidity), ophthalmoplegia and nystagmus, fulfilling the diagnostic criteria of encephalitis lethargica. Laboratory tests showed pleocytosis and positive oligoclonal band in CSF, consistent with other reports. SC Substantia nigra lesion could inhibit cortex activity by reducing dopaminergic input to striatum in cortexbasal ganglia-thalamus circuit, which explain for the parkinson like syndrome in this boy. However, somnolence, ophthalmoplegia and nystagmus indicate multifocal damage more than substantia nigra lesion. Neuro- M AN U pathological study in the outbreak also had evidence that inflammatory infiltrations could be widespread in basal ganglia, substantia nigra, thalamus, midbrain, pons and cortex.13 Therefore, MRI imaging in our boy only reflect the most remarkable injury in the brain. The etiology of encephalitis lethargica remains mysterious. Since the epidemic occurred during the same period as the Spanish influenza pandemic, encephalitis lethargica has been linked to influenza A virus. However, RT-PCR analyses for influenza A virus mRNA were all negative in archived brain samples from TE D patients.14 Transmission electron microscopy and immunohistochemistry examination support enterovirus as etiology.14 Fernando Alarcón recently reported EB virus as the etiology of a pregnant woman inflicted with EL, backing up the virological hypothesis.12 Post-infectious autoimmunity might also play a pivotal role in the pathogenesis, for the presence of oligoclonal bands in CSF, anti-basal ganglia antibody in serum and suc- EP cessful treatment with corticosteroids.1,3 Our boy has a history of humoral immunity deficiency, which might make him more susceptible to an unknown virus infection leading. On the other hand, there is a high incidence of autoimmune diseases in immunodeficient patients.15 which means autoimmune reaction could be AC C easily initiated in these patients. Although positive oligoclonal bands in both CSF and serum could not indicate specific inflammation in central nervous system, beneficial treatment with immunoglobulin and methylprednisolone indicate autoimmune mechanism in our case. A second encephalitis with white matter injury after encephalitis lethargica has never been reported before. Literature review did not reveal hypersomnia or fatigue as the chronic clinical course of encephalitis lethargica. So we believe the combined symptom of hypersomnia and fatigue appearing 85 days after first dischargement was another episode of encephalitis. Successful treatment with corticosteroids and immunoglobulin suggests the second encephalitis was caused by autoimmune reaction which might start after encephalitis lethargica. The most common autoimmunity-mediated encephalitis in children include acute disseminated encephalomyelitis(ADEM) and autoimmune encephalitis. The major diagnostic criteria of ADEM are a first clinical attack of central nervous system indicating polyfocal demyelinating lesion; encephalopa- ACCEPTED MANUSCRIPT thy that can not explained by fever, system illness, or postictal symptoms; diffuse, poorly demarcated, large lesions(>1-2cm) predominantly involving the white matter on MRI during the acute phase; the absence of new clinical and MRI findings three months after onset. The diagnosis of autoimmune encephalitis is based on the recognition of the specific neurologic symptoms(usually neuropsychiatric syndrome, movement disorder, seizure, and autonomic dysfunction, et al..) and the detection of the specific antibodies in cerebrospinal fluid. The second encephalitis in our case does not meet the diagnostic criteria for ADEM and autoim- RI PT mune encephalitis. We could only diagnose the second encephalitis as “autoimmunity-mediated encephalitis”. The reported mortality of the epidemic form encephalitis lethargica ranged between 20%-40%.2 Of the survivors, many were left with parkinsonism, dyskinesia or psychiatric disease. The most serious sequelae was postencephalitic parkinsonism, which may developed immediately after encephalitis or several years after an apparently complete recovery. Although our boy achieved full recovery without obvious sequelae SC after encephalitis lethargica and the second encephalitis, he needs long term follow-up for possible parkinson syndrome and recurrent encephalitis. M AN U References 1. Howard RS, Lees AJ. Encephalitis lethargica. A report of four recent cases. Brain. 1987;110:19-33. 2. Lopez-Alberola R, Georgiou M, Sfakianakis GN, Singer C, Papapetropoulos S. Contemporary encephalitis lethargica: phenotype, laboratory findings and treatment outcomes. J Neurol. 2009; 256: 396-404. 3. Dale RC, Church AJ, Surtees RA, et al. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain. 2004; 127:21-33. TE D 4. Pradhan S, Pandey N, Shashank S, Gupta PK, Mathur A. Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis. Neurology. 1999;53:1781-1786. 5. Cerna F, Mehrad B, Luby JP, Burns D, Fleckenstein JL. St. Louis encephalitis and the substantia nigra: MR imaging evaluation. AJNR Am J Neuroradiol. 1999;20:1281-1283. EP 6. Guan J, Lu Z, Zhou Q. Reversible parkinsonism due to involvement of substantia nigra in Epstein-Barr virus encephalitis. Mov Disord. 2012;27:156-157. AC C 7. Mihara M, Utsugisawa K, Konno S, Tohgi H. Isolated lesions limited to the bilateral substantial nigra on MRI associated with influenza A infection. Eur Neurol. 2001;45:290-291. 8. Lin SK, Lu CS, Vingerhoets F, et al. Isolated involvement of substantia nigra in acute transient parkinsonism: MRI and PET observations. Parkinsonism Relat Disord. 1995;1:67-72. 9. Alves RS, Barbosa ER, Scaff M. Postvaccinal parkinsonism. Mov Disord. 1992;7:178-180. 10. Kun LN, Yian SY, Haur LS, Tjia H. Bilateral substantia nigra changes on MRI in a patient with encephalitis lethargica. Neurology. 1999;53:1860-1862. 11. Verschueren H, Crols R. Bilateral substantia nigra lesions on magnetic resonance imaging in a patient with encephalitis lethargica. J Neurol Neurosurg Psychiatry. 2001;71:275. 12. Alarcón F, Dueñas G, Lees A. Encephalitis lethargica due to Epstein-Barr virus infection. Mov Disord. 2011;26:2132-2134. ACCEPTED MANUSCRIPT 13. Anderson LL, Vilensky JA, Duvoisin RC. Review: neuropathology of acute phase encephalitis lethargica: a review of cases from the epidemic period. Neuropathol Appl Neurobiol. 2009;35:462-472. 14. Tappe D, Alquezar-Planas DE. Medical and molecular perspectives into a forgotten epidemic: encephalitis lethargica, viruses, and high-throughput sequencing. Journal of clinical virology. 2014;61:189-195. 15. Singh K, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. 2014;13:163-177. Figure legends: AC C EP TE D M AN U SC RI PT Figure 1 Axial brain MRI scan showed bilateral substantia nigra lesions(arrows) on T1-weighted and T2weighted images. A,B: Brain MRI on the fourth day of first admission showed symmetric T2 hyperintense lesions confined to substantia nigra, which were hypointense on T1-weighted image. C,D: The second MRI scan at 1 month after the first admission showed bilateral substantia nigra lesions isotense to cerebrospinal fluid. Figure 2 Brain MRI scan showed subcortical white matter lesions in bilateral frontal lobe on T2 flair images during the second encephalitis which were not seen during the first admission(arrows). A,B: MRI at two weeks after the first dischargement showed no lesion in frontal lobe. C,D: MRI during readmission showed frontal lobe subcortical white matter lesions on T2 flair image. AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT