Chronic granulomatous Herpes simplex encephalitis in a child with DiGeorge syndrome- Expanding the spectrum of Herpes-associated neurological disease

Chronic granulomatous Herpes simplex encephalitis in a child with DiGeorge syndrome- Expanding the spectrum of Herpes-associated neurological disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Chronic granulomatous Herpes simplex encephalitis in a child with DiGeorge syndrome- Expanding the spectrum of Herpes-associated neurological disease Deepti Ashok Kewalramani, Yathwin Kanagavel, Visvanathan Krishnaswamy, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6017714/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Sep, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted 6 You are reading this latest preprint version Abstract Background: Herpes simplex virus(HSV) encephalitis is typically an acute, monophasic illness but can rarely present as a chronic granulomatous encephalitis, especially among immunocompromised individuals. The diagnosis of chronic HSV encephalitis is challenging due to its prolonged latency period, atypical imaging findings, and potential false-negative cerebrospinal fluid (CSF) polymerase chain reaction (PCR) results. This report describes a rare case of chronic granulomatous HSV encephalitis in a child with an underlying immunodeficiency disorder- DiGeorge syndrome (DGS). Case Presentation: A developmentally normal 10-month-old girl initially presented with fever and seizures, was diagnosed with acute encephalitis, and received intravenous acyclovir. Following the illness, she exhibited neurodevelopmental delay and gliotic changes in brain imaging. At 12 years of age, she was admitted with refractory seizures and a respiratory infection. MRI revealed new cortical lesions and CSF analysis showed mild pleocytosis with elevated proteins. Despite symptomatic management, her condition worsened, with progressive neurological decline and radiological evidence of tumefactive or granulomatous lesions. A brain biopsy was performed, revealing HSV-1 positivity on PCR and immunohistochemistry, confirming chronic HSE. Given the atypical course, genetic testing was conducted, showing a 22q11.2 microdeletion consistent with DGS. The patient was treated with intravenous acyclovir and corticosteroids, followed by long-term oral acyclovir prophylaxis. Over two years of follow-up, she showed significant clinical and radiological improvement, with seizure resolution and partial recovery of developmental milestones. Conclusion: This case highlights the potential for HSV to cause chronic granulomatous encephalitis, particularly among children with underlying immunodeficiency. It underscores the diagnostic challenge posed by prolonged latency and false-negative CSF PCR results and the importance of brain biopsy for definitive diagnosis. Additionally, this report suggests a potential link between DGS-related immunodeficiency and chronic HSV infection, emphasizing the need for genetic evaluation in atypical encephalitis cases. Long-term acyclovir therapy may be beneficial in such patients, although the optimal duration remains uncertain. Chronic granulomatous encephalitis Herpes simplex virus encephalitis primary immunodeficiency DiGeorge syndrome lesional brain biopsy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Herpes simplex virus (HSV) can cause a varied spectrum of neurological illnesses. Both type 1&2 HSV can cause encephalitis in children, HSV-1 being commoner( 1 ). Acute febrile encephalopathy with behavioral changes and focal seizures are the typical presenting symptoms of HSV encephalitis (HSE). Typical radiological and electroencephalographic changes demonstrate a temporal lobe involvement in the brain. Microbiological diagnosis of the disease is possible from viral polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). HSE is usually an acute monophasic disease process. Rarely, it may persist or relapse with a chronic form of disease, manifesting with granulomatous changes in the brain( 2 ). As this relapse can occur years after the primary infection, this presentation in childhood is infrequent. These few presentations have been described in both immunocompetent and immunocompromised children( 3 ). We report a child with post-encephalitic sequelae, who presented with refractory seizures and after evaluation was diagnosed to have chronic granulomatous herpetic encephalitis and a primary immunodeficiency disorder (DiGeorge syndrome). Case presentation The child was developmentally normal till 10 months of age when she presented to a hospital outside with fever and seizures. MRI brain showed subtle T2/Flair hyperintensities in bilateral frontal lobes. She was diagnosed with acute encephalitis syndrome and empirically treated with intravenous acyclovir and ceftriaxone. After the illness, the child was noted to have developmental delays predominantly in socio-cognitive and motor milestones. Neuroimaging on follow-up showed post-encephalitic changes with gliosis in bilateral frontal regions. She was started on rehabilitation therapy and began gaining developmental milestones; however, she was later lost to follow-up. At 12 years of age, she was admitted to our hospital with a respiratory infection. On assessment, she was found to have a global developmental delay. She could walk but not run and needed help climbing up and down the stairs. Her language and cognitive milestones were more significantly affected than her motor milestones. On clinical examination, there was no facial dysmorphism or neurocutaneous markers. Her general examination was normal. Neurological examination showed mild hypertonia and hyperreflexia of all four limbs. The child developed seizures after hospitalization which needed multiple antiseizure medications (ASM) for management. MRI brain showed an area of gyral swelling, hyperintensity, and patchy enhancement in the right high parietal lobe along with bilateral frontal and left temporal lobe gliosis attributed to previous illness (Fig. 1 ). CSF analysis revealed elevated proteins with 4 lymphocytes. The child was managed with ceftriaxone and ASM, with both seizures and respiratory complaints settling. A month later, she was readmitted with right focal seizures in the form of twitching of eyes, persistent right-sided gaze, and jerking of the right upper limb. MRI brain demonstrated increased in ill-defined cortical-based enhancing lesions in the right temporoparietal region with diffuse pachymeningeal thickening (Fig. 2 ). Clinico-radiological differential diagnosis of tumefactive demyelination and chronic encephalitic infections were considered. Blood counts, HIV testing, and immunoglobulin profile were normal. CSF cell count and biochemistry were inconclusive. CSF-PCR for Burkholderia pseudomallei and HSV type 1&2 were negative. Anti-aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody were negative. Given the persistent seizures, a trial of intravenous methylprednisolone pulse therapy was given and her seizures gradually decreased. As there was a favorable clinical response, oral steroids were started which were later tapered off. On follow-up, she presented with loss of previously attained milestones and seizures. MRI brain repeated at this stage showed an increase in the extent and severity of gliosis involving bilateral frontal, left temporal, and right parietal-temporal lobes spreading to the opposite hemisphere via the corpus callosum. There was also the presence of new gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening. These bilateral frontal changes were suggestive of a tumor-like lesion or a chronic granulomatous lesion (Fig. 3 ). As the investigations done so far were inconclusive, a ‘lesional’ brain biopsy was considered. Histopathology of the brain biopsy tissue revealed microglial infiltration suggestive of inflammation (Figs. 4 a and 4 b). Viral PCR and immuno-histochemistry performed on the tissue were strongly positive for HSV type 1 (Fig. 4 c). The child received intravenous acyclovir and steroids for 21 days. After starting acyclovir, there was an improvement in her clinical condition and the seizures were controlled as well. Given the unusually persistent picture of the viral encephalitis, an underlying genetic immunodeficiency patho-mechanism was considered, and an extensive immunodeficiency workup was initiated. The T cell and B cell total and subset populations were normal and immunoglobulin levels were also within normal ranges. The immunoglobulin functional assay couldn’t be performed due to logistic issues. Since the immunoglobulin workup was inconclusive, clinical exome sequencing (CES) was performed. CES revealed heterozygous micro-deletion in chromosome 22, suggestive of DiGeorge syndrome (DGS). While the child did not have any craniofacial features suggestive of DiGeorge syndrome, she did have a history of recurrent respiratory infections indicative of the underlying immunodeficiency. Also, the computed tomography thorax done at 12 years of age for respiratory complaints did not show a thymic shadow. 2D ECHO was performed to rule out any cardiac defects and showed a normal study. There was no parental consanguinity and the parents are phenotypically normal and asymptomatic. However, genetic testing was not done for the parents due to logistic reasons. Since no other specific clinical manifestations of DGS were present in this patient, CES helped us establish the diagnosis. The child was continued on oral acyclovir prophylaxis and started regaining milestones slowly (Table 1 ). MRI brain was repeated after 6 months of acyclovir therapy and demonstrated a significant reduction in the size of the lesion (Fig. 5 ). At 2 years follow-up, the child is seizure-free, walking with some support, and speaking in short sentences. Table 1 Summary of clinical course, investigations and management of the patient over the years Age Clinical features Laboratory investigations Neuroimaging - MRI Brain Suspected diagnosis Treatment 10 months Fever, seizures, altered sensorium CSF Counts – 5 lymphocytes 4 Polymorphs 1 Glucose 63 Electrolytes, calcium, magnesium – Normal CRP – Increased Subtle flair hyperintensities Bilateral Frontal Lobes Viral Meningoencephalitis Antiseizure medicines Acyclovir Ceftriaxone 10 months – 3 years Development delay - - Post encephalitic sequelae Phenobarbitone, sodium valproate 3 years Fever, cough, Respiratory Distress Seizures Gastric aspirate for AFB – Negative Genxpert – Negative - Pneumonia + Seizures Respiratory support Topiramate for seizures 3y – 12y Developmental delay Seizure free No chronic respiratory issues - - - Lost to follow up 12 years Fever, cough, Respiratory distress, Developed seizures in ICU CSF – 4 cells Glucose – 61 Area of gyral swelling, hyperintensity and faint enhancement in right high parietal lobe. Gliotic areas in bilateral frontal lobes and left temporal lobe Meningoencephalitis with H1N1 pneumonia Antibiotics-Ceftriaxone Ventilation Oseltamivir Meropenem Vancomycin Antiseizure medicines- Valproate Phenobartbitone Topiramate Levetiracetam Clobazam 12 years 2 months Right focal seizures Respiratory distress CSF – 8 cells Glucose 83 Burkholderia – Negative AFB – Negative Occasional pus cells in CSF Anti-NMO/MOG Antibody – Negative Tuberculosis workup - Negative Increase in ill-defined cortical based enhancing lesions in the right temporo-parietal region with diffuse pachymeningeal thickening. Tumefactive demyelination vs Chronic infections like Neuromeliodosis Methylprednisolone pulse therapy followed by oral steroid taper 12 years 4 months Loss of attained milestones, drug refractory epilepsy Lesional Biopsy- Viral PCR and immuno-histochemistry positive for HSV type1 Primary Immunodeficiency workup - normal New gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening Chronic granulomatous encephalitis – Chronic Herpes Simplex type1 encephalitis 21 days of Intravenous acyclovir followed by oral acyclovir 13 years Follow-up – Slowly regaining milestones, seizure free Whole Exome sequencing - heterozygous microdeletion in chromosome22, suggestive of DiGeorge syndrome MRI brain- Partial resolution of gyral enhancements along bilateral frontal lobes and right high parietal lobe with mild increase in parenchymal atrophy and volume loss. Chronic Herpes Simplex type1 encephalitis Oral acyclovir continued Discussion Although HSE is classically a monophasic illness, it can sometimes progress to a chronic indolent stage, rarely to a granulomatous infection( 4 ). Chronic HSE is usually characterized by a late complication or relapse, manifesting with new neurological deficits, seizures, and new radiological changes. As described previously and in this case, there was a period of latency between the initial acute encephalitic presentation and the secondary chronic phase of the disease. The reason for such latency is elusive( 5 , 6 ). This also raises the importance of suspecting this entity in patients who had HSE in early childhood. CSF HSV PCR is the gold standard for diagnosis of both initial and recurrent infections. This test may be falsely negative when tested too early in the disease course or if a sample has insufficient cells( 7 ). In cases where CSF examination is negative, histopathology and PCR of the biopsy sample are required to confirm the diagnosis 8 . As for initial infection, intravenous acyclovir has been tried for both recurrent and chronic HSE( 8 ). Some case reports suggest continuing oral acyclovir prophylaxis after 21 days of intravenous therapy but there is no consensus on the total duration of the treatment. Further studies are needed to determine the recommended duration of the antiviral retreatment in chronic HSE. Oral acyclovir prophylaxis was provided for our patient as well. Although childhood HSE is mostly sporadic some reports suggest that in some children it may result from mendelian predisposition, particularly from the autosomal recessive susceptibility( 9 ). However, there was no family history of herpetic infections and parental consanguinity in our patient. Several genetic mutations are associated with increased susceptibility to HSE and its recurrence. Most mutations involve the INF-alpha/beta/gamma signaling pathways, as well as the toll-like receptor (TLR) pathway. These mutations are thought to impair cell immunity in neurons and oligodendrocytes( 10 ). Interestingly in this patient, CES did not detect any mutations or deficiencies known to confer an increased risk of HSE recurrence, but it revealed a relatively common syndromic condition with immunodeficiency. DGS overlaps considerably with velocardiofacial syndrome and to a lesser extent with conotruncal anomaly face syndrome. These are associated with hemizygous22q.11 deletions and manifest a wide spectrum of clinical features. This deletion is also associated with neurodevelopmental delay, behavioral disturbances, and psychiatric features( 11 ). DGS is associated with a range of T-cell deficiencies from normal T-cell numbers and function to complete T-negative severe combined immunodeficiency-like picture. The majority of children with thymic insufficiency as part of DGS, have only a partial form of immunodeficiency. The consequences are an increased susceptibility to infections and sometimes immune dysregulation resulting in autoimmunity( 12 ). Similarly, our patient also had only a history of recurrent respiratory infections. Di George syndrome has been associated with repeated HSV 1 infection but granulomatous changes are seldom noticed( 13 ). To our knowledge, chronic HSE with an underlying T-cell immunodeficiency syndrome like DGS has not been reported previously. We could not perform acyclovir sensitivity testing for the viral isolates, which is a limitation of this study. Conclusion HSV can cause chronic granulomatous encephalitis, especially among immunodeficient children, and chronic acyclovir can be used for its treatment. This case report highlights the importance and need for a lesional brain biopsy for reaching a precise diagnosis in such presentations. It also emphasizes performing genetic analysis for such cases to rule out underlying immunodeficiency syndromes. Abbreviations HSV Herpes simplex virus CSF Cerebrospinal fluid PCR Polymerase chain reaction DGS DiGeorge syndrome HSE Herpes simplex virus encephalitis CES Clinical exome sequencing ASM Antiseizure medications TLR Toll like receptor MRI Magnetic resonance imaging CRP C–Reactive protein AFB Acid fast bacteria Anti NMO–anti–Neuromyelitis optica(Aquaporin–4 antibody) Anti MOG–anti–myelin oligodendrocyte glycoprotein antibody Declarations Ethics approval and consent to participate: SRIHER institutional ethics committee Consent for publication: Written informed consent for publication was obtained from patient’s parents. Availability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Competing interests: The authors declare that they have no competing interests. Funding: No funding was obtained for the report. Authors' contributions: RKM, YK, and DAK made the draft. LR, RM, PVR, and VK made multiple revisions of the report. RKM was responsible for the conception of the report and has agreed to be personally accountable for any questions on the integrity or accuracy of the work. YK, DAK, PVR, and LDC were responsible for the acquisition, analysis and interpretation of the data. YKM and DAK made the final manuscript to be submitted, which was approved by all the other authors. Acknowledgements: No further contributions to be acknowledged. References Kennedy PGE, Chaudhuri A. Herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002;73(3):237–8. Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry. 2003;74(2):262–4. Kimura H, Aso K, Kuzushima K, Hanada N, Shibata M, Morishima T. Relapse of herpes simplex encephalitis in children. Pediatrics. 1992;89(5 Pt 1):891–4. Adamo MA, Abraham L, Pollack IF. Chronic granulomatous herpes encephalitis: a rare entity posing a diagnostic challenge. J Neurosurg Pediatr. 2011;8(4):402–6. Grinde B. Herpesviruses: latency and reactivation – viral strategies and host response. J Oral Microbiol. 2013;5. 10.3402/jom.v5i0.22766 . Spiegel R, Miron D, Yodko H, Lumelsky D, Habib A, Horovitz Y. Late relapse of herpes simplex virus encephalitis in a child due to reactivation of latent virus: clinicopathological report and review. J Child Neurol. 2008;23(3):344–8. Diagnosis and surveillance of herpes simplex virus infection of the central. nervous system - Najioullah – 2000 - Journal of Medical Virology - Wiley Online Library [Internet]. [cited 2024 Oct 28]. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/1096-9071%28200008%2961%3A4%3C468%3A%3AAID-JMV9%3E3.0.CO%3B2-9 Hackney JR, Harrison DK, Rozzelle C, Kankirawatana S, Kankirawatana P, Palmer CA. Chronic Granulomatous Herpes Encephalitis in a Child with Clinically Intractable Epilepsy. Case Rep Pediatr. 2012;2012:849812. Abel L, Plancoulaine S, Jouanguy E, Zhang SY, Mahfoufi N, Nicolas N, et al. Age-Dependent Mendelian Predisposition to Herpes Simplex Virus Type 1 Encephalitis in Childhood. J Pediatr. 2010;157(4):623–e6291. Zhang SY, Jouanguy E, Sancho-Shimizu V, von Bernuth H, Yang K, Abel L, et al. Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev. 2007;220(1):225–36. de la Chapelle A, Herva R, Koivisto M, Aula P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet. 1981;57(3):253–6. Immunodeficiency in. DiGeorge Syndrome and Options for Treating Cases with Complete Athymia - PubMed [Internet]. [cited 2024 Oct 30]. Available from: https://pubmed.ncbi.nlm.nih.gov/24198816/ Chinen J, Kline MW, Shearer WT. CHAPTER 79 - PRIMARY IMMUNODEFICIENCIES. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, editors. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases (Sixth Edition) [Internet]. Philadelphia: W.B. Saunders; 2009 [cited 2025 Mar 19]. pp. 1021–37. Available from: https://www.sciencedirect.com/science/article/pii/B9781416040446500844 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Sep, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Accepted 02 Apr, 2025 Reviews received at journal 20 Mar, 2025 Reviewers agreed at journal 20 Mar, 2025 Reviewers invited by journal 20 Mar, 2025 Submission checks completed at journal 20 Mar, 2025 First submitted to journal 19 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6017714","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":432636736,"identity":"244c1b04-b52e-424c-9fca-e28c3a92366b","order_by":0,"name":"Deepti Ashok Kewalramani","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Deepti","middleName":"Ashok","lastName":"Kewalramani","suffix":""},{"id":432636737,"identity":"06f93511-2e88-4cc8-b946-14f4b648af29","order_by":1,"name":"Yathwin Kanagavel","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Yathwin","middleName":"","lastName":"Kanagavel","suffix":""},{"id":432636738,"identity":"d123f974-e082-4997-b87e-e772bb9ec550","order_by":2,"name":"Visvanathan Krishnaswamy","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Visvanathan","middleName":"","lastName":"Krishnaswamy","suffix":""},{"id":432636739,"identity":"27e31880-a1b6-4a6d-8ae1-b1025643e5e8","order_by":3,"name":"Latha Ravichandran","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Latha","middleName":"","lastName":"Ravichandran","suffix":""},{"id":432636740,"identity":"ba22bd5b-9b92-4a56-9fcf-ff98fa5251aa","order_by":4,"name":"Lawrence D Cruz","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Lawrence","middleName":"D","lastName":"Cruz","suffix":""},{"id":432636741,"identity":"68098790-3f99-4958-8f66-5fbfedfc47ab","order_by":5,"name":"Padmasani Venkat Ramanan","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Padmasani","middleName":"Venkat","lastName":"Ramanan","suffix":""},{"id":432636742,"identity":"52aaadbb-4104-4635-8c9c-1bfdb9f4a74f","order_by":6,"name":"Ram Mohan","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Ram","middleName":"","lastName":"Mohan","suffix":""},{"id":432636743,"identity":"78dc1ce1-d4f3-4a97-8dfe-773759acb3c9","order_by":7,"name":"Ranjith Kumar Manokaran","email":"data:image/png;base64,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","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":true,"prefix":"","firstName":"Ranjith","middleName":"Kumar","lastName":"Manokaran","suffix":""}],"badges":[],"createdAt":"2025-02-12 19:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6017714/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6017714/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11385-5","type":"published","date":"2025-09-26T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79322415,"identity":"72d6c264-b0b8-437a-988e-3401b8f8f271","added_by":"auto","created_at":"2025-03-27 04:39:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":814641,"visible":true,"origin":"","legend":"\u003cp\u003e(Images at first presentation – clinical presentation of respiratory infection and seizures) Axial T2 weighted images (a to c) and post gadolinium T1 fat saturated images (d to f) show area of gyral swelling, hyperintensity and patchy enhancement (arrowheads) in right high parietal lobe. In addition, there are large areas of gliosis involving both frontal lobes and left temporal lobe (arrows). Note that the regions of gliosis show no post gadolinium enhancement.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/6161a94487672bcff735aa59.png"},{"id":79322413,"identity":"5425b89d-e7ba-409c-a2aa-a2a1ab5ff988","added_by":"auto","created_at":"2025-03-27 04:39:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":767640,"visible":true,"origin":"","legend":"\u003cp\u003e(Images after one month – clinical presentation with status epilepticus) Axial T2 weighted images (a to c) and post gadolinium T1 fat saturated images (d to f) show increase in gyral swelling, hyperintensity and enhancement (arrowheads) in right parietal lobe which has extended to involve the right temporal lobe along with diffuse pachymeningeal thickening. Stable areas of gliosis involving both frontal lobes and left temporal lobe (arrows) are noted.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/26dc8ba3813ae58cecd9c5c1.png"},{"id":79322867,"identity":"29445315-b358-45f7-b51d-a67563f4879f","added_by":"auto","created_at":"2025-03-27 04:47:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":757373,"visible":true,"origin":"","legend":"\u003cp\u003e(Images after 2 months of initial presentation – clinical presentation with neuro-regression) Axial T2 weighted images (a to c) show increase in extent and severity of gliosis involving both frontal lobes, left temporal lobe and right parietal-temporal lobes (arrows). Post gadolinium T1 fat saturated images (d to f) show reduction in enhancement in right parieto-temporal lobe but presence of new gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening (arrowheads).\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/76124d37bc65896c2cbcc711.png"},{"id":79322416,"identity":"cc9ab224-163a-4dfb-be67-4233550ae316","added_by":"auto","created_at":"2025-03-27 04:39:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2311682,"visible":true,"origin":"","legend":"\u003cp\u003eA- Hematoxylin and Eosin (H\u0026amp;E) stained section of neural parenchyma at 400x magnification, exhibiting chronic inflammation characterized by a dense lymphocytic infiltrate and surrounding histiocytic infiltration.\u003c/p\u003e\n\u003cp\u003eB- Hematoxylin and Eosin (H\u0026amp;E) stained section of neural parenchyma at 400x magnification, exhibiting histiocytic aggregates showing vague, ill-defined granulomatous inflammatory changes.\u003c/p\u003e\n\u003cp\u003eC- IHC HSV, brain, 400x: Focal positive staining in neurons, demonstrating viral inclusions and cytopathic changes indicative of Herpes simplex virus encephalitis.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/90aa735210abb7411b583bcf.png"},{"id":79322869,"identity":"c23d2ce8-fa7c-407c-b146-c594fdfae693","added_by":"auto","created_at":"2025-03-27 04:47:04","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":340525,"visible":true,"origin":"","legend":"\u003cp\u003e(Images on follow-up)Axial T2 weighted images (a to c) show increase in volume loss and gliosis involving both frontal lobes, left temporal lobe and right parietal-temporal lobes (arrows). Post gadolinium T1 fat saturated images (d to f) complete resolution of enhancement in right parieto-temporal lobe and reduction in thickness of gyral enhancement in the gliotic regions in both frontal lobes (arrowheads).\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/e72644b5e74984baf0339839.png"},{"id":92430620,"identity":"f889750c-6502-484a-ba95-00ff70bb9162","added_by":"auto","created_at":"2025-09-29 16:06:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5960002,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6017714/v1/6a781f4d-d399-4cfb-8666-1b1fb6fa882c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eChronic granulomatous Herpes simplex encephalitis in a child with DiGeorge syndrome- Expanding the spectrum of Herpes-associated neurological disease\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eHerpes simplex virus (HSV) can cause a varied spectrum of neurological illnesses. Both type 1\u0026amp;2 HSV can cause encephalitis in children, HSV-1 being commoner(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Acute febrile encephalopathy with behavioral changes and focal seizures are the typical presenting symptoms of HSV encephalitis (HSE). Typical radiological and electroencephalographic changes demonstrate a temporal lobe involvement in the brain. Microbiological diagnosis of the disease is possible from viral polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). HSE is usually an acute monophasic disease process. Rarely, it may persist or relapse with a chronic form of disease, manifesting with granulomatous changes in the brain(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). As this relapse can occur years after the primary infection, this presentation in childhood is infrequent. These few presentations have been described in both immunocompetent and immunocompromised children(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). We report a child with post-encephalitic sequelae, who presented with refractory seizures and after evaluation was diagnosed to have chronic granulomatous herpetic encephalitis and a primary immunodeficiency disorder (DiGeorge syndrome).\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe child was developmentally normal till 10 months of age when she presented to a hospital outside with fever and seizures. MRI brain showed subtle T2/Flair hyperintensities in bilateral frontal lobes. She was diagnosed with acute encephalitis syndrome and empirically treated with intravenous acyclovir and ceftriaxone. After the illness, the child was noted to have developmental delays predominantly in socio-cognitive and motor milestones. Neuroimaging on follow-up showed post-encephalitic changes with gliosis in bilateral frontal regions. She was started on rehabilitation therapy and began gaining developmental milestones; however, she was later lost to follow-up.\u003c/p\u003e \u003cp\u003eAt 12 years of age, she was admitted to our hospital with a respiratory infection. On assessment, she was found to have a global developmental delay. She could walk but not run and needed help climbing up and down the stairs. Her language and cognitive milestones were more significantly affected than her motor milestones. On clinical examination, there was no facial dysmorphism or neurocutaneous markers. Her general examination was normal. Neurological examination showed mild hypertonia and hyperreflexia of all four limbs. The child developed seizures after hospitalization which needed multiple antiseizure medications (ASM) for management. MRI brain showed an area of gyral swelling, hyperintensity, and patchy enhancement in the right high parietal lobe along with bilateral frontal and left temporal lobe gliosis attributed to previous illness (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). CSF analysis revealed elevated proteins with 4 lymphocytes. The child was managed with ceftriaxone and ASM, with both seizures and respiratory complaints settling.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA month later, she was readmitted with right focal seizures in the form of twitching of eyes, persistent right-sided gaze, and jerking of the right upper limb. MRI brain demonstrated increased in ill-defined cortical-based enhancing lesions in the right temporoparietal region with diffuse pachymeningeal thickening (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Clinico-radiological differential diagnosis of tumefactive demyelination and chronic encephalitic infections were considered. Blood counts, HIV testing, and immunoglobulin profile were normal. CSF cell count and biochemistry were inconclusive. CSF-PCR for Burkholderia pseudomallei and HSV type 1\u0026amp;2 were negative. Anti-aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody were negative. Given the persistent seizures, a trial of intravenous methylprednisolone pulse therapy was given and her seizures gradually decreased. As there was a favorable clinical response, oral steroids were started which were later tapered off.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn follow-up, she presented with loss of previously attained milestones and seizures. MRI brain repeated at this stage showed an increase in the extent and severity of gliosis involving bilateral frontal, left temporal, and right parietal-temporal lobes spreading to the opposite hemisphere via the corpus callosum. There was also the presence of new gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening. These bilateral frontal changes were suggestive of a tumor-like lesion or a chronic granulomatous lesion (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). As the investigations done so far were inconclusive, a \u0026lsquo;lesional\u0026rsquo; brain biopsy was considered. Histopathology of the brain biopsy tissue revealed microglial infiltration suggestive of inflammation (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). Viral PCR and immuno-histochemistry performed on the tissue were strongly positive for HSV type 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec). The child received intravenous acyclovir and steroids for 21 days. After starting acyclovir, there was an improvement in her clinical condition and the seizures were controlled as well.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the unusually persistent picture of the viral encephalitis, an underlying genetic immunodeficiency patho-mechanism was considered, and an extensive immunodeficiency workup was initiated. The T cell and B cell total and subset populations were normal and immunoglobulin levels were also within normal ranges. The immunoglobulin functional assay couldn\u0026rsquo;t be performed due to logistic issues. Since the immunoglobulin workup was inconclusive, clinical exome sequencing (CES) was performed. CES revealed heterozygous micro-deletion in chromosome 22, suggestive of DiGeorge syndrome (DGS). While the child did not have any craniofacial features suggestive of DiGeorge syndrome, she did have a history of recurrent respiratory infections indicative of the underlying immunodeficiency. Also, the computed tomography thorax done at 12 years of age for respiratory complaints did not show a thymic shadow. 2D ECHO was performed to rule out any cardiac defects and showed a normal study. There was no parental consanguinity and the parents are phenotypically normal and asymptomatic. However, genetic testing was not done for the parents due to logistic reasons. Since no other specific clinical manifestations of DGS were present in this patient, CES helped us establish the diagnosis.\u003c/p\u003e \u003cp\u003eThe child was continued on oral acyclovir prophylaxis and started regaining milestones slowly (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). MRI brain was repeated after 6 months of acyclovir therapy and demonstrated a significant reduction in the size of the lesion (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). At 2 years follow-up, the child is seizure-free, walking with some support, and speaking in short sentences.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of clinical course, investigations and management of the patient over the years\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClinical features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLaboratory investigations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNeuroimaging - MRI Brain\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSuspected diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFever, seizures, altered sensorium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCSF\u003c/p\u003e \u003cp\u003eCounts \u0026ndash; 5 lymphocytes 4\u003c/p\u003e \u003cp\u003ePolymorphs 1\u003c/p\u003e \u003cp\u003eGlucose 63\u003c/p\u003e \u003cp\u003eElectrolytes, calcium, magnesium \u0026ndash; Normal\u003c/p\u003e \u003cp\u003eCRP \u0026ndash; Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSubtle flair hyperintensities Bilateral Frontal Lobes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eViral Meningoencephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAntiseizure medicines\u003c/p\u003e \u003cp\u003eAcyclovir\u003c/p\u003e \u003cp\u003eCeftriaxone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10 months \u0026ndash; 3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDevelopment delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePost encephalitic sequelae\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhenobarbitone, sodium valproate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFever, cough, Respiratory Distress\u003c/p\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGastric aspirate for AFB \u0026ndash; Negative\u003c/p\u003e \u003cp\u003eGenxpert \u0026ndash; Negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePneumonia\u0026thinsp;+\u0026thinsp;Seizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRespiratory support\u003c/p\u003e \u003cp\u003eTopiramate for seizures\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3y \u0026ndash; 12y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDevelopmental delay\u003c/p\u003e \u003cp\u003eSeizure free\u003c/p\u003e \u003cp\u003eNo chronic respiratory issues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLost to follow up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFever, cough, Respiratory distress,\u003c/p\u003e \u003cp\u003eDeveloped seizures in ICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCSF \u0026ndash; 4 cells\u003c/p\u003e \u003cp\u003eGlucose \u0026ndash; 61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eArea of gyral swelling, hyperintensity and faint\u003c/p\u003e \u003cp\u003eenhancement in right high parietal lobe. Gliotic areas in bilateral\u003c/p\u003e \u003cp\u003efrontal\u003c/p\u003e \u003cp\u003elobes and left temporal lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMeningoencephalitis with H1N1 pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAntibiotics-Ceftriaxone\u003c/p\u003e \u003cp\u003eVentilation\u003c/p\u003e \u003cp\u003eOseltamivir\u003c/p\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003cp\u003eVancomycin\u003c/p\u003e \u003cp\u003eAntiseizure medicines-\u003c/p\u003e \u003cp\u003eValproate\u003c/p\u003e \u003cp\u003ePhenobartbitone\u003c/p\u003e \u003cp\u003eTopiramate\u003c/p\u003e \u003cp\u003eLevetiracetam\u003c/p\u003e \u003cp\u003eClobazam\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 years 2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRight focal seizures\u003c/p\u003e \u003cp\u003eRespiratory distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCSF \u0026ndash; 8 cells\u003c/p\u003e \u003cp\u003eGlucose 83\u003c/p\u003e \u003cp\u003eBurkholderia \u0026ndash; Negative\u003c/p\u003e \u003cp\u003eAFB \u0026ndash; Negative\u003c/p\u003e \u003cp\u003eOccasional pus cells in CSF\u003c/p\u003e \u003cp\u003eAnti-NMO/MOG Antibody \u0026ndash; Negative\u003c/p\u003e \u003cp\u003eTuberculosis workup - Negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncrease in ill-defined cortical based enhancing lesions in the right temporo-parietal region with diffuse pachymeningeal thickening.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTumefactive demyelination vs\u003c/p\u003e \u003cp\u003eChronic infections like Neuromeliodosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMethylprednisolone pulse therapy followed by oral steroid taper\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 years 4 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoss of attained milestones, drug refractory epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLesional Biopsy-\u003c/p\u003e \u003cp\u003eViral PCR and immuno-histochemistry positive for HSV type1\u003c/p\u003e \u003cp\u003ePrimary Immunodeficiency workup - normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNew gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChronic granulomatous encephalitis \u0026ndash; Chronic Herpes Simplex type1 encephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21 days of Intravenous acyclovir followed by oral acyclovir\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFollow-up \u0026ndash; Slowly regaining milestones, seizure free\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWhole Exome sequencing - heterozygous microdeletion in chromosome22, suggestive of DiGeorge syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMRI brain- Partial resolution of gyral enhancements along bilateral frontal lobes and right high parietal lobe with mild increase in parenchymal atrophy and volume loss.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChronic Herpes Simplex type1 encephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOral acyclovir continued\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough HSE is classically a monophasic illness, it can sometimes progress to a chronic indolent stage, rarely to a granulomatous infection(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Chronic HSE is usually characterized by a late complication or relapse, manifesting with new neurological deficits, seizures, and new radiological changes. As described previously and in this case, there was a period of latency between the initial acute encephalitic presentation and the secondary chronic phase of the disease. The reason for such latency is elusive(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This also raises the importance of suspecting this entity in patients who had HSE in early childhood.\u003c/p\u003e \u003cp\u003eCSF HSV PCR is the gold standard for diagnosis of both initial and recurrent infections. This test may be falsely negative when tested too early in the disease course or if a sample has insufficient cells(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In cases where CSF examination is negative, histopathology and PCR of the biopsy sample are required to confirm the diagnosis\u003csup\u003e8\u003c/sup\u003e. As for initial infection, intravenous acyclovir has been tried for both recurrent and chronic HSE(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Some case reports suggest continuing oral acyclovir prophylaxis after 21 days of intravenous therapy but there is no consensus on the total duration of the treatment. Further studies are needed to determine the recommended duration of the antiviral retreatment in chronic HSE. Oral acyclovir prophylaxis was provided for our patient as well.\u003c/p\u003e \u003cp\u003eAlthough childhood HSE is mostly sporadic some reports suggest that in some children it may result from mendelian predisposition, particularly from the autosomal recessive susceptibility(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, there was no family history of herpetic infections and parental consanguinity in our patient. Several genetic mutations are associated with increased susceptibility to HSE and its recurrence. Most mutations involve the INF-alpha/beta/gamma signaling pathways, as well as the toll-like receptor (TLR) pathway. These mutations are thought to impair cell immunity in neurons and oligodendrocytes(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Interestingly in this patient, CES did not detect any mutations or deficiencies known to confer an increased risk of HSE recurrence, but it revealed a relatively common syndromic condition with immunodeficiency.\u003c/p\u003e \u003cp\u003eDGS overlaps considerably with velocardiofacial syndrome and to a lesser extent with conotruncal anomaly face syndrome. These are associated with hemizygous22q.11 deletions and manifest a wide spectrum of clinical features. This deletion is also associated with neurodevelopmental delay, behavioral disturbances, and psychiatric features(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). DGS is associated with a range of T-cell deficiencies from normal T-cell numbers and function to complete T-negative severe combined immunodeficiency-like picture. The majority of children with thymic insufficiency as part of DGS, have only a partial form of immunodeficiency. The consequences are an increased susceptibility to infections and sometimes immune dysregulation resulting in autoimmunity(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Similarly, our patient also had only a history of recurrent respiratory infections. Di George syndrome has been associated with repeated HSV 1 infection but granulomatous changes are seldom noticed(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). To our knowledge, chronic HSE with an underlying T-cell immunodeficiency syndrome like DGS has not been reported previously. We could not perform acyclovir sensitivity testing for the viral isolates, which is a limitation of this study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHSV can cause chronic granulomatous encephalitis, especially among immunodeficient children, and chronic acyclovir can be used for its treatment. This case report highlights the importance and need for a lesional brain biopsy for reaching a precise diagnosis in such presentations. It also emphasizes performing genetic analysis for such cases to rule out underlying immunodeficiency syndromes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHerpes simplex virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolymerase chain reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiGeorge syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHerpes simplex virus encephalitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical exome sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntiseizure medications\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTLR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eToll like receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC\u0026ndash;Reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAFB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcid fast bacteria\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAnti\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNMO\u0026ndash;anti\u0026ndash;Neuromyelitis optica(Aquaporin\u0026ndash;4 antibody)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAnti\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMOG\u0026ndash;anti\u0026ndash;myelin oligodendrocyte glycoprotein antibody\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: SRIHER institutional ethics committee\u003c/p\u003e\n\u003cp\u003eConsent for publication: Written informed consent for publication was obtained from patient\u0026rsquo;s parents.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: No funding was obtained for the report.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: RKM, YK, and DAK made the draft. LR, RM, PVR, and VK made multiple revisions of the report. RKM was responsible for the conception of the report and has agreed to be personally accountable for any questions on the integrity or accuracy of the work. YK, DAK, PVR, and LDC were responsible for the acquisition, analysis and interpretation of the data. YKM and DAK made the final manuscript to be submitted, which was approved by all the other authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgements: No further contributions to be acknowledged.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKennedy PGE, Chaudhuri A. Herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002;73(3):237\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry. 2003;74(2):262\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKimura H, Aso K, Kuzushima K, Hanada N, Shibata M, Morishima T. Relapse of herpes simplex encephalitis in children. Pediatrics. 1992;89(5 Pt 1):891\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdamo MA, Abraham L, Pollack IF. Chronic granulomatous herpes encephalitis: a rare entity posing a diagnostic challenge. J Neurosurg Pediatr. 2011;8(4):402\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrinde B. Herpesviruses: latency and reactivation \u0026ndash; viral strategies and host response. J Oral Microbiol. 2013;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3402/jom.v5i0.22766\u003c/span\u003e\u003cspan address=\"10.3402/jom.v5i0.22766\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpiegel R, Miron D, Yodko H, Lumelsky D, Habib A, Horovitz Y. Late relapse of herpes simplex virus encephalitis in a child due to reactivation of latent virus: clinicopathological report and review. J Child Neurol. 2008;23(3):344\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiagnosis and surveillance of herpes simplex virus infection of the central. nervous system - Najioullah \u0026ndash;\u0026thinsp;2000 - Journal of Medical Virology - Wiley Online Library [Internet]. [cited 2024 Oct 28]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/abs/10.1002/1096-9071%28200008%2961%3A4%3C468%3A%3AAID-JMV9%3E3.0.CO%3B2-9\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/abs/10.1002/1096-9071%28200008%2961%3A4%3C468%3A%3AAID-JMV9%3E3.0.CO%3B2-9\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHackney JR, Harrison DK, Rozzelle C, Kankirawatana S, Kankirawatana P, Palmer CA. Chronic Granulomatous Herpes Encephalitis in a Child with Clinically Intractable Epilepsy. Case Rep Pediatr. 2012;2012:849812.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbel L, Plancoulaine S, Jouanguy E, Zhang SY, Mahfoufi N, Nicolas N, et al. Age-Dependent Mendelian Predisposition to Herpes Simplex Virus Type 1 Encephalitis in Childhood. J Pediatr. 2010;157(4):623\u0026ndash;e6291.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang SY, Jouanguy E, Sancho-Shimizu V, von Bernuth H, Yang K, Abel L, et al. Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev. 2007;220(1):225\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede la Chapelle A, Herva R, Koivisto M, Aula P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet. 1981;57(3):253\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImmunodeficiency in. DiGeorge Syndrome and Options for Treating Cases with Complete Athymia - PubMed [Internet]. [cited 2024 Oct 30]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/24198816/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/24198816/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChinen J, Kline MW, Shearer WT. CHAPTER 79 - PRIMARY IMMUNODEFICIENCIES. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, editors. Feigin and Cherry\u0026rsquo;s Textbook of Pediatric Infectious Diseases (Sixth Edition) [Internet]. Philadelphia: W.B. Saunders; 2009 [cited 2025 Mar 19]. pp. 1021\u0026ndash;37. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.sciencedirect.com/science/article/pii/B9781416040446500844\u003c/span\u003e\u003cspan address=\"https://www.sciencedirect.com/science/article/pii/B9781416040446500844\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Chronic granulomatous encephalitis, Herpes simplex virus encephalitis, primary immunodeficiency, DiGeorge syndrome, lesional brain biopsy","lastPublishedDoi":"10.21203/rs.3.rs-6017714/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6017714/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eHerpes simplex virus(HSV) encephalitis is typically an acute, monophasic illness but can rarely present as a chronic granulomatous encephalitis, especially among immunocompromised individuals. The diagnosis of chronic HSV encephalitis is challenging due to its prolonged latency period, atypical imaging findings, and potential false-negative cerebrospinal fluid (CSF) polymerase chain reaction (PCR) results. This report describes a rare case of chronic granulomatous HSV encephalitis in a child with an underlying immunodeficiency disorder- DiGeorge syndrome (DGS).\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA developmentally normal 10-month-old girl initially presented with fever and seizures, was diagnosed with acute encephalitis, and received intravenous acyclovir. Following the illness, she exhibited neurodevelopmental delay and gliotic changes in brain imaging. At 12 years of age, she was admitted with refractory seizures and a respiratory infection. MRI revealed new cortical lesions and CSF analysis showed mild pleocytosis with elevated proteins. Despite symptomatic management, her condition worsened, with progressive neurological decline and radiological evidence of tumefactive or granulomatous lesions. A brain biopsy was performed, revealing HSV-1 positivity on PCR and immunohistochemistry, confirming chronic HSE. Given the atypical course, genetic testing was conducted, showing a 22q11.2 microdeletion consistent with DGS. The patient was treated with intravenous acyclovir and corticosteroids, followed by long-term oral acyclovir prophylaxis. Over two years of follow-up, she showed significant clinical and radiological improvement, with seizure resolution and partial recovery of developmental milestones.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis case highlights the potential for HSV to cause chronic granulomatous encephalitis, particularly among children with underlying immunodeficiency. It underscores the diagnostic challenge posed by prolonged latency and false-negative CSF PCR results and the importance of brain biopsy for definitive diagnosis. Additionally, this report suggests a potential link between DGS-related immunodeficiency and chronic HSV infection, emphasizing the need for genetic evaluation in atypical encephalitis cases. Long-term acyclovir therapy may be beneficial in such patients, although the optimal duration remains uncertain.\u003c/p\u003e","manuscriptTitle":"Chronic granulomatous Herpes simplex encephalitis in a child with DiGeorge syndrome- Expanding the spectrum of Herpes-associated neurological disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:38:59","doi":"10.21203/rs.3.rs-6017714/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-04-02T04:56:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-20T20:59:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"329921839212723370143360212636762302822","date":"2025-03-20T20:43:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-20T20:27:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-20T13:32:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-03-19T20:23:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e796eb06-64ab-415b-8f9f-ba3d040cfd04","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T16:03:28+00:00","versionOfRecord":{"articleIdentity":"rs-6017714","link":"https://doi.org/10.1186/s12879-025-11385-5","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-09-26 15:57:44","publishedOnDateReadable":"September 26th, 2025"},"versionCreatedAt":"2025-03-27 04:38:59","video":"","vorDoi":"10.1186/s12879-025-11385-5","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11385-5","workflowStages":[]},"version":"v1","identity":"rs-6017714","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6017714","identity":"rs-6017714","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}