Meningoencephalitis in Children with Primary Antibody Deficiency: A Single-Center Experience From Northwest India and Review of Literature

Meningoencephalitis in Children with Primary Antibody Deficiency: A Single-Center Experience From Northwest India and Review of Literature | 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 Research Article Meningoencephalitis in Children with Primary Antibody Deficiency: A Single-Center Experience From Northwest India and Review of Literature Ankur Kumar Jindal, Himanshi Chaudhary, Rahul Tyagi, Amit Rawat, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-723651/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Patients with primary antibody deficiency (PAD) are predisposed to develop meningoencephalitis that is often considered to be enteroviral. However, there is a paucity of literature on this subject, and there are no studies from developing countries. We analyzed our cohort of children with PAD who developed meningoencephalitis. This complication was observed in 11/135 (8.1%) patients with PAD - 4 patients had X-linked agammaglobulinemia (XLA), and 7 had common variable immunodeficiency (CVID). The mean age at onset of neurological illness was 8.6 years (range: 2-28 years). Presenting features included seizures (n=7), neurodevelopmental delay (n=2), regression of milestones (n=1), and acute flaccid paralysis (n=1). Trough IgG levels were found to be low in 9 (81.8%) patients at the time of development of neurological symptoms. Herpes simplex virus (HSV), cytomegalovirus (CMV), and Streptococcus pneumoniae were isolated in 1 patient each. No etiological agent was identified in cerebrospinal fluid of 8 patients. Eight (72.7%) patients had altered signal hyperintensities in gray matter and deep white matter on magnetic resonance imaging (MRI), while 3 patients showed global cerebral atrophy. All patients were treated with high-dose intravenous immunoglobulin (IVIg). Fluoxetine was given to 2 patients. Eight (72.7%) patients in the present series have succumbed, while three have recovered with varying degrees of neurological sequelae. To conclude, meningoencephalitis is an uncommon complication in patients with PAD and is associated with high morbidity and mortality in our setting. Early diagnosis of immune deficiency and initiation of replacement immunoglobulin therapy may prevent the development of neurological complications. Clinical Pharmacology Immunology Common Variable Immunodeficiency Enterovirus Intravenous immunoglobulin Meningoencephalitis Primary antibody deficiency X-linked agammaglobulinemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Primary antibody deficiencies (PADs) (such as X-linked agammaglobulinemia [XLA] and common variable immunodeficiency [CVID]) are inborn errors of immunity (IEI) caused by a predominant defect in the humoral arm of the adaptive immune system[ 1 , 2 , 3 ]. The most common clinical presentation of PADs is recurrent sinopulmonary infection. Pyogenic meningitis is also a common infection in patients with PAD[ 2 ]. In addition, these patients are predisposed to develop viral infections and non-infectious autoimmune complications[ 4 ]. Although meningoencephalitis (often caused by enteroviruses) has been reported in patients with PADs, most published literature pertains to anecdotal clinical reports. There is a paucity of data from large patient cohorts studied over extended periods of time, and no information is available on this subject from developing countries. We report herein our experience on meningoencephalitis in patients with PADs. Patient And Methods We carried out a review of records of all patients who were diagnosed to have XLA or CVID and were registered at the Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Our center is a not-for-profit tertiary care referral teaching institute in northwest India. Patients with XLA or CVID who were also diagnosed to have meningoencephalitis were analyzed in detail. For the purpose of this study, the terms' XLA' and 'CVID' were defined as per criteria given by the European Society of Immunodeficiencies[ 5 , 6 ]. Patients who had pyogenic meningitis without any evidence of encephalitis (clinical or radiological) were excluded from this analysis. Clinical details, laboratory and imaging findings, treatment, and outcome of these patients were recorded. A pan-enterovirus reverse transcriptase-polymerase chain reaction (RT-PCR) targeting the highly conserved 5' untranslated region of enterovirus genome was performed at the Department of Neurovirology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, for identification of enteroviruses from the cerebrospinal fluid (CSF). Results In this study, we retrieved clinical details of 70 patients with XLA and 65 patients with CVID. Of these, 11 were diagnosed to have meningoencephalitis. Case 1 A 7-year-old boy presented with complaints of headache, 1 episode of generalized tonic-clonic seizure, and two episodes of transient loss of consciousness for 1 week. He had had a history of recurrent ear discharge and chronic diarrhea since the age of 1 and one episode of pyogenic meningitis at 6 years. On examination, he had absent tonsils, and lymph nodes were not palpable. CSF examination was normal. Magnetic resonance imaging (MRI) of the brain revealed altered signal intensities in parieto-occipital regions. Investigations are summarized in Table 1. He was diagnosed to have XLA with possible viral encephalitis. He was empirically treated with intravenous acyclovir (60 mg/kg/day) and one dose of intravenous immunoglobulin (IVIg) (1 g/kg). He showed clinical improvement. Acyclovir was continued for 21 days. Over 77 months of follow-up, he is clinically well without any neurological sequelae and is being continued on IVIg replacement therapy (0.4g/kg/month) and cotrimoxazole prophylaxis (5mg/kg/day of trimethoprim component). Case 2 A 4-year-old boy presented with fever and diarrhea. He had had a history of molluscum contagiosum over his face and legs since the age of 1. On examination, he had hypoplastic tonsils and non-palpable lymph nodes. Laboratory investigations are summarized in Table 1. A clinical possibility of CVID was considered, and he was given cotrimoxazole prophylaxis and IVIg replacement therapy (0.4g/kg/month). A month later, he started developing left focal seizures and weakness of the left lower limb. On examination, he was noted to have Epilepsia partialis continua, hypotonia, and decreased power in the left lower limb. CSF examination is shown in Table 2. Trough IgG at this time was 3.72 g/L. MRI brain was suggestive of altered signal intensities in the right paracentral lobule, right thalamus, and right internal capsule (Figure 1). He was initiated on high dose IVIg (1 g/kg every 3 weeks) and fluoxetine (initially 0.5 mg/kg/day, and gradually hiked to 2.5 mg/kg/day). He showed some clinical improvement, and seizures were controlled. Fluoxetine and antiepileptic drugs were gradually tapered and discontinued over the next 2 years. He continued to receive cotrimoxazole prophylaxis and monthly IVIg replacement therapy. At 6 years, he developed acute onset, painless loss of vision in both eyes (visual acuity restricted to finger counting at 1-meter). Fundus examination showed necrotizing retinitis involving macula in both eyes (figure 2 a and b). Optical coherence tomography showed diffuse hypo-reflectivity of the inner retina, between the overlying inner limiting membrane and underlying retinal pigment epithelium, suggestive of loss of inner retinal layers (Figure 2 c and d). Electroencephalography (EEG) showed quasi-periodic complexes occurring at an interval of 5-10 seconds (more prominent over the left frontal region) with occasional generalization. CSF analysis showed IgG anti-measles antibody titers>1:625 (Table 1). This elevation in antibody titers could be due to gammaglobulin replacement therapy or due to remote measles infection (subacute sclerosing panencephalitis). He was given intravenous pulse methylprednisolone (30mg/kg/day) for three days and later continued on monthly IVIg replacement therapy and cotrimoxazole prophylaxis. No improvement was noted in his vision. He had to be re-hospitalized a few days later for generalized seizures that were refractory to multiple antiepileptic drugs. He succumbed to this illness. Case 3 A 2-year-old boy with suggestive X-linked family history and recurrent infections since infancy was diagnosed to have XLA and initiated on IVIg replacement therapy (0.4 g/kg/month) and cotrimoxazole prophylaxis. Two months later, he developed left focal seizures and left hemiparesis. The trough IgG level was 3.87 g/L. MRI brain was suggestive of hyperintense signal intensities in bilateral occipital, temporal and peri-Rolandic region (Figure 3). EEG showed periodic lateralized epileptiform discharges suggestive of an underlying cortical irritative zone. He was empirically treated with acyclovir (60 mg/kg/day) and high dose IVIg (1 g/kg every 3 weeks). He showed some clinical improvement initially; however, he had to be re-hospitalized one month later for recurrence of seizures and persistent encephalopathy. Repeat CSF examination was normal. MRI brain revealed cystic encephalomalacia and gliosis in the bilateral peri-Rolandic cortex and occipital lobes. He was re-initiated on acyclovir along with a high dose IVIg (1 g/kg). He had progressive neurological deterioration and succumbed to the illness. Autopsy findings in the brain suggested hypoxic damage and perivascular inflammation within the cerebral cortex and brainstem. Immunohistochemical analysis of neuronal tissue for neurotropic viruses (herpes virus, cytomegalovirus (CMV), parvovirus, Epstein-Barr virus, and measles virus) was non-contributory. (This case has previously been reported as clinicopathologic conference) [7]. Case 4 A 2-year-old boy, firstborn to a third-degree consanguineously married couple, was symptomatic since the age of 6 months. A clinical possibility of CVID was considered (Table 1), and he was initiated on IVIg replacement therapy (0.4 g/kg/month). He remained clinically well for the next 2 years. He was hospitalized at the age of 4 in view of regression of milestones, dysarthria, and encephalopathy. Examination showed pallor, diminished consciousness, and signs of cerebellar dysfunction (truncal ataxia and intention tremors). Trough IgG was low (3.94 g/L). MRI brain was suggestive of generalized cerebral atrophy, altered signal intensities in centrum semiovale and periventricular white matter, along with mild hydrocephalus (Figure 4). He was empirically initiated on acyclovir, high dose IVIg (1g/kg/3 weeks), and fluoxetine (initially 0.5mg/kg/day, gradually hiked to 1mg/kg/day). He showed some improvement in sensorium. However, he developed an episode of pneumonia one month later. He was hospitalized at a nearby health care facility, where he succumbed to this illness. Case 5 A 4-year-old boy was symptomatic since the age of 1. A clinical possibility of XLA was considered based on clinical presentation, laboratory investigations (Table 1), and family history (elder brother died at 1.5 years because of a prolonged febrile illness; 2 maternal uncles had had a history of neuro-regression and died in early childhood). However, further genetic studies could not be carried out. He was initiated on cotrimoxazole prophylaxis and IVIg replacement therapy (0.4 g/kg/month). He remained clinically well for the next 1 year and then presented with acute generalized dystonia. Examination revealed hypotonia with dystonia, brisk deep tendon reflexes, and extensor plantar reflexes. MRI brain showed periventricular hyperintense signals in the right parieto-occipital lobe. Trough serum IgG at this time was 3.96 g/L. He was empirically treated with high dose IVIg (1g/kg every 3 weeks), acyclovir (60mg/kg/day), and trihexyphenidyl. He developed progressive neurological deterioration and died. Case 6 A 16-year-old boy was symptomatic since infancy when he developed fever, severe pallor, hepatosplenomegaly, and pancytopenia. Bone marrow examination revealed a marked reduction in erythroid precursors and fibrosis (Figure 5). He was being followed up under pediatric hematology services and was treated with intravenous methylprednisolone pulse (30mg/kg/day for 5 days) followed by tapering doses of oral prednisolone (2mg/kg/day initial dose). He showed some clinical improvement but developed anemia every time an attempt was made to taper prednisolone. On follow-up, he was also noted to have short stature and skeletal abnormalities such as pectus carinatum, small head, hallux valgus, and pes planus. Low-dose prednisolone (0.5mg/kg/day) was continued till 5 years of age and later tapered and stopped. He was re-hospitalized at the age of 17 with complaints of generalized seizures following a short febrile illness. On examination, he was drowsy, had papilledema, signs of meningeal irritation, raised intracranial pressure, and hepatosplenomegaly. Laboratory investigations revealed anemia (hemoglobin: 86g/L) and a positive PCR for HSV in CSF (Table 2). MRI brain revealed non-enhancing mild diffusion restricted T2 hyperintensities involving bilateral frontal and insular cortex. A clinical diagnosis of CVID was made (Table 1), and he was treated with IVIg (1g/kg), acyclovir, and antiepileptic drugs. He remained seizure-free and without any neurological deficits for the next 3 years. He had to be re-hospitalized at the age of 20 when he presented with red eyes and was noted to have hypertonia, brisk deep tendon reflexes, and vascular tortuosity in the peripapillary region of the retina with mild optic atrophy. Laboratory investigations showed hemoglobin: 106 g/L, total leucocyte count 10.3X10 9 /L, and platelet count 356X10 9 /L. The trough IgG level was 2.95g/L. MRI brain revealed areas of encephalomalacia with gliosis in bilateral frontal lobes with a prominence of frontal horns of lateral ventricles that suggested a sequela of old ischemic insult. CSF opening pressure was 60 cm H2O. However, the CSF examination was normal. A clinical possibility of benign intracranial hypertension was considered. He was continued on IVIg replacement therapy, but there was progressive neurological deterioration. One month later, he developed an episode of pneumonia and died at a hospital elsewhere. Case 7 A 5-year-old boy had intermittent fever, recurrent ear discharge, and progressive abdominal distension. He also had a global developmental delay. He was born to a third-degree consanguineously married couple with a history of death of two siblings and two cousins (all because of some infections during the neonatal period). Examination showed generalized lymphadenopathy, splenomegaly, hepatomegaly, frontal bossing, long slender fingers and toes, pectus carinatum, and multiple joint contractures. Laboratory investigations are summarized in Table 1. A radiograph of the arms showed exostosis of the right humerus. Investigations suggested a clinical possibility of CVID. MRI brain was normal. He was initiated on monthly IVIg replacement therapy (0.4g/kg/month), following which his cytopenias started improving, and there was gradual regression in hepatosplenomegaly. There was, however, no improvement in his neurological status. A year later, he developed a short febrile illness requiring hospitalization and succumbed soon thereafter. Case 8 A 4-year-old boy presented with recurrent pneumonia and ear discharge since early infancy. He was born to a second-degree consanguineously married couple. On examination, he had wasting, stunting, absent tonsils, small lymph nodes, tachypnea, diffuse crepitations in bilateral lung fields, and mild hepatomegaly. Investigations are summarized in Table 1. He was initiated on monthly IVIg replacement therapy (0.4g/kg/month) and cotrimoxazole prophylaxis. He was re-hospitalized at the age of 6 with complaints of subacute ascending paralysis of all four limbs that appeared two weeks after an acute upper respiratory tract infection. Examination showed proximal muscle weakness in all limbs, upper motor neuron type left-sided facial nerve palsy, a retinal scar in the left eye, and brisk deep tendon reflexes. CMV PCR in CSF was positive. CMV viral load in blood was 946 copies/ml. MRI brain showed diffuse cerebral atrophy with T2 hyperintense signals in the tegmental tract on both sides. He was treated with high dose IVIg (1g/kg every 2 weeks), ganciclovir (5 mg/kg/day for 3 weeks) followed by oral valganciclovir (5 mg/kg/day for 4 weeks), and intravenous ceftriaxone (0.1g/kg/day) for 2 weeks. He was given IVIg 1g/kg every 2 weeks (6 doses) followed by monthly replacement doses of 0.4 g/kg/month and showed gradual improvement. He is doing well with no breakthrough infections and no evidence of muscle weakness at 11 months of follow-up. Case 9 A 5-year-old boy had had an acute febrile illness with left-sided tonic-clonic convulsions and altered sensorium. Examination showed encephalopathy, nuchal rigidity, left hemiparesis, and brisk deep tendon reflexes. He was also found to have bilateral tympanic perforation and profound hearing loss in both ears. Computed tomography (CT) head showed ill-defined hypodense lesion in the right frontal cortex and bilateral thalami posteriorly and mild hydrocephalus. Details of the CSF examination are given in Table 1. He was treated with intravenous ceftriaxone and amikacin for 14 days and showed gradual improvement in sensorium. However, he continued to have recurrent sinopulmonary and ear infections thereafter and developed bilateral lower motor neuron facial nerve palsy at 12 years that needed middle ear exploration and tympanoplasty. Meanwhile, his nephew had been diagnosed to have XLA and was initiated on IVIg replacement therapy. After the diagnosis of XLA in his nephew, the index patient was brought to our clinic at the age of 18, evaluated (Table 1), and diagnosed with XLA. He showed poor compliance to IVIg replacement therapy, developed an episode of pneumonia at the age of 20, and succumbed to the illness. Case 10 A 13-year-old boy presented with recurrent pneumonia, loose stools, and skin infections since the age of three. He was the second-born child of a non-consanguineously married couple. His elder sibling had expired at 8 months because of pneumonia and diarrhea. He developed progressive regression of his milestones, paucity of movements, ataxia, and lost partial control of his bowel and bladder at 13 years. Examination revealed supranuclear gaze palsy, hypertonia, rigidity, bradykinesia, exaggerated deep tendon reflexes, and clinical signs suggestive of cerebellar dysfunction. MRI brain showed diffuse cerebral and cerebellar atrophy with the widening of sulci and folial spaces (Figure 6). Investigations are summarized in Tables 1 and 2. Whole-exome sequencing showed no pathogenic variants. A clinical possibility of CVID was considered, and he was given one dose of IVIg (1g/kg), cotrimoxazole prophylaxis, fluoxetine (0.5mg/kg/day), and levodopamine. He is being continued on IVIg replacement therapy (0.4g/kg/month). At 4 months of follow-up, there have been no further breakthrough infections. However, he continues to be neurologically impaired. Case 11 A 28-year-old male was diagnosed to have CVID (Table 1). Chest CT showed changes suggestive of bronchiectasis. He was initiated on IVIg replacement therapy and cotrimoxazole prophylaxis. He developed multiple episodes of generalized seizures 2 months after initiation of IVIg. The trough IgG level at this time was 6.81g/L. MRI brain showed T2 weighted hyperintensities in bilateral centrum semiovale, peri-Rolandic white matter in the right cerebral hemisphere, and temporo-occipital lobe in the left cerebral hemisphere, right midbrain, and thalamus. He was continued on replacement IVIg (0.4g/kg every month), antiepileptics, and cotrimoxazole. He remained seizure-free thereafter but had progressive neurological worsening. At the age of 29, he developed acute chest pain, for which he was taken to a nearby health care facility and died within a few hours. The exact cause of death could not be ascertained. Discussion Patients with PADs are predisposed to develop a spectrum of neurological complications[8]. Bacterial meningitis (commonly caused by Streptococcus pneumoniae, N. meningitidis, S. aureus, and Pseudomonas sp.) is the most common CNS infection[9,10]. Meningoencephalitis is usually caused by enteroviruses (e.g., echovirus, coxsackievirus, and poliovirus)(10,11). There is a paucity of published literature on large patient cohorts followed up over extended periods and, there are no studies from developing countries. Under the National Immunization Program in India, oral poliovirus vaccine is still being used routinely, and most patients with PADs in India would have received this vaccine prior to their diagnosis getting confirmed. This further predisposes them to develop neurological complications related to the vaccine strain of poliovirus. Our center was part of a Jeffrey Modell Foundation (JMF) funded study on poliovirus excretion in patients with PADs. However, the vaccine strain of poliovirus in the stool sample was not detected in any of the patients with PAD who were screened for it from India[13]. The incidence of meningoencephalitis in XLA has been reported to be 1.1% in the registry of United States Immunodeficiency Network, 1% in the ESID registry, and 3% in the registry of Latin American Society for Immunodeficiencies[14]. In a recent multicenter experience on patients with XLA from India, 23% were reported to develop pyogenic meningitis, while 4.8% of patients had evidence of encephalitis (likely viral)[15]. In the present study, we report our experience of meningoencephalitis in patients with PAD. We also reviewed all previously published reports on meningoencephalitis in patients with XLA or CVID (Table 2). We observed meningoencephalitis in 11/135 (8.1%) patients- 4 with XLA and 7 with CVID. One patient had low CD40L expression with low IgG, low IgA and high IgM suggesting a possibility of Hyper-IgM syndrome. Whole exome sequencing, however, failed to identify any pathogenic variant in that patient. Low CD40 ligand expression has also been reported in patients with CVID[16]. The mean age of diagnosis of primary illness (hypogammaglobulinemia) in our cohort was 9.36 years (range: 2-28 years), and the mean age of onset of CNS illness was 8.6 years (2-28 years). Children with XLA were diagnosed earlier, except for one patient (case no 9) whose diagnosis was made at the age of 18. These results are similar to what has been reported previously[17]. In five patients (case 1,6,7,9,10) the diagnosis of PAD was made while they were being investigated for the neurological illness. The remaining six patients developed this complication while they were receiving replacement IVIg. It is important to note that all patients who developed meningoencephalitis while on replacement IVIg did so within the first two years of initiation of therapy. As compared to reports from the West (Table 2), the diagnosis of PAD was delayed in this series. Whether this delay has any direct bearing on the occurrence of meningoencephalitis, remains conjectural. Although commonly used immunoglobulin preparations usually have detectable titers of antibodies to many enteroviruses, coverage is not universal. Viral infections have been shown to occur even with adequate IVIg replacement therapy[18]. In the present study, trough IgG levels were found to be low in 9/11 patients at the time of development of neurological symptoms despite replacement immunoglobulin therapy. American Academy of Allergy, Asthma & Immunology recommends maintaining a trough level of at least 5 g/L in patients with agammaglobulinemia[19]. In our published experience on serial serum IgG trough levels in patients with XLA at Chandigarh, the median trough IgG level was 3.97 g/L. This was found to be protective against the development of serious infections in our setup[20]. It has been suggested that higher doses of IVIg and higher trough IgG levels are needed for protection against enteroviral encephalitis due to the presence of low levels of antibodies against prevalent enteroviruses in commercial IVIg preparations[21]. Because of lack of universal insurance coverage in India, access to replacement immunoglobulin therapy is a challenging task. In the past few years, the cost of replacement immunoglobulin therapy for some patients is being supported by a few state governments and philanthropic organizations in our country. However, despite this support, the dose of replacement immunoglobulin remains suboptimal, and therefore, it is difficult to maintain an adequate trough IgG level in most of our patients[22]. Identification of causative organism for meningoencephalitis is challenging, especially in resource-limited settings. Laboratory evaluation is limited due to high costs and low reliability of currently available diagnostic tests. Serological tests are erratic in presence of hypogammaglobulinemia. Viral infections can be identified by isolating the virus in cell lines or in laboratory animals or by detection of viral nucleic acids by PCR in CSF samples (latter has higher sensitivity for virus detection)[23]. No etiological pathogen was identified in 8 (72.7%) patients in our study. Enteroviruses could not be isolated in any patient. This may be due to low sensitivity of enteroviral detection in CSF samples. While the specificity is high (92–100%), sensitivity of PCR based assays for detection of enteroviral RNA in CSF varies from 31–95%[24]. Sensitivity of the test can be increased by performing PCR in stool, throat swabs and urine samples[13,25]. A PCR can also be performed on brain biopsy in settings of high clinical suspicion[13,10]. Metagenomic next-generation sequencing is a novel approach that allows unbiased detection of any microbial nucleic acid present in a biological specimen, including divergent and novel pathogens. This can provide enhanced detection of etiological agents, when used in conjunction with conventional microbiological testing[26,27]. Neuroimaging may be normal in up to 25% of patients with viral encephalitis within the first few days[28]. In the present series, MRI brain was performed in 10 and CT head in 1. Nine patients had altered signal hyperintensities in gray and deep white matter, while 3 showed global cerebral atrophy. Neuroimaging in patients with enteroviral encephalitis often shows symmetric bilateral T2 weighted hyperintense lesion in the dorsal brainstem, cerebellum and spinal cord while it may show cerebral atrophy in later stages[28]. Neuroimaging findings in the present series, however, did not show the characteristic findings of enteroviral encephalitis. Management is guided by the identification of causative organism. Most patients are initially managed empirically using broad-spectrum antimicrobials. High-dose IVIg therapy has been found to be useful. Ten patients needed high-dose IVIg therapy (1 g/kg every 2 weeks). Intrathecal immunoglobulin has also been reported to be beneficial in treating enteroviral encephalitis [30-33]. However, this therapy was not administered to any of our patients. Selective serotonin reuptake inhibitor, fluoxetine, has been shown to have antiviral effects and may be useful in enterovirus encephalitis[36]. Two of our patients also received fluoxetine. However, the use of fluoxetine did not result in significant clinical improvement. Several antiviral drugs (e.g., pleconaril, vapendavir, enviroxime, ViroD7000 and pocapavir) are undergoing clinical trials for their therapeutic use in these cases. However, none of these drugs could be used in the present series because of lack of availability. Eight (72.7%) patients in the present series have died. Three patients are on replacement IVIg, and the mean follow-up duration is 29.6 months (Table 2). Two amongst these (case 1 and 8) have shown complete neurological recovery, while one patient has shown some clinical improvement at follow-up of 3 months (case 10). Viral encephalitis in patients with PAD has been reported to have a poor prognosis. Rudge et al reported 13 patients with encephalomyelitis, and all patients succumbed to neurological illnesses[8]. McKinney et al. reported 23 deaths in their series of 41 patients with chronic enteroviral meningoencephalitis, while 6 patients improved with a combination of IVIg and intraventricular IgG therapy[41]. Halliday et al. reviewed 90 patients with primary immunodeficiencies and enteroviral infections. Of these, only 5 patients were reported to be well on follow-up[42]. Of the 117 cases reported so far with hypogammaglobulinemia and meningoencephalitis, only 52 (44.4%) patients survived (Table 2), and a large majority of these patients continued to have neurological deficits. The strengths of this study are that diagnosis and treatment of all patients were done at a single center, thereby bringing uniformity to patient management. This is the largest single-center cohort of patients with meningoencephalitis in patients with PADs from India. Limitations include a limited diagnostic armamentarium for identification of pathogenic organisms, especially enteroviruses. To conclude, patients with PADs may present with a spectrum of neurological manifestations. identification of a causative organism is extremely difficult in resource-limited settings such as ours. Treatment is largely limited to high doses of IVIg, and prognosis remains guarded in most patients. Early diagnosis and initiation of replacement immunoglobulin therapy (maintaining a trough IgG >5 g/L) may prevent the occurrence of neurological complications. Declarations Funding: None Conflicts of interest/Competing interests: All authors declare no conflicts of interests Availability of data and material: Not applicable Code availability: Not applicable Author’s contribution: AKJ: Writing of initial draft, patient management, editing of manuscript at all stages of its production, review of literature HC: Writing of initial draft, patient management, editing of manuscript at all stages of its production, review of literature RT/AR/KA/MUSS/MS/RSM: Editing of manuscript, laboratory investigations, review of literature DS/PKP/SV/RB/AG/VP/NS/RenuS/RajniS/RuchiS: Editing of manuscript, patient management, review of literature KI/OO/SN/LM/KWC/YLL: Editing of manuscript, laboratory investigations, review of literature SS: Patient management, critical revision of manuscript, review of literature, final approval Ethics approval: The manuscript was approved by Department Review Board (DRB-85-21). As it pertains only to retrospective collation of data of patients from clinic records, approval of the extant Institute Ethics Committee was not considered necessary. This is as per existing practice in the institute. Consent to participate: Not applicable, as per existing practice in the institute. Consent for publication: Not applicable, as per existing practice in the institute. Acknowledgement: None References McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2018;14:61. Suri D, Rawat A, Singh S. X-linked Agammaglobulinemia. Indian J Pediatr. 2016;83:331–7. Bogaert DJA, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53:575–90. Ameratunga R, Ahn Y, Steele R, Woon S-T. 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Common variable immunodeficiency presenting as herpes simplex virus encephalitis. J Allergy Clin Immunol. 2011;127:541–3. Sempere AP, Tahoces M, Palao-Duarte S, Garcia-Perez A. Bilateral optic neuritis in a 26-year-old man with common variable immunodeficiency: a case report. J Med Case Reports. 2011;5:319. Bakri FG, Bahou YG, Al-Sammarrai FA, Hadidy A, Gharaibeh A, Zaid GK, et al. Fatal encephalitis due to BK virus in a patient with common variable immunodeficiency: a case report. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2013;57:363–9. M Khair A. Autoimmune Encephalitis as the Sole Presentation of Common Variable Immunodeficiency: First Report in a Child. J Clin Case Rep [Internet]. 2015 [cited 2019 Jul 5];05. Available from: http://www.omicsgroup.org/journals/autoimmune-encephalitis-as-the-sole-presentation-of-common-varaibleimmunodeficiency-first-report-in-a-child-2165-7920-1000665.php?aid=66975 Najem CE, Springer J, Prayson R, Culver DA, Fernandez J, Tavee J, et al. Intracranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature. Semin Arthritis Rheum. 2018;47:890–6. Shribman SE, Katanga J, Ali N, Hayman GR, Bridges LR, Habibi MS, et al. Encephalomyelitis with Retinopathy in Common Variable Immunodeficiency (CVID). Neuro-Ophthalmol. 2020;44:38–40. Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults. Front Immunol. 2018;9:694. Tables Table 1: Clinical details and immunological workup in the present cohort of patients with primary antibody deficiency and meningoencephalitis Case no. Type of disease Age at diagnosis(years) Clinical features at diagnosis Immunoglobulin profile at diagnosis Lymphocyte subsets at diagnosis Other immunological tests Genetic abnormality 1 XLA 7 Recurrent diarrhea, ear discharge, headache, seizures, transient ischemic attacks IgG: 3.1 g/L (normal range: 5.4-16.1 g/L) CD19+B lymphocytes: 0.1% (normal: 10-31%), Btk protein expression on patient’s monocytes (20.5%, MFI: 1.28) when compared to control (90.5%, MFI: 1.6) Missense pathogenic variant detected in exon 17 of BTK (c.1732T>C, p. Ser578Pro) IgM: <0.12 g/L (normal: 0.5-1.8 g/L) CD3+T lymphocytes: 87.5% (normal: 55-78%), IgA:<0.17 g/L (normal: 0.7-2.5 g/L) CD56+NK lymphocytes 13.9% (normal: 4-26%) 2 CVID 4 Fever, diarrhea, molluscum contagiosum IgG: 0.39 g/L (normal range: 5.4-16.1 g/L)] CD19+B lymphocytes: 9.56% (normal: 14-44%) Antibody response to vaccinations against diphtheria: 0.03 IU/ml(protective: ≥0.1 IU/mL) Not done CD3+T lymphocytes: 82.6% (normal:43-76%) Switched memory B lymphocytes 0.73% (normal: 6.5-29.1%] CD56+NK lymphocytes: 12.39% (normal: 4-23%) Unswitched memory B lymphocytes: 3.18% (normal: 7.4-32.5%) IgM: <0.23 g/L (normal: 0.5-1.8 g/L)] CD4+T lymphocytes: 73.54% (normal: 43-76%) IgA: <0.17 g/L (normal: 0.7-2.5 g/L)] CD8+T lymphocytes: 23.03% (normal: 14-33%) 3 XLA 2 Recurrent infections IgG: 0.92 g/L (normal: 3.7-15.8 g/L) CD19+B lymphocytes: 0.07% (normal:14-33%) Btk protein expression on CD14+ monocytes in patient: 11.5%; MFI: 1.89; Btk protein expression on CD14+ monocytes in control :87.4%; MFI: 5.84 BTK (c.310-8C>A [Splice-site acceptor variant]) IgM: <0.25 g/L (normal: 0.5-2.2 g/L) CD3+T lymphocytes: 83.93% (normal: 56-75%) IgA:<0.17 g/L (normal: 0.3-1.3 g/L) CD56+NK cells: 9.74% (normal:4-17%) 4 CVID 2 Recurrent episodes of fever, oral ulcers and sinopulmonary infections IgG: 0.39 g/L (normal: 4.9-16.1 g/L), CD19+B lymphocytes: 16% (normal range: 14-44 %) Naïve B lymphocytes: 66.3% (normal: 43-83%), and Not done CD3+T lymphocytes: 58.6% (normal: 43-76%) Unswitched memory B lymphocytes: 19.9% (normal:7.4-32.5%) CD56+NK lymphocytes: 20.9% (normal: 4-23%) Switched memory B lymphocytes: 0.21% of CD19+ lymphocytes (normal range: 6.5-29.1%) IgM: <0.25 g/L (normal: 0.5-2.0 g/L), CD4+T lymphocytes: 50.2% (normal: 23-48%) IgA:<0.17 g/L (normal: 0.4-2 g/L) CD8+T lymphocytes: 42.3% (normal: 14-33%) 5 XLA 4 Recurrent sino-pulmonary infections, 1 episode of pyogenic meningitis and global development delay IgG: 0.39 g/L (normal range: 4.9-16.1 g/L) CD19+B lymphocytes: 0.21% (normal: 14-44%) Not done IgM: <0.25 g/L (normal: 0.5-2.0 g/L) CD3+T lymphocytes: 76.3% (normal: 43-76%) IgA:<0.17 g/L (normal: 0.4-2 g/L)] 6 CVID 16 Fever, severe pallor, hepatosplenomegaly, pancytopenia IgG <0.95 g/L (normal: 5.4-16.1g/L) CD19+: B lymphocytes 1.3% (normal: 8-10%), Btk protein expression on monocytes normal Not done CD3+T lymphocytes: 90.19% (normal: 52-76%) CD56+NK lymphocytes: 2.3% (normal: 2-26%) IgM <0.25 g/L (normal: 0.5-1.9) CD4+T lymphocytes: 17.6% (normal: 28-50%) IgA <0.17 g/L(normal: 0.8-2.8g/L) CD8+T lymphocytes: 68.9% (normal: 15-35%) 7 CVID 5 Intermittent fever, ear discharge since infancy and progressive abdominal distension IgG: 0.49 g/L (0.49-1.6 g/L) CD20+ B lymphocytes: 24.13% (normal: 14-33%) Hb: 80 g/L, TLC: 3.2x10 9 /L, platelet counts: 118x10 9 /L. and Not done CD3+ T lymphocytes: 74.14% (normal: 56-75%) Naïve B lymphocytes: 22.4% (normal: 42-82%), CD 56+ NK lymphocytes: 1.32% (normal:4-17%) Unswitched memory B lymphocytes: 1.4% (normal:7.4-32.5%) IgM <0.25 g/L (normal: 0.5-2.0 g/L) CD4+T lymphocytes: 42.6% (normal 28-50%) and Class switched memory B lymphocytes: 2.41% (normal 8-31%) IgA:0.1IU/ml) Transferrin isoelectric focusing for congenital disorder of glycosylation: normal 8 CVID 4 Recurrent pneumonia and ear discharge since early infancy IgG: 3.89 g/L (normal: 4.9-16.1g/L) CD19+B lymphocytes: 13.5% (normal:14-44%) Naïve B lymphocytes: 83.8% (normal: 43-82%) No pathogenic variants IgM: 1.13 g/L (normal: 0.5-2.0g/L) CD3+ T lymphocytes: 81% (normal: 43-76%) unswitched memory B lymphocytes: 7.04% (normal:7.4-32.5%) IgA: <0.17 g/L (normal: 0.4-2.0g/L) NK lymphocytes 0.08% (normal:4-23%) switched memory B lymphocytes: 0.82% (normal: 6.5-29.1%) CD40 ligand expression on CD4+T lymphocytes 82.34% as compared to 96.25% in control 9 XLA 18 Recurrent pneumonia and bilateral ear discharge IgG <0.93 g/L(normal: 5.4-16.1g/L) CD19+B lymphocytes: 0.1% (normal: 6-23%) BTK gene (intron 8~intron 9 deletion IgM <0.11 g/L (normal: 0.5-1.9g/L) IgA: 0.18 g/L (normal: 0.8-2.8g/L) 10 HIGM 13 Recurrent pneumonia, loose stools and skin infections IgG: 0.12 g/L (normal: 5.4-16.1g/L) CD19+ B lymphocytes: 7.71% (normal: 6-23%) Naïve B lymphocyte: 63.3% (normal: 43-82%), No pathogenic variants CD3+T lymphocytes: 74.05% (56-84%) Unswitched memory B lymphocytes: 35.9% (normal: 7.4-32.5%) CD56+ lymphocytes: 2.57% (normal: 3-22%) Switched memory B lymphocytes: 0.57% (normal: 6.5-29.1%) IgM: 2.17 g/L (normal: 0.5-1.9g/L) CD40L expression on activated helper T lymphocytes: 8.3% (control: 47.1%) IgA: <0.26 g/L (normal: 0.8-2.8g/L) Regulatory T lymphocytes 2.17% (control: 4.14%) 11 CVID 28 Recurrent pneumonia, diarrhea, ear discharge and sinusitis since early childhood IgG: 5.0 g/L (normal: 9.77-15.19), CD19+ B lymphocytes: 0.1% (normal: 6-19%) Btk protein expression on monocytes normal Not done IgM: 0.81 g/L (normal: 0.85-1.13g/L) CD3+ T lymphocytes: 45.4% (normal: 55-83%), IgA: 1.15 g/L (normal: 1.4-2.5g/L), CD56+ NK lymphocytes: 56.5% (normal: 7-31%) Abbreviations used: XLA:X linked agammaglobulinemia, CVID: common variable immunodeficiency, HIGM: Hyper IgM syndrome, Btk protein: Bruton tyrosine kinase protein, MFI: Mean florescent intensity, Hb: hemoglobin, TLC: total leucocyte count, CD40L: CD40 ligand Due to technical limitations, table 2 is only available as a download in the Supplemental Files section. Table 3: Review of previously reported cases with primary antibody deficiency and meningoencephalitis Study, country, year [reference] No of patients Type of disease Neurological manifestations Age at diagnosis(in years) Age at time of illness(in years) Organism isolated Treatment Outcome Linnemann et al, USA, 1973[43] 2 XLA Encephalitis 1 1.5 9 1.5 Herpes simplex virus, Echovirus 2 None Died Ziegler, USA, 1975[44] 1 XLA Viral meningoencephalitis 14 14 Echovirus 30 Intramuscular gamma globulin Died Wilfert et al, USA, 1977[45] 5 3 XLA, 2 hypogammaglobulinemia Chronic meningoencephalitis: 4; dermatomyositis: 3 Mean age: 2.4(1.5-3.5) Mean: 10.8(3.5-24) Echovirus 9, 19, 30, 33 Steroids; immune serum globulin 3 died, 2 recovered Bardelas et al, USA, 1977[46] 1 Hypogammaglobulinemia Meningoencephalitis, polymyositis, edema Echovirus 24 Specific serum anti- Echovirus 24 plasma Died Webster et al, England, 1978[23] 2 XLA, Hypogammaglobulinemia Encephalitis: 2 dermatomyositis:1 1.5, 2 11, 2 Echovirus 11, Echovirus 25 Hyper- immune plasma, steroids Died Weiner et al, USA, 1979[47] 1 XLA Chronic myositis, encephalitis 3 5 Echovirus 5 Hyperimmune plasma Died Bodensteiner et al, USA, 1979[48] 1 X linked Hypogammaglobulinemia Chronic meningoencephalitis 17 Echovirus 5 High-titer, specific plasma Died Mease et al,USA, 1981[33] 1 XLA Meningoencephalitis, myositis 22 32 Echovirus 11 IVIg Recovered Erlendsson et al, USA, 1985[34] 1 XLA Chronic meningoencephalitis 6 6 Enterovirus IVIg, intraventricular Ig Recovered Johnson et al, USA, 1985[49] 1 XLA Chronic meningoencephalitis 11 Echovirus 11 IVIg, intraventricular Ig Died Crennan et al, USA, 1986[32] 1 XLA Meningoencephalitis, dermatomyositis 4 28 Coxsackievirus B3 Cyclophosphamide, Steroids Died McKinney et al, USA, 1987[41] 42 18 XLA, 20 CVID, 4 acquired hypogammaglobulinemia Chronic enteroviral meningoencephalitis Mean age: 14.2(3 mo-35 years) Mean age: 20.1(2-42 years) Enterovirus Echovirus 11(11 cases) IVIg, intraventricular Ig 19 recovered 23 died Kondoh et al, Japan, 1987[21] 1 XLA Meningoeneephalitis 7 12 Echovirus type 11 IVIg, intraventricular Ig Recovered Dwyer et al, Australia, 1988[35] 3 XLA Chronic enteroviral meningoencephalitis 7 3 months 5 7 4 9 Enterovirus IVIg, intraventricular Ig Recovered Roberton et al, Australia, 1989[50] 1 XLA Chronic enteroviral meningoencephalitis 3 9 Picornavirus IVIg, intraventricular Ig Died Maldergem et al, Belgium, 1989[51] 1 XLA Chronic enteroviral meningoencephalitis 6 months 8.5 Echovirus type 13. High dose IVIg Died Misbah et al, UK, 1992`[30] 1 XLA Chronic enteroviral meningoencephalitis 4 8 Echovirus High-dose IVIg (2.5 to 7.5 g) Rudge et al, USA, 1996[8] 13 7 XLA 6 CVID Myelopathy: 5/13 Encephalopathy: 12/13 Myositis: 3/13 Hearing loss: 2/13 Retinopathy: 3/13 Seizures: 6/13 13.4(0.5-56) 31.4(6-62) Echovirus 3: 1 Echovirus 11: 1 JC virus: 2 Immunoglobulin: 12 Plasma: 2 IFN-µ: 1 13 died Wense et al, Germany, 1998[52] 1 XLA Chronic enteroviral meningoencephalitis 9 Echovirus type 6 Intraventricular and intravenous immunoglobulin Recovery Bezrodnik et al, Argentina, 1998[53] 1 XLA Progressive Multifocal Leukoencephalopathy 1.5 5 JC virus Cytosine arabinoside subcutaneous IFN-a Partial recovery Cunningham et al , USA, 1999[54] 3 XHIGM Enteroviral meningoencephalitis 8months, 11 months, 7 months 30 months 21 months 30 months Echovirus 14 Echovirus 14 Enterovirus IVIG, 1 g/kg/week IVIG, 1.5 g/kg per week IVIG, 1 g/kg/week 1 died 1 Survived with severe neurological impairment, 1 recovered Plebani et al, Italy, 2002[55] 3 XLA Meningitis, meningoencephalitis Neisseria meningitidis in 1 High dose IVIg, antimicrobials Cucchiara et al, USA, 2003[56] 1 Good syndrome Encephalitis 58 62 Cytomegalovirus Foscarnet Died Halliday et al, USA, 2003[42] 40 XLA, CVID,HIGM Chronic encephalitis and meningitis Enterovirus High dose IVIg, intrathecal immunoglobulin Shiroma et al, Japan,2004[31] 1 XLA Progressive Encephalitis 6 0.5 IVIg, IFN-µ Partial recovery Ansari et al, India, 2010[57] 1 CVID Herpes simplex encephalitis 18 18 HSV-1 Acyclovir, IVIg Recovery Borish et al, USA, 2011[58] 3 CVID Herpes simplex encephalitis 40 40 HSV-1 Acyclovir, IVIg Recovery Sempere et al, Spain, 2011[59] 1 CVID Bilateral optic neuritis 14 26 Steroids, IVIg Recovered Bakri et al, Jordan, 2013[60] 1 CVID Encephalitis 16 23 BK virus IVIg, ganciclovir Death Khair et al, Qatar, 2015[61] 1 CVID Autoimmune encephalitis 3 3 IVIG Recovery Nguyen Et al, USA, 2016[9] 1 CVID Left monoparesis, enhancing lesions of the left cerebellar hemisphere with mass effect, optic neuritis 33 42 Steroids, rituximab and azathioprine Recovered Najem et a, USA, l 2017[62] 19 CVID Intracranial granulomatous disease 24 21.5 Steroids 4/19 Steroids + IVIg: 5/19 IVIG: 3/19 Infliximab: 3/19 Others: 3/19 Remission: 11 Recurrence: 6 Died: 2 Gofshteyn et al, USA, 2018[36] 1 XLA Chronic Enterovirus Encephalitis 1 5 Enterovirus High dose IVIg, fluoxetine Recovered Shribman et al, England, 2018[63] 1 CVID Encephalomyelitis with retinopathy Teenage 31 IVIg Slade et al, Australia, 2019[64] 1 CVID Chronic lymphocytic meningoencephalitis 9 27 Enterovirus High-dose IVIG (2 g/kg) and methylprednisolone 2 mg/kg, cyclophosphamide Died Abbreviations used: XLA:X linked agammaglobulinemia, CVID: common variable immunodeficiency, Ig: Immunoglobulin, IVIg: intravenous immunoglobulin, HIGM: Hyper-IgM syndrome, CMV: cytomegalovirus, HSV-1: Herpes simplex virus-1, JC virus: human polyomavirus 2, IFN-µ: Interferon-µ, USA: United States of America Supplementary Files Table2.docx Table 2: Details of neurological illness, investigations, treatment, and outcome in our cohort of patients with primary antibody deficiency and meningoencephalitis Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-723651","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":44589019,"identity":"2b57b0db-753a-4722-abd3-59d8b7d12533","order_by":0,"name":"Ankur Kumar Jindal","email":"","orcid":"https://orcid.org/0000-0002-7954-0661","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ankur","middleName":"Kumar","lastName":"Jindal","suffix":""},{"id":44589020,"identity":"9299f670-82aa-4c64-ac99-656e2c4dafa0","order_by":1,"name":"Himanshi Chaudhary","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Himanshi","middleName":"","lastName":"Chaudhary","suffix":""},{"id":44589021,"identity":"59a5acf0-092a-439c-ba2d-e33491331eb8","order_by":2,"name":"Rahul Tyagi","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rahul","middleName":"","lastName":"Tyagi","suffix":""},{"id":44589022,"identity":"c1150e09-a30a-4fa4-8208-df208655d488","order_by":3,"name":"Amit Rawat","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amit","middleName":"","lastName":"Rawat","suffix":""},{"id":44589023,"identity":"83196b4d-4c11-4496-9f50-6495e92edc0c","order_by":4,"name":"Deepti Suri","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Deepti","middleName":"","lastName":"Suri","suffix":""},{"id":44589024,"identity":"ae933c21-0ca0-4748-9f83-5666d0c41758","order_by":5,"name":"Pratap Kumar Patra","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pratap","middleName":"Kumar","lastName":"Patra","suffix":""},{"id":44589025,"identity":"efd0caf5-d683-4603-9866-0e9bf8bead2d","order_by":6,"name":"Kanika Arora","email":"","orcid":"","institution":"PGIMER","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kanika","middleName":"","lastName":"Arora","suffix":""},{"id":44589026,"identity":"ca8d923c-008a-4c54-977a-607fbdfdd944","order_by":7,"name":"Sameer Vyas","email":"","orcid":"","institution":"Post Graduate Institute of Medical Education and 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Kong","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koon","middleName":"Wing","lastName":"Chan","suffix":""},{"id":44589042,"identity":"d1f2f05b-99a0-4265-b7a3-ba779fdf23a2","order_by":23,"name":"Yu Lung Lau","email":"","orcid":"","institution":"Queen Mary Hospital, University of Hong Kong","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"Lung","lastName":"Lau","suffix":""},{"id":44589043,"identity":"19806bf6-de1e-4d09-bf06-081ee700f895","order_by":24,"name":"Surjit Singh","email":"data:image/png;base64,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","orcid":"","institution":"PGIMER","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Surjit","middleName":"","lastName":"Singh","suffix":""}],"badges":[],"createdAt":"2021-07-16 04:54:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-723651/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-723651/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":12341515,"identity":"73e642d2-09d2-4a54-aa8c-0ccd053968b2","added_by":"auto","created_at":"2021-08-11 19:14:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":871984,"visible":true,"origin":"","legend":"Axial T2-weighted (A and C) and FLAIR (B and D) MRI images at 4-years of age showing hyperintense lesion in the right thalamus and internal capsule (arrow). No diffusion restriction or susceptibility changes seen. Similar lesion is also seen in the right paracentral lobule involving cortex and white matter. At 6-years of age, axial T2-weighted (E and G) and FLAIR (F and H) MRI images showing hyperintense lesion in the central part of pons (arrow) and left lateral thalamus. The right thalamic lesion seen in the previous MRI is no longer visible.","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/c04dc23ecd12d3fe9bb93e7b.png"},{"id":12341620,"identity":"eb600675-3857-4f13-b1d6-c677b1914d96","added_by":"auto","created_at":"2021-08-11 19:17:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1248286,"visible":true,"origin":"","legend":"Fundus examination of case 2 showed necrotizing retinitis involving posterior pole in both eyes (a and b). Optical coherence tomography (OCT) showed hypo-reflective spaces in retinal layers, suggestive of tissue loss, with sparing of the internal limiting membrane (c and d).","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/4af8b27079c85a590484c1c8.png"},{"id":12341519,"identity":"70f13a0f-cb3c-489e-9eb6-21c5c5a249fa","added_by":"auto","created_at":"2021-08-11 19:14:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":458136,"visible":true,"origin":"","legend":"Axial T2 (A, D, and G), FLAIR (B, E, H and J to L), and T1-weighted (C, F and I) MR images of a child with chronic progressive meningoencephalitis. The first MRI shows a right frontal cortical-subcortical lesion (A-C, arrows). MRI after 2 months (D-I) shows progression with mild gliosis in the frontal lesion, and there is the involvement of bilateral occipital lobes as well (arrows in G). Subsequent MRI (J-L) demonstrated multiple new lesions involving the cortex of bilateral cerebral hemispheres and deep grey matter involving thalami and basal ganglia. ","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/876dded6ea50da9a9a5b3f78.png"},{"id":12341621,"identity":"a816e25a-16e6-48b3-a288-1174c2a0e08f","added_by":"auto","created_at":"2021-08-11 19:17:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":669977,"visible":true,"origin":"","legend":"MR Axial T2 (A and D), FLAIR (B and E), and T1-weighted (C and F) images showing mild diffuse cerebral atrophy. There is ventriculomegaly with periventricular white matter changes. Multiple small white matter lesions are seen in bilateral cerebral hemispheres (arrows). ","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/e526850a9928a0e1f62b6987.png"},{"id":12341518,"identity":"9a9b30b5-1ab9-46bf-8323-1bbb3047b46d","added_by":"auto","created_at":"2021-08-11 19:14:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2106287,"visible":true,"origin":"","legend":"A) Peripheral blood smear showing decreased red blood cell density with an admixture of normocytic and few microcytic red cells (May Grunwald-Giemsa stain, original magnification 1000x); B) bone marrow aspirate smear showing myeloid series of cells in varying stages of maturation with a marked reduction in erythroid precursors (May Grunwald-Giemsa stain, original magnification 1000x); C) bone marrow trephine biopsy section at low magnification showing cellular marrow spaces (Hematoxylin \u0026 Eosin stain, original magnification 100x); D) bone marrow trephine section at high magnification showing predominance of myeloid series of cells along with few lymphocytes (arrows) and scattered megakaryocytes (arrowheads) and near absence of erythroid precursors (Hematoxylin \u0026 Eosin stain, original magnification 400x); the inset shows increased reticulin fibrosis of bone marrow (reticulin stain, original magnification 200x)","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/5ef833ccfe938cbeab106f1d.png"},{"id":12341516,"identity":"1cfd88d2-b309-4834-b028-1290c7e5ceb3","added_by":"auto","created_at":"2021-08-11 19:14:37","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":731809,"visible":true,"origin":"","legend":"Axial T2 (A and D), FLAIR (B and E), and T1-weighted (C and F) MR images showing diffuse cerebral atrophy with prominent ventricles and extra-axial spaces. Multifocal small white matter lesions are seen in bilateral cerebral hemispheres (arrows).","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/92c4e7f561a53b838b13e25e.png"},{"id":13708809,"identity":"f5323a59-f02e-471e-860c-90d3040dd0fa","added_by":"auto","created_at":"2021-09-17 14:09:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6892097,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/2be4e48f-1164-4017-aa01-eaa5a329ab4a.pdf"},{"id":12341514,"identity":"0fb42e82-0742-4c18-9ddb-373a2e34e53f","added_by":"auto","created_at":"2021-08-11 19:14:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20683,"visible":true,"origin":"","legend":"Table 2: Details of neurological illness, investigations, treatment, and outcome in our cohort of patients with primary antibody deficiency and meningoencephalitis","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-723651/v1/48bb15a6e7e8d16255cf7ff6.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eMeningoencephalitis in Children with Primary Antibody Deficiency: A Single-Center Experience From Northwest India and Review of Literature\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary antibody deficiencies (PADs) (such as X-linked agammaglobulinemia [XLA] and common variable immunodeficiency [CVID]) are inborn errors of immunity (IEI) caused by a predominant defect in the humoral arm of the adaptive immune system[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The most common clinical presentation of PADs is recurrent sinopulmonary infection. Pyogenic meningitis is also a common infection in patients with PAD[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In addition, these patients are predisposed to develop viral infections and non-infectious autoimmune complications[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although meningoencephalitis (often caused by enteroviruses) has been reported in patients with PADs, most published literature pertains to anecdotal clinical reports. There is a paucity of data from large patient cohorts studied over extended periods of time, and no information is available on this subject from developing countries. We report herein our experience on meningoencephalitis in patients with PADs.\u003c/p\u003e"},{"header":"Patient And Methods","content":"\u003cp\u003eWe carried out a review of records of all patients who were diagnosed to have XLA or CVID and were registered at the Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Our center is a not-for-profit tertiary care referral teaching institute in northwest India. Patients with XLA or CVID who were also diagnosed to have meningoencephalitis were analyzed in detail. For the purpose of this study, the terms' XLA' and 'CVID' were defined as per criteria given by the European Society of Immunodeficiencies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Patients who had pyogenic meningitis without any evidence of encephalitis (clinical or radiological) were excluded from this analysis. Clinical details, laboratory and imaging findings, treatment, and outcome of these patients were recorded. A pan-enterovirus reverse transcriptase-polymerase chain reaction (RT-PCR) targeting the highly conserved 5' untranslated region of enterovirus genome was performed at the Department of Neurovirology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, for identification of enteroviruses from the cerebrospinal fluid (CSF).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, we retrieved clinical details of 70 patients with XLA and 65 patients with CVID. Of these, 11 were diagnosed to have meningoencephalitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 7-year-old boy presented with complaints of headache, 1 episode of generalized tonic-clonic seizure, and two episodes of transient loss of consciousness for 1 week. He had had a history of recurrent ear discharge and chronic diarrhea since the age of 1 and one episode of pyogenic meningitis at 6 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn examination, he had absent tonsils, and lymph nodes were not palpable. CSF examination was normal. Magnetic resonance imaging (MRI) of the brain revealed altered signal intensities in parieto-occipital regions. Investigations are summarized in Table 1. He was diagnosed to have XLA with possible viral encephalitis. He was empirically treated with intravenous acyclovir (60 mg/kg/day) and one dose of intravenous immunoglobulin (IVIg) (1 g/kg). He showed clinical improvement. Acyclovir was continued for 21 days. Over 77 months of follow-up, he is clinically well without any neurological sequelae and is being continued on IVIg replacement therapy (0.4g/kg/month) and cotrimoxazole prophylaxis (5mg/kg/day of trimethoprim component).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 4-year-old boy presented with fever and diarrhea. He had had a history of molluscum contagiosum over his face and legs since the age of 1. On examination, he had hypoplastic tonsils and non-palpable lymph nodes. Laboratory investigations are summarized in Table 1. A clinical possibility of CVID was considered, and he was given cotrimoxazole prophylaxis and IVIg replacement therapy (0.4g/kg/month).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA month later, he started developing left focal seizures and weakness of the left lower limb. On examination, he was noted to have Epilepsia partialis continua, hypotonia, and decreased power in the left lower limb. CSF examination is shown in Table 2. Trough IgG at this time was 3.72 g/L. MRI brain was suggestive of altered signal intensities in the right paracentral lobule, right thalamus, and right internal capsule (Figure 1). He was initiated on high dose IVIg (1 g/kg every 3 weeks) and fluoxetine (initially 0.5 mg/kg/day, and gradually hiked to 2.5 mg/kg/day). He showed some clinical improvement, and seizures were controlled. Fluoxetine and antiepileptic drugs were gradually tapered and discontinued over the next 2 years. He continued to receive cotrimoxazole prophylaxis and monthly IVIg replacement therapy. At 6 years, he developed acute onset, painless loss of vision in both eyes (visual acuity restricted to finger counting at 1-meter). Fundus examination showed necrotizing retinitis involving macula in both eyes (figure 2 a and b). Optical coherence tomography showed diffuse hypo-reflectivity of the inner retina, between the overlying inner limiting membrane and underlying retinal pigment epithelium, suggestive of loss of inner retinal layers (Figure 2 c and d). \u0026nbsp; Electroencephalography (EEG) showed quasi-periodic complexes occurring at an interval of 5-10 seconds (more prominent over the left frontal region) with occasional generalization. CSF analysis showed IgG anti-measles antibody titers\u0026gt;1:625 (Table 1). This elevation in antibody titers could be due to gammaglobulin replacement therapy or due to remote measles infection (subacute sclerosing panencephalitis). He was given intravenous pulse methylprednisolone (30mg/kg/day) for three days and later continued on monthly IVIg replacement therapy and cotrimoxazole prophylaxis. No improvement was noted in his vision. He had to be re-hospitalized a few days later for generalized seizures that were refractory to multiple antiepileptic drugs. He succumbed to this illness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 2-year-old boy with suggestive X-linked family history and recurrent infections since infancy was diagnosed to have XLA and initiated on IVIg replacement therapy (0.4 g/kg/month) and cotrimoxazole prophylaxis. Two months later, he developed left focal seizures and left hemiparesis. The trough IgG level was 3.87 g/L. MRI brain was suggestive of hyperintense signal intensities in bilateral occipital, temporal and peri-Rolandic region (Figure 3). EEG showed periodic lateralized epileptiform discharges suggestive of an underlying cortical irritative zone. He was empirically treated with acyclovir (60 mg/kg/day) and high dose IVIg (1 g/kg every 3 weeks). He showed some clinical improvement initially; however, he had to be re-hospitalized one month later for recurrence of seizures and persistent encephalopathy. Repeat CSF examination was normal. MRI brain revealed cystic encephalomalacia and gliosis in the bilateral peri-Rolandic cortex and occipital lobes. He was re-initiated on acyclovir along with a high dose IVIg (1 g/kg). He had progressive neurological deterioration and succumbed to the illness. Autopsy findings in the brain suggested hypoxic damage and perivascular inflammation within the cerebral cortex and brainstem. Immunohistochemical analysis of neuronal tissue for neurotropic viruses (herpes virus, cytomegalovirus (CMV), parvovirus, Epstein-Barr virus, and measles virus) was non-contributory. (This case has previously been reported as clinicopathologic conference) [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 4\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 2-year-old boy, firstborn to a third-degree consanguineously married couple, was symptomatic since the age of 6 months. A clinical possibility of CVID was considered (Table 1), and he was initiated on IVIg replacement therapy (0.4 g/kg/month). He remained clinically well for the next 2 years. He was hospitalized at the age of 4 in view of regression of milestones, dysarthria, and encephalopathy. Examination showed pallor, diminished consciousness, and signs of cerebellar dysfunction (truncal ataxia and intention tremors). Trough IgG was low (3.94 g/L). \u0026nbsp;MRI brain was suggestive of generalized cerebral atrophy, altered signal intensities in centrum semiovale and periventricular white matter, along with mild hydrocephalus (Figure 4). He was empirically initiated on acyclovir, high dose IVIg (1g/kg/3 weeks), and fluoxetine (initially 0.5mg/kg/day, gradually hiked to 1mg/kg/day). He showed some improvement in sensorium. However, he developed an episode of pneumonia one month later. He was hospitalized at a nearby health care facility, where he succumbed to this illness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 5\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 4-year-old boy was symptomatic since the age of 1. A clinical possibility of XLA was considered based on clinical presentation, laboratory investigations (Table 1), and family history (elder brother died at 1.5 years because of a prolonged febrile illness; 2 maternal uncles had had a history of neuro-regression and died in early childhood). However, further genetic studies could not be carried out. He was initiated on cotrimoxazole prophylaxis and IVIg replacement therapy (0.4 g/kg/month). He remained clinically well for the next 1 year and then presented with acute generalized dystonia. Examination revealed hypotonia with dystonia, brisk deep tendon reflexes, and extensor plantar reflexes. MRI brain showed periventricular hyperintense signals in the right parieto-occipital lobe. Trough serum IgG at this time was 3.96 g/L. He was empirically treated with high dose IVIg (1g/kg every 3 weeks), acyclovir (60mg/kg/day), and trihexyphenidyl. He developed progressive neurological deterioration and died. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 6\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 16-year-old boy was symptomatic since infancy when he developed fever, severe pallor, hepatosplenomegaly, and pancytopenia. Bone marrow examination revealed a marked reduction in erythroid precursors and fibrosis (Figure 5). \u0026nbsp;He was being followed up under pediatric hematology services and was treated with intravenous methylprednisolone pulse (30mg/kg/day for 5 days) followed by tapering doses of oral prednisolone (2mg/kg/day initial dose). He showed some clinical improvement but developed anemia every time an attempt was made to taper prednisolone. On follow-up, he was also noted to have short stature and skeletal abnormalities such as pectus carinatum, small head, hallux valgus, and pes planus. Low-dose prednisolone (0.5mg/kg/day) was continued till 5 years of age and later tapered and stopped.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHe was re-hospitalized at the age of 17 with complaints of generalized seizures following a short febrile illness. On examination, he was drowsy, had papilledema, signs of meningeal irritation, raised intracranial pressure, and hepatosplenomegaly. Laboratory investigations revealed anemia (hemoglobin: 86g/L) and a positive PCR for HSV in CSF (Table 2). MRI brain revealed non-enhancing mild diffusion restricted T2 hyperintensities involving bilateral frontal and insular cortex. A clinical diagnosis of CVID was made (Table 1), and he was treated with IVIg (1g/kg), acyclovir, and antiepileptic drugs. He remained seizure-free and without any neurological deficits for the next 3 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHe had to be re-hospitalized at the age of 20 when he presented with red eyes and was noted to have hypertonia, brisk deep tendon reflexes, and vascular tortuosity in the peripapillary region of the retina with mild optic atrophy. Laboratory investigations showed hemoglobin: 106 g/L, total leucocyte count 10.3X10\u003csup\u003e9\u003c/sup\u003e/L, and platelet count 356X10\u003csup\u003e9\u003c/sup\u003e/L. The trough IgG level was 2.95g/L. MRI brain revealed areas of encephalomalacia with gliosis in bilateral frontal lobes with a prominence of frontal horns of lateral ventricles that suggested a sequela of old ischemic insult. CSF opening pressure was 60 cm H2O. However, the CSF examination was normal. A clinical possibility of benign intracranial hypertension was considered. He was continued on IVIg replacement therapy, but there was progressive neurological deterioration. One month later, he developed an episode of pneumonia and died at a hospital elsewhere.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 7\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 5-year-old boy had intermittent fever, recurrent ear discharge, and progressive abdominal distension. He also had a global developmental delay. He was born to a third-degree consanguineously married couple with a history of death of two siblings and two cousins (all because of some infections during the neonatal period). Examination showed generalized lymphadenopathy, splenomegaly, hepatomegaly, frontal bossing, long slender fingers and toes, pectus carinatum, and multiple joint contractures. Laboratory investigations are summarized in Table 1. A radiograph of the arms showed exostosis of the right humerus. Investigations suggested a clinical possibility of CVID. MRI brain was normal. He was initiated on monthly IVIg replacement therapy (0.4g/kg/month), following which his cytopenias started improving, and there was gradual regression in hepatosplenomegaly. There was, however, no improvement in his neurological status. A year later, he developed a short febrile illness requiring hospitalization and succumbed soon thereafter.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 8\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 4-year-old boy presented with recurrent pneumonia and ear discharge since early infancy. He was born to a second-degree consanguineously married couple. On examination, he had wasting, stunting, absent tonsils, small lymph nodes, tachypnea, diffuse crepitations in bilateral lung fields, and mild hepatomegaly. Investigations are summarized in Table 1. He was initiated on monthly IVIg replacement therapy (0.4g/kg/month) and cotrimoxazole prophylaxis. He was re-hospitalized at the age of 6 with complaints of subacute ascending paralysis of all four limbs that appeared two weeks after an acute upper respiratory tract infection. \u0026nbsp;Examination showed proximal muscle weakness in all limbs, upper motor neuron type left-sided facial nerve palsy, a retinal scar in the left eye, and brisk deep tendon reflexes. CMV PCR in CSF was positive. CMV viral load in blood was 946 copies/ml. MRI brain showed diffuse cerebral atrophy with T2 hyperintense signals in the tegmental tract on both sides. He was treated with high dose IVIg (1g/kg every 2 weeks), ganciclovir (5 mg/kg/day for 3 weeks) followed by oral valganciclovir (5 mg/kg/day for 4 weeks), and intravenous ceftriaxone (0.1g/kg/day) for 2 weeks. He was given IVIg 1g/kg every 2 weeks (6 doses) followed by monthly replacement doses of 0.4 g/kg/month and showed gradual improvement. He is doing well with no breakthrough infections and no evidence of muscle weakness at 11 months of follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 9\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 5-year-old boy had had an acute febrile illness with left-sided tonic-clonic convulsions and altered sensorium. Examination showed encephalopathy, nuchal rigidity, left hemiparesis, and brisk deep tendon reflexes. He was also found to have bilateral tympanic perforation and profound hearing loss in both ears. Computed tomography (CT) head showed ill-defined hypodense lesion in the right frontal cortex and bilateral thalami posteriorly and mild hydrocephalus. Details of the CSF examination are given in Table 1. He was treated with intravenous ceftriaxone and amikacin for 14 days and showed gradual improvement in sensorium. However, he continued to have recurrent sinopulmonary and ear infections thereafter and developed bilateral lower motor neuron facial nerve palsy at 12 years that needed middle ear exploration and tympanoplasty.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeanwhile, his nephew had been diagnosed to have XLA and was initiated on IVIg replacement therapy. After the diagnosis of XLA in his nephew, the index patient was brought to our clinic at the age of 18, evaluated (Table 1), and diagnosed with XLA. He showed poor compliance to IVIg replacement therapy, developed an episode of pneumonia at the age of 20, and succumbed to the illness.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 10\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 13-year-old boy presented with recurrent pneumonia, loose stools, and skin infections since the age of three. He was the second-born child of a non-consanguineously married couple. His elder sibling had expired at 8 months because of pneumonia and diarrhea. He developed progressive regression of his milestones, paucity of movements, ataxia, and lost partial control of his bowel and bladder at 13 years. Examination revealed supranuclear gaze palsy, hypertonia, rigidity, bradykinesia, exaggerated deep tendon reflexes, and clinical signs suggestive of cerebellar dysfunction. MRI brain showed diffuse cerebral and cerebellar atrophy with the widening of sulci and folial spaces (Figure 6). Investigations are summarized in Tables 1 and 2. Whole-exome sequencing showed no pathogenic variants. A clinical possibility of CVID was considered, and he was given one dose of IVIg (1g/kg), cotrimoxazole prophylaxis, fluoxetine (0.5mg/kg/day), and levodopamine. He is being continued on IVIg replacement therapy (0.4g/kg/month). At 4 months of follow-up, there have been no further breakthrough infections. However, he continues to be neurologically impaired.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 11\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 28-year-old male was diagnosed to have CVID (Table 1). Chest CT showed changes suggestive of bronchiectasis. He was initiated on IVIg replacement therapy and cotrimoxazole prophylaxis. He developed multiple episodes of generalized seizures 2 months after initiation of IVIg. The trough IgG level at this time was 6.81g/L. MRI brain showed T2 weighted hyperintensities in bilateral centrum semiovale, peri-Rolandic white matter in the right cerebral hemisphere, and temporo-occipital lobe in the left cerebral hemisphere, right midbrain, and thalamus. He was continued on replacement IVIg (0.4g/kg every month), antiepileptics, and cotrimoxazole. He remained seizure-free thereafter but had progressive neurological worsening. At the age of 29, he developed acute chest pain, for which he was taken to a nearby health care facility and died within a few hours. The exact cause of death could not be ascertained. \u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with PADs are predisposed to develop a spectrum of neurological complications[8]. Bacterial meningitis (commonly caused by Streptococcus pneumoniae, N. meningitidis, S. aureus, and Pseudomonas sp.) is the most common CNS infection[9,10]. Meningoencephalitis is usually caused by enteroviruses (e.g., echovirus, coxsackievirus, and poliovirus)(10,11). There is a paucity of published literature on large patient cohorts followed up over extended periods and, there are no studies from developing countries.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnder the National Immunization Program in India, oral poliovirus vaccine is still being used routinely, and most patients with PADs in India would have received this vaccine prior to their diagnosis getting confirmed. This further predisposes them to develop neurological complications related to the vaccine strain of poliovirus. Our center was part of a Jeffrey Modell Foundation (JMF) funded study on poliovirus excretion in patients with PADs. However, the vaccine strain of poliovirus in the stool sample was not detected in any of the patients with PAD who were screened for it from India[13].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe incidence of meningoencephalitis in XLA has been reported to be 1.1% in the registry of United States Immunodeficiency Network, 1% in the ESID registry, and 3% in the registry of Latin American Society for Immunodeficiencies[14]. In a recent multicenter experience on patients with XLA from India, 23% were reported to develop pyogenic meningitis, while 4.8% of patients had evidence of encephalitis (likely viral)[15].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, we report our experience of meningoencephalitis in patients with PAD. We also reviewed all previously published reports on meningoencephalitis in patients with XLA or CVID (Table 2). We observed meningoencephalitis in 11/135 (8.1%) patients- 4 with XLA and 7 with CVID. One patient had low CD40L expression with low IgG, low IgA and high IgM suggesting a possibility of Hyper-IgM syndrome. Whole exome sequencing, however, failed to identify any pathogenic variant in that patient. Low CD40 ligand expression has also been reported in patients with CVID[16].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean age of diagnosis of primary illness (hypogammaglobulinemia) in our cohort was 9.36 years (range: 2-28 years), and the mean age of onset of CNS illness was 8.6 years (2-28 years). Children with XLA were diagnosed earlier, except for one patient (case no 9) whose diagnosis was made at the age of 18. These results are similar to what has been reported previously[17].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn five patients (case 1,6,7,9,10) the diagnosis of PAD was made while they were being investigated for the neurological illness. The remaining six patients developed this complication while they were receiving replacement IVIg. It is important to note that all patients who developed meningoencephalitis while on replacement IVIg did so within the first two years of initiation of therapy. As compared to reports from the West (Table 2), the diagnosis of PAD was delayed in this series. Whether this delay has any direct bearing on the occurrence of meningoencephalitis, remains conjectural. Although commonly used immunoglobulin preparations usually have detectable titers of antibodies to many enteroviruses, coverage is not universal. Viral infections have been shown to occur even with adequate IVIg replacement therapy[18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, trough IgG levels were found to be low in 9/11 patients at the time of development of neurological symptoms despite replacement immunoglobulin therapy. American Academy of Allergy, Asthma \u0026amp; Immunology recommends maintaining a trough level of at least 5 g/L in patients with agammaglobulinemia[19]. In our published experience on serial serum IgG trough levels in patients with XLA at Chandigarh, the median trough IgG level was 3.97 g/L. This was found to be protective against the development of serious infections in our setup[20]. It has been suggested that higher doses of IVIg and higher trough IgG levels are needed for protection against enteroviral encephalitis due to the presence of low levels of antibodies against prevalent enteroviruses in commercial IVIg preparations[21]. Because of lack of universal insurance coverage in India, access to replacement immunoglobulin therapy is a challenging task. In the past few years, the cost of replacement immunoglobulin therapy for some patients is being supported by a few state governments and philanthropic organizations in our country. However, despite this support, the dose of replacement immunoglobulin remains suboptimal, and therefore, it is difficult to maintain an adequate trough IgG level in most of our patients[22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIdentification of causative organism for meningoencephalitis is challenging, especially in resource-limited settings. Laboratory evaluation is limited due to high costs and low reliability of currently available diagnostic tests. Serological tests are erratic in presence of hypogammaglobulinemia. Viral infections can be identified by isolating the virus in cell lines or in laboratory animals or by detection of viral nucleic acids by PCR in CSF samples (latter has higher sensitivity for virus detection)[23]. No etiological pathogen was identified in 8 (72.7%) patients in our study. Enteroviruses could not be isolated in any patient. This may be due to low sensitivity of enteroviral detection in CSF samples. While the specificity is high (92\u0026ndash;100%), sensitivity of PCR based assays for detection of enteroviral RNA in CSF varies from 31\u0026ndash;95%[24]. Sensitivity of the test can be increased by performing PCR in stool, throat swabs and urine samples[13,25]. A PCR can also be performed on brain biopsy in settings of high clinical suspicion[13,10]. Metagenomic next-generation sequencing is a novel approach that allows unbiased detection of any microbial nucleic acid present in a biological specimen, including divergent and novel pathogens. This can provide enhanced detection of etiological agents, when used in conjunction with conventional microbiological testing[26,27].\u003c/p\u003e\n\u003cp\u003eNeuroimaging may be normal in up to 25% of patients with viral encephalitis within the first few days[28]. In the present series, MRI brain was performed in 10 and CT head in 1. Nine patients had altered signal hyperintensities in gray and deep white matter, while 3 showed global cerebral atrophy. Neuroimaging in patients with enteroviral encephalitis often shows symmetric bilateral T2 weighted hyperintense lesion in the dorsal brainstem, cerebellum and spinal cord while it may show cerebral atrophy in later stages[28]. Neuroimaging findings in the present series, however, did not show the characteristic findings of enteroviral encephalitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eManagement is guided by the identification of causative organism. Most patients are initially managed empirically using broad-spectrum antimicrobials. High-dose IVIg therapy has been found to be useful. Ten patients needed high-dose IVIg therapy (1 g/kg every 2 weeks). Intrathecal immunoglobulin has also been reported to be beneficial in treating enteroviral encephalitis [30-33]. However, this therapy was not administered to any of our patients. Selective serotonin reuptake inhibitor, fluoxetine, has been shown to have antiviral effects and may be useful in enterovirus encephalitis[36]. Two of our patients also received fluoxetine. However, the use of fluoxetine did not result in significant clinical improvement. Several antiviral drugs (e.g., pleconaril, vapendavir, enviroxime, ViroD7000 and pocapavir) are undergoing clinical trials for their therapeutic use in these cases. However, none of these drugs could be used in the present series because of lack of availability.\u003c/p\u003e\n\u003cp\u003eEight (72.7%) patients in the present series have died. Three patients are on replacement IVIg, and the mean follow-up duration is 29.6 months (Table 2). Two amongst these (case 1 and 8) have shown complete neurological recovery, while one patient has shown some clinical improvement at follow-up of 3 months (case 10). Viral encephalitis in patients with PAD has been reported to have a poor prognosis. Rudge et al reported 13 patients with encephalomyelitis, and all patients succumbed to neurological illnesses[8]. McKinney et al. reported 23 deaths in their series of 41 patients with chronic enteroviral meningoencephalitis, while 6 patients improved with a combination of IVIg and intraventricular IgG therapy[41]. Halliday et al. reviewed 90 patients with primary immunodeficiencies and enteroviral infections. Of these, only 5 patients were reported to be well on follow-up[42]. Of the 117 cases reported so far with hypogammaglobulinemia and meningoencephalitis, only 52 (44.4%) patients survived (Table 2), and a large majority of these patients continued to have neurological deficits.\u003c/p\u003e\n\u003cp\u003eThe strengths of this study are that diagnosis and treatment of all patients were done at a single center, thereby bringing uniformity to patient management. This is the largest single-center cohort of patients with meningoencephalitis in patients with PADs from India. Limitations include a limited diagnostic armamentarium for identification of pathogenic organisms, especially enteroviruses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo conclude, patients with PADs may present with a spectrum of neurological manifestations. identification of a causative organism is extremely difficult in resource-limited settings such as ours. Treatment is largely limited to high doses of IVIg, and prognosis remains guarded in most patients. Early diagnosis and initiation of replacement immunoglobulin therapy (maintaining a trough IgG \u0026gt;5 g/L) may prevent the occurrence of neurological complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests:\u0026nbsp;\u003c/strong\u003eAll authors declare no conflicts of interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAKJ: Writing of initial draft, patient management, editing of manuscript at all stages of its production, review of literature\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHC:\u0026nbsp;Writing of initial draft, patient management, editing of manuscript at all stages of its production, review of literature\u003c/p\u003e\n\u003cp\u003eRT/AR/KA/MUSS/MS/RSM:\u0026nbsp;\u0026nbsp;Editing of manuscript, laboratory investigations, review of literature\u003c/p\u003e\n\u003cp\u003eDS/PKP/SV/RB/AG/VP/NS/RenuS/RajniS/RuchiS: Editing of manuscript, patient management, review of literature\u003c/p\u003e\n\u003cp\u003eKI/OO/SN/LM/KWC/YLL: Editing of manuscript, laboratory investigations, review of literature\u003c/p\u003e\n\u003cp\u003eSS: Patient management, critical revision of manuscript, review of literature, final approval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe manuscript was approved by Department Review Board (DRB-85-21). As it pertains only to retrospective collation of data of patients from clinic records, approval of the extant Institute Ethics Committee was not considered necessary. This is as per existing practice in the institute.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable, as per\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eexisting practice in the institute.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable, as per\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eexisting practice in the institute.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2018;14:61. \u003c/li\u003e\n\u003cli\u003eSuri D, Rawat A, Singh S. X-linked Agammaglobulinemia. Indian J Pediatr. 2016;83:331\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eBogaert DJA, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53:575\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eAmeratunga R, Ahn Y, Steele R, Woon S-T. The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID). Front Immunol. 2019;10:1541. \u003c/li\u003e\n\u003cli\u003eConley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol Orlando Fla. 1999;93:190\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSeidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7:1763\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eSaini AG, Radotra BD, Bhattarai D, Rawat A, Bhatia V. X-Linked Agammaglobulinemia With Chronic Meningoencephalitis: A Diagnostic Challenge. Indian Pediatr. 2021;58:169\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eRudge P, Webster AD, Revesz T, Warner T, Espanol T, Cunningham-Rundles C, et al. Encephalomyelitis in primary hypogammaglobulinaemia. Brain J Neurol. 1996;119 ( Pt 1):1\u0026ndash;15. \u003c/li\u003e\n\u003cli\u003eNguyen JT, Gundling KE. Neurologic Complications of Common Variable Immunodeficiency: A Case Report and Review of the Literature. J Allergy Clin Immunol. 2016;137:AB21. \u003c/li\u003e\n\u003cli\u003eSingh S, Rawat A, Suri D, Gupta A, Garg R, Saikia B, et al. X-linked agammaglobulinemia. Ann Allergy Asthma Immunol. 2016;117:405\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eRuffner MA, Sullivan KE, Henrickson SE. Recurrent and Sustained Viral Infections in Primary Immunodeficiencies. Front Immunol. 2017;8:665. \u003c/li\u003e\n\u003cli\u003eOchs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore). 1996;75:287\u0026ndash;99. \u003c/li\u003e\n\u003cli\u003eAghamohammadi A, Abolhassani H, Kutukculer N, Wassilak SG, Pallansch MA, Kluglein S, et al. Patients with Primary Immunodeficiencies Are a Reservoir of Poliovirus and a Risk to Polio Eradication. Front Immunol [Internet]. 2017 [cited 2019 Feb 18];8. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2017.00685/full\u003c/li\u003e\n\u003cli\u003eBearden D, Collett M, Quan PL, Costa-Carvalho BT, Sullivan KE. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy\u0026lowast;. J Allergy Clin Immunol Pract. 2016;4:1059\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eRawat A, Jindal AK, Suri D, Vignesh P, Gupta A, Saikia B, et al. Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India. Front Immunol. 2021;11:612323. \u003c/li\u003e\n\u003cli\u003eFarrington M, Grosmaire LS, Nonoyama S, Fischer SH, Hollenbaugh D, Ledbetter JA, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A. 1994;91:1099\u0026ndash;103. \u003c/li\u003e\n\u003cli\u003eBallow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol. 2002;109:581\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eGalama JMD, Gielen M, Weemaes CMR. Enterovirus antibody titers after IVIG replacement in agammaglobulinemic children. Clin Microbiol Infect. 2000;6:630\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003ePerez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139:S1\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eSuri D, Bhattad S, Sharma A, Gupta A, Rawat A, Sehgal S, et al. Serial Serum Immunoglobulin G (IgG) Trough Levels in Patients with X-linked Agammaglobulinemia on Replacement Therapy with Intravenous Immunoglobulin: Its Correlation with Infections in Indian Children. J Clin Immunol. 2017;37:311\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eKondoh H, Kobayashi K, Sugio Y, Hayashi T. Successful treatment of echovirus meningoencephalitis in sex-linked agammaglobulinaemia by intrathecal and intravenous injection of high titre gammaglobulin. Eur J Pediatr. 1987;146:610\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003eJindal AK, Pilania RK, Rawat A, Singh S. Primary Immunodeficiency Disorders in India\u0026mdash;A Situational Review. Front Immunol [Internet]. 2017 [cited 2019 Feb 21];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474457/\u003c/li\u003e\n\u003cli\u003eWebster AD, Tripp JH, Hayward AR, Dayan AD, Doshi R, Macintyre EH, et al. Echovirus encephalitis and myositis in primary immunoglobulin deficiency. Arch Dis Child. 1978;53:33\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSteiner I, Schmutzhard E, Sellner J, Chaudhuri A, Kennedy PGE, European Federation of Neurological Sciences, et al. EFNS-ENS guidelines for the use of PCR technology for the diagnosis of infections of the nervous system. Eur J Neurol. 2012;19:1278\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eJain S, Patel B, Bhatt GC. Enteroviral encephalitis in children: clinical features, pathophysiology, and treatment advances. Pathog Glob Health. 2014;108:216\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eZanella M-C, Lenggenhager L, Schrenzel J, Cordey S, Kaiser L. High-throughput sequencing for the aetiologic identification of viral encephalitis, meningoencephalitis, and meningitis. A narrative review and clinical appraisal. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2019;25:422\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eXing X-W, Zhang J-T, Ma Y-B, He M-W, Yao G-E, Wang W, et al. Metagenomic Next-Generation Sequencing for Diagnosis of Infectious Encephalitis and Meningitis: A Large, Prospective Case Series of 213 Patients. Front Cell Infect Microbiol. 2020;10:88. \u003c/li\u003e\n\u003cli\u003eGupta RK, Soni N, Kumar S, Khandelwal N. Imaging of central nervous system viral diseases. J Magn Reson Imaging. 2012;35:477\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eQuartier P, Debr\u0026eacute; M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134:589\u0026ndash;96. \u003c/li\u003e\n\u003cli\u003eMisbah SA, Spickett GP, Ryba PC, Hockaday JM, Kroll JS, Sherwood C, et al. Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol. 1992;12:266\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eShiroma N, Omi T, Hasegawa H, Nagashima K, Ohta T. A case of X-linked agammaglobulinemia with progressive encephalitis. Pediatr Neurol. 2004;31:371\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eCrennan JM, Van Scoy RE, McKenna CH, Smith TF. Echovirus polymyositis in patients with hypogammaglobulinemia. Failure of high-dose intravenous gammaglobulin therapy and review of the literature. Am J Med. 1986;81:35\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eMease PJ, Ochs HD, Wedgwood RJ. Successful treatment of echovirus meningoencephalitis and myositis-fasciitis with intravenous immune globulin therapy in a patient with X-linked agammaglobulinemia. N Engl J Med. 1981;304:1278\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eErlendsson K, Swartz T, Dwyer JM. Successful Reversal of ECHOvirus Encephalitis in X-Linked Hypogammaglobulinemia by Intraventricular Administration of Immunoglobulin. N Engl J Med. 1985;312:351\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eDwyer JM, Erlendsson K. Intraventricular gammaglobulin for the management of enterovirus encephalitis. Pediatr Infect Dis J. 1988;7:S30-33. \u003c/li\u003e\n\u003cli\u003eGofshteyn J, C\u0026aacute;rdenas AM, Bearden D. Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia. Pediatr Neurol. 2016;64:94\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eZhang G, Zhou F, Gu B, Ding C, Feng D, Xie F, et al. In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection. Arch Virol. 2012;157:669\u0026ndash;79. \u003c/li\u003e\n\u003cli\u003eThibaut HJ, De Palma AM, Neyts J. Combating enterovirus replication: State-of-the-art on antiviral research. Biochem Pharmacol. 2012;83:185\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eAbzug MJ, Michaels MG, Wald E, Jacobs RF, Romero JR, S\u0026aacute;nchez PJ, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis. J Pediatr Infect Dis Soc. 2016;5:53\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eMcKinlay MA, Collett MS, Hincks JR, Oberste MS, Pallansch MA, Okayasu H, et al. Progress in the development of poliovirus antiviral agents and their essential role in reducing risks that threaten eradication. J Infect Dis. 2014;210 Suppl 1:S447-453. \u003c/li\u003e\n\u003cli\u003eMcKinney RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis. 1987;9:334\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003eHalliday E. Enteroviral Infections in Primary Immunodeficiency (PID): A Survey of Morbidity and Mortality. J Infect. 2003;46:1\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eLinnemann CC. Fatal Viral Encephalitis in Children With X-Linked Hypogammaglobulinemia. Arch Pediatr Adolesc Med. 1973;126:100. \u003c/li\u003e\n\u003cli\u003eZiegler JB, Penny R. Fatal echo 30 virus infection and amyloidosis in X-linked hypogammaglobulinemia. Clin Immunol Immunopathol. 1975;3:347\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eWilfert CM, Buckley RH, Mohanakumar T, Griffith JF, Katz SL, Whisnant JK, et al. Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. N Engl J Med. 1977;296:1485\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eBardelas JA, Winkelstein JA, Seto DSY, Tsai T, Rogol AD. Fatal ECHO 24 infection in a patient with hypogammaglobulinemia: Relationship to dermatomyositis-like syndrome. J Pediatr. 1977;90:396\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eWeiner LS, Howell JT, Langford MP, Stanton GJ, Baron S, Goldblum RM, et al. Effect of Specific Antibodies on Chronic Echovirus Type 5 Encephalitis in a Patient with Hypogammaglobulinemia. J Infect Dis. 1979;140:858\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eBodensteiner JB, Morris HH, Howell JT, Schochet SS. Chronic ECHO type 5 virus meningoencephalitis in X-linked hypogammaglobulinemia: Treatment with immune plasma. Neurology. 1979;29:815\u0026ndash;815. \u003c/li\u003e\n\u003cli\u003eFailure of Intraventricular Gamma Globulin to Eradicate ECHOvirus Encephalitis in a Patient with X-Linked agammaglobulinemia. N Engl J Med. 1985;313:1546\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eRoberton DM, Jack I, Joshi W, Law F, Hosking CS. Failure of intraventricular gammaglobulin and alpha interferon for persistent encephalitis in congenital hypogammaglobulinaemia. Arch Dis Child. 1988;63:948\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eMaldergem L, Mascart F, Ureel D, Jauniaux E, Broeckx W, Vainsel M. Echovirus Meningoencephalitis in X-Linked Hypogammaglobulinemia. Acta Paediatr. 1989;78:325\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003evon der Wense A, Herrmann B, Deppermann R, Harms F, Wehinger H. [Intrathecal interferon therapy in chronic echovirus meningoencephalitis in Bruton type agammaglobulinemia]. Klin Padiatr. 1998;210:51\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eBezrodnik L, Samara R, Krasovec S, Erro MG, Sevlever GE. Progressive multifocal leukoencephalopathy in a patient with hypogammaglobulinemia. Clin Infect Dis Off Publ Infect Dis Soc Am. 1998;27:181\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eCunningham CK, Bonville CA, Ochs HD, Seyama K, John PA, Rotbart HA, et al. Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr. 1999;134:584\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003ePlebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical, Immunological, and Molecular Analysis in a Large Cohort of Patients with X-Linked Agammaglobulinemia: An Italian Multicenter Study. Clin Immunol. 2002;104:221\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eCucchiara BL, Forman MS, McGarvey ML, Kasner SE, King D. Fatal Subacute Cytomegalovirus Encephalitis Associated With Hypogammaglobulinemia and Thymoma. Mayo Clin Proc. 2003;78:223\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eJha S, Ansari M. Herpes simplex encephalitis in a patient having common variable immuno-deficiency. Ann Trop Med Public Health. 2010;3:30. \u003c/li\u003e\n\u003cli\u003eBorish L, Ayars AG, Kirkpatrick CH. Common variable immunodeficiency presenting as herpes simplex virus encephalitis. J Allergy Clin Immunol. 2011;127:541\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eSempere AP, Tahoces M, Palao-Duarte S, Garcia-Perez A. Bilateral optic neuritis in a 26-year-old man with common variable immunodeficiency: a case report. J Med Case Reports. 2011;5:319. \u003c/li\u003e\n\u003cli\u003eBakri FG, Bahou YG, Al-Sammarrai FA, Hadidy A, Gharaibeh A, Zaid GK, et al. Fatal encephalitis due to BK virus in a patient with common variable immunodeficiency: a case report. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2013;57:363\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eM Khair A. Autoimmune Encephalitis as the Sole Presentation of Common Variable Immunodeficiency: First Report in a Child. J Clin Case Rep [Internet]. 2015 [cited 2019 Jul 5];05. Available from: http://www.omicsgroup.org/journals/autoimmune-encephalitis-as-the-sole-presentation-of-common-varaibleimmunodeficiency-first-report-in-a-child-2165-7920-1000665.php?aid=66975\u003c/li\u003e\n\u003cli\u003eNajem CE, Springer J, Prayson R, Culver DA, Fernandez J, Tavee J, et al. Intracranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature. Semin Arthritis Rheum. 2018;47:890\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eShribman SE, Katanga J, Ali N, Hayman GR, Bridges LR, Habibi MS, et al. Encephalomyelitis with Retinopathy in Common Variable Immunodeficiency (CVID). Neuro-Ophthalmol. 2020;44:38\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eSlade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults. Front Immunol. 2018;9:694. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Clinical details and immunological workup in the present cohort of patients with primary antibody deficiency and meningoencephalitis\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003eCase no. \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eType of disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003eAge at diagnosis(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eClinical features at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eImmunoglobulin profile at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eLymphocyte subsets at diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eOther immunological tests\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eGenetic abnormality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e7\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent diarrhea, ear discharge, headache, seizures, transient ischemic attacks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 3.1 g/L (normal range: 5.4-16.1 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 0.1% (normal: 10-31%),\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eBtk protein expression on patient\u0026rsquo;s monocytes (20.5%, MFI: 1.28) when compared to control (90.5%, MFI: 1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eMissense pathogenic variant detected in exon 17 of \u003cem\u003eBTK\u003c/em\u003e (c.1732T\u0026gt;C, p. Ser578Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: \u0026lt;0.12 g/L (normal: 0.5-1.8 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 87.5% (normal: 55-78%),\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA:\u0026lt;0.17 g/L (normal: 0.7-2.5 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD56+NK lymphocytes 13.9% (normal: 4-26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eFever, diarrhea, molluscum contagiosum\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 0.39 g/L (normal range: 5.4-16.1 g/L)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 9.56% (normal: 14-44%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eAntibody response to vaccinations against diphtheria: 0.03 IU/ml(protective: \u0026ge;0.1 IU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 82.6% (normal:43-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eSwitched memory B lymphocytes 0.73% (normal: 6.5-29.1%]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD56+NK lymphocytes: 12.39% (normal: 4-23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eUnswitched memory B lymphocytes: 3.18% (normal: 7.4-32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: \u0026lt;0.23 g/L (normal: 0.5-1.8 g/L)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD4+T lymphocytes: 73.54% (normal: 43-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA: \u0026lt;0.17 g/L (normal: 0.7-2.5 g/L)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD8+T lymphocytes: 23.03% (normal: 14-33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent infections\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 0.92 g/L (normal: 3.7-15.8 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 0.07% (normal:14-33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eBtk protein expression on CD14+ monocytes in patient: 11.5%; MFI: 1.89; Btk protein expression on CD14+ monocytes in control :87.4%; MFI: 5.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003e\u003cem\u003eBTK\u003c/em\u003e (c.310-8C\u0026gt;A [Splice-site acceptor variant])\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: \u0026lt;0.25 g/L (normal: 0.5-2.2 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 83.93% (normal: 56-75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA:\u0026lt;0.17 g/L (normal: 0.3-1.3 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD56+NK cells: 9.74% (normal:4-17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent episodes of fever, oral ulcers and sinopulmonary infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 0.39 g/L (normal: 4.9-16.1 g/L),\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 16% (normal range: 14-44 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eNa\u0026iuml;ve B lymphocytes: 66.3% (normal: 43-83%), and\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 58.6% (normal: 43-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eUnswitched memory B lymphocytes: 19.9% (normal:7.4-32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003e\u0026nbsp;CD56+NK lymphocytes: 20.9% (normal: 4-23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eSwitched memory B lymphocytes: 0.21% of CD19+ lymphocytes (normal range: 6.5-29.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: \u0026lt;0.25 g/L (normal: 0.5-2.0 g/L),\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD4+T lymphocytes: 50.2% (normal: 23-48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA:\u0026lt;0.17 g/L (normal: 0.4-2 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD8+T lymphocytes: 42.3% (normal: 14-33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent sino-pulmonary infections, 1 episode of pyogenic meningitis and global development delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 0.39 g/L (normal range: 4.9-16.1 g/L)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 0.21% (normal: 14-44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: \u0026lt;0.25 g/L (normal: 0.5-2.0 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 76.3% (normal: 43-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA:\u0026lt;0.17 g/L (normal: 0.4-2 g/L)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eFever, severe pallor, hepatosplenomegaly, pancytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG \u0026lt;0.95 g/L (normal: 5.4-16.1g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+: B lymphocytes 1.3% (normal: 8-10%),\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eBtk protein expression on monocytes normal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 90.19% (normal: 52-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eCD56+NK lymphocytes: 2.3% (normal: 2-26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM \u0026lt;0.25 g/L (normal: 0.5-1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD4+T lymphocytes: 17.6% (normal: 28-50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA \u0026lt;0.17 g/L(normal: 0.8-2.8g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD8+T lymphocytes: 68.9% (normal: 15-35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eIntermittent fever, ear discharge since infancy and progressive abdominal distension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 0.49 g/L (0.49-1.6 g/L)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD20+ B lymphocytes: 24.13% (normal: 14-33%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eHb: 80 g/L, TLC: 3.2x10\u003csup\u003e9\u003c/sup\u003e /L, platelet counts: 118x10\u003csup\u003e9\u003c/sup\u003e/L. and\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD3+ T lymphocytes: 74.14% (normal: 56-75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eNa\u0026iuml;ve B lymphocytes: 22.4% (normal: 42-82%),\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD 56+ NK lymphocytes: 1.32% (normal:4-17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eUnswitched memory B lymphocytes: 1.4% (normal:7.4-32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.212290502793294%\"\u003e\n \u003cp\u003eIgM \u0026lt;0.25 g/L (normal: 0.5-2.0 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"33.37988826815643%\"\u003e\n \u003cp\u003eCD4+T lymphocytes: 42.6% (normal 28-50%) and\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"38.40782122905028%\"\u003e\n \u003cp\u003eClass switched memory B lymphocytes: 2.41% (normal 8-31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"28.212290502793294%\"\u003e\n \u003cp\u003eIgA:\u0026lt;0.36 g/L (normal: 0.4-2 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"33.37988826815643%\"\u003e\n \u003cp\u003eCD8+T lymphocytes: 47.5% (normal: 15-35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"38.40782122905028%\"\u003e\n \u003cp\u003eAnti-diphtheria antibodies: \u0026nbsp;0.031 IU/ml (protective antibodies \u0026gt;0.1IU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eTransferrin isoelectric focusing for congenital disorder of glycosylation: normal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent pneumonia and ear discharge since early infancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 3.89 g/L (normal: 4.9-16.1g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 13.5% (normal:14-44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eNa\u0026iuml;ve B lymphocytes: 83.8% (normal: 43-82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNo pathogenic variants\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"28.212290502793294%\"\u003e\n \u003cp\u003eIgM: 1.13 g/L (normal: 0.5-2.0g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"33.37988826815643%\"\u003e\n \u003cp\u003eCD3+ T lymphocytes: 81% (normal: 43-76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"38.40782122905028%\"\u003e\n \u003cp\u003eunswitched memory B lymphocytes: 7.04% (normal:7.4-32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"28.212290502793294%\"\u003e\n \u003cp\u003eIgA: \u0026lt;0.17 g/L (normal: 0.4-2.0g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"33.37988826815643%\"\u003e\n \u003cp\u003eNK lymphocytes 0.08% (normal:4-23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"38.40782122905028%\"\u003e\n \u003cp\u003eswitched memory B lymphocytes: 0.82% (normal: 6.5-29.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eCD40 ligand expression on CD4+T lymphocytes 82.34% as compared to 96.25% in control\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent pneumonia and bilateral ear discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG \u0026lt;0.93 g/L(normal: 5.4-16.1g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+B lymphocytes: 0.1% (normal: 6-23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eBTK gene (intron 8~intron 9 deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eIgM \u0026lt;0.11 g/L (normal: 0.5-1.9g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eIgA: 0.18 g/L (normal: 0.8-2.8g/L) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eHIGM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent pneumonia, loose stools and skin infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003e\u0026nbsp;IgG: 0.12 g/L (normal: 5.4-16.1g/L)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+ B lymphocytes: 7.71% (normal: 6-23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eNa\u0026iuml;ve B lymphocyte: 63.3% (normal: 43-82%),\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNo pathogenic variants\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD3+T lymphocytes: 74.05% (56-84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eUnswitched memory B lymphocytes: 35.9% (normal: 7.4-32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"46.49805447470817%\"\u003e\n \u003cp\u003eCD56+ lymphocytes: 2.57% (normal: 3-22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"53.50194552529183%\"\u003e\n \u003cp\u003eSwitched memory B lymphocytes: 0.57% (normal: 6.5-29.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"42.34800838574424%\"\u003e\n \u003cp\u003eIgM: 2.17 g/L (normal: 0.5-1.9g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"57.65199161425576%\"\u003e\n \u003cp\u003eCD40L expression on activated helper T lymphocytes: 8.3% (control: 47.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"42.34800838574424%\"\u003e\n \u003cp\u003eIgA: \u0026lt;0.26 g/L (normal: 0.8-2.8g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"57.65199161425576%\"\u003e\n \u003cp\u003eRegulatory T lymphocytes 2.17% (control: 4.14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"4.003267973856209%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"3.9215686274509802%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"6.5359477124183005%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"14.379084967320262%\"\u003e\n \u003cp\u003eRecurrent pneumonia, diarrhea, ear discharge and sinusitis since early childhood\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.50326797385621%\"\u003e\n \u003cp\u003eIgG: 5.0 g/L (normal: 9.77-15.19),\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"19.526143790849673%\"\u003e\n \u003cp\u003eCD19+ B lymphocytes: 0.1% (normal: 6-19%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"22.46732026143791%\"\u003e\n \u003cp\u003eBtk protein expression on monocytes normal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"12.663398692810457%\"\u003e\n \u003cp\u003eNot done\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgM: 0.81 g/L (normal: 0.85-1.13g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD3+ T lymphocytes: 45.4% (normal: 55-83%),\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"45.80498866213152%\"\u003e\n \u003cp\u003eIgA: 1.15 g/L (normal: 1.4-2.5g/L),\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"54.19501133786848%\"\u003e\n \u003cp\u003eCD56+ NK lymphocytes: 56.5% (normal: 7-31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eAbbreviations used: XLA:X linked agammaglobulinemia, CVID: common variable immunodeficiency, HIGM: Hyper IgM syndrome, Btk protein: Bruton tyrosine kinase protein, MFI: Mean florescent intensity, Hb: hemoglobin, TLC: total leucocyte count, CD40L: CD40 ligand\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eDue to technical limitations, table 2 \u0026nbsp;is only available as a download in the Supplemental Files section.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3: Review of previously reported cases with primary antibody deficiency and meningoencephalitis\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"111%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy, country, year [reference]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological manifestations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis(in years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at time of illness(in years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrganism isolated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eLinnemann et al, USA, 1973[43]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEncephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eHerpes\u003c/p\u003e\n \u003cp\u003esimplex virus, Echovirus 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eZiegler, USA, 1975[44]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eViral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIntramuscular gamma globulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eWilfert et al, USA, 1977[45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003e3 XLA, 2 hypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic meningoencephalitis: 4; dermatomyositis: 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eMean age: 2.4(1.5-3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eMean: 10.8(3.5-24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 9, 19, 30, 33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eSteroids; immune serum globulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e3 died, 2 recovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;Bardelas et al, USA, 1977[46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eHypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMeningoencephalitis, polymyositis,\u003c/p\u003e\n \u003cp\u003eedema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eSpecific serum anti- Echovirus 24 plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eWebster et al, England, 1978[23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA, Hypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEncephalitis: 2 dermatomyositis:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e1.5, 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e11, 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 11,\u003c/p\u003e\n \u003cp\u003eEchovirus 25\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHyper- immune plasma, steroids\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eWeiner et al, USA, 1979[47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic myositis, encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHyperimmune plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;Bodensteiner et al, USA, 1979[48]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003e\u0026nbsp;X linked Hypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh-titer, specific plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eMease et al,USA, \u0026nbsp;1981[33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMeningoencephalitis, myositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eErlendsson et al, USA, 1985[34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eJohnson et al, USA, \u0026nbsp;1985[49]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eCrennan et al, USA, 1986[32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMeningoencephalitis, dermatomyositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eCoxsackievirus B3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eCyclophosphamide, Steroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eMcKinney et al, USA, 1987[41]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003e18 XLA, 20 CVID, 4 acquired hypogammaglobulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eMean age: 14.2(3 mo-35 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eMean age: 20.1(2-42 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003cp\u003eEchovirus 11(11 cases)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e19 recovered\u003c/p\u003e\n \u003cp\u003e23 died\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eKondoh et al, Japan, 1987[21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMeningoeneephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus type 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eDwyer et al, Australia, 1988[35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e3 months\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eRoberton et al, Australia, 1989[50]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003ePicornavirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, intraventricular Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eMaldergem et al, Belgium, 1989[51]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus type 13.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh dose IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eMisbah et al, UK, 1992`[30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh-dose\u003c/p\u003e\n \u003cp\u003eIVIg (2.5 to 7.5 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eRudge et al, USA, 1996[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003e7 XLA\u003c/p\u003e\n \u003cp\u003e6 CVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMyelopathy: 5/13\u003c/p\u003e\n \u003cp\u003eEncephalopathy: 12/13\u003c/p\u003e\n \u003cp\u003eMyositis: 3/13\u003c/p\u003e\n \u003cp\u003eHearing loss: 2/13\u003c/p\u003e\n \u003cp\u003eRetinopathy: 3/13\u003c/p\u003e\n \u003cp\u003eSeizures: \u0026nbsp;6/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e13.4(0.5-56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e31.4(6-62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 3: 1\u003c/p\u003e\n \u003cp\u003eEchovirus 11: 1\u003c/p\u003e\n \u003cp\u003eJC virus: 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eImmunoglobulin: 12\u003c/p\u003e\n \u003cp\u003ePlasma: 2\u003c/p\u003e\n \u003cp\u003eIFN-\u0026micro;: 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e13 died\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eWense et al, Germany, 1998[52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic enteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus type 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIntraventricular and intravenous immunoglobulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eBezrodnik et al, Argentina, 1998[53]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eProgressive Multifocal Leukoencephalopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eJC virus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eCytosine arabinoside\u003c/p\u003e\n \u003cp\u003esubcutaneous IFN-a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003ePartial recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eCunningham et al , USA, 1999[54]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXHIGM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEnteroviral meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e8months,\u003c/p\u003e\n \u003cp\u003e11 months,\u003c/p\u003e\n \u003cp\u003e7 months\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e30 months\u003c/p\u003e\n \u003cp\u003e21 months\u003c/p\u003e\n \u003cp\u003e30 months\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEchovirus 14\u003c/p\u003e\n \u003cp\u003eEchovirus 14\u003c/p\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIG, 1 g/kg/week\u003c/p\u003e\n \u003cp\u003eIVIG, 1.5 g/kg per week\u003c/p\u003e\n \u003cp\u003eIVIG, 1 g/kg/week\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e1 died\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 Survived with severe neurological impairment, 1 recovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003ePlebani et al, Italy, 2002[55]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eMeningitis, meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eNeisseria meningitidis in 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh dose IVIg, antimicrobials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eCucchiara et al, USA, \u0026nbsp;2003[56]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eGood syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEncephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eCytomegalovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eFoscarnet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eHalliday et al, USA,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2003[42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA, CVID,HIGM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic encephalitis and meningitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh dose IVIg, intrathecal immunoglobulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eShiroma et al, Japan,2004[31]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eProgressive Encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg,\u0026nbsp;IFN-\u0026micro;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003ePartial recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eAnsari et al, India, 2010[57]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eHerpes simplex encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eHSV-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eAcyclovir, IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eBorish et al, USA, \u0026nbsp;2011[58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eHerpes simplex encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e40\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eHSV-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eAcyclovir, IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eSempere et al, Spain, 2011[59]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eBilateral optic neuritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eSteroids, IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eBakri et al, Jordan, 2013[60]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEncephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eBK virus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg, ganciclovir\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eKhair et al, Qatar, \u0026nbsp;2015[61]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eAutoimmune encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eNguyen\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEt al, USA, 2016[9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eLeft monoparesis, enhancing lesions of the left cerebellar hemisphere with mass effect, optic neuritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eSteroids, rituximab and azathioprine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eNajem et a, USA, l 2017[62]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eIntracranial granulomatous disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eSteroids 4/19\u003c/p\u003e\n \u003cp\u003eSteroids + IVIg: 5/19\u003c/p\u003e\n \u003cp\u003eIVIG: 3/19\u003c/p\u003e\n \u003cp\u003eInfliximab: 3/19\u003c/p\u003e\n \u003cp\u003eOthers: 3/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRemission: 11\u003c/p\u003e\n \u003cp\u003eRecurrence: 6\u003c/p\u003e\n \u003cp\u003eDied: 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eGofshteyn et al, USA,\u003c/p\u003e\n \u003cp\u003e2018[36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eXLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic Enterovirus Encephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh dose IVIg, fluoxetine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eRecovered\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eShribman et al, England, 2018[63]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eEncephalomyelitis with retinopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eTeenage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"13.68421052631579%\"\u003e\n \u003cp\u003eSlade et al, Australia, 2019[64]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.789473684210526%\"\u003e\n \u003cp\u003eCVID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.894736842105264%\"\u003e\n \u003cp\u003eChronic lymphocytic meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.526315789473685%\"\u003e\n \u003cp\u003eEnterovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.631578947368421%\"\u003e\n \u003cp\u003eHigh-dose IVIG (2 g/kg) and methylprednisolone\u003c/p\u003e\n \u003cp\u003e2 mg/kg, cyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.473684210526315%\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eAbbreviations used: XLA:X linked agammaglobulinemia, CVID: common variable immunodeficiency, Ig: Immunoglobulin, IVIg: intravenous immunoglobulin, HIGM: Hyper-IgM syndrome, CMV: cytomegalovirus, HSV-1: Herpes simplex virus-1, JC virus: human polyomavirus 2, IFN-\u0026micro;: Interferon-\u0026micro;, USA: United States of America\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Common Variable Immunodeficiency, Enterovirus, Intravenous immunoglobulin, Meningoencephalitis, Primary antibody deficiency, X-linked agammaglobulinemia","lastPublishedDoi":"10.21203/rs.3.rs-723651/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-723651/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with primary antibody deficiency (PAD) are predisposed to develop meningoencephalitis that is often considered to be enteroviral. However, there is a paucity of literature on this subject, and there are no studies from developing countries. We analyzed our cohort of children with PAD who developed meningoencephalitis. This complication was observed in 11/135 (8.1%) patients with PAD - 4 patients had X-linked agammaglobulinemia (XLA), and 7 had common variable immunodeficiency (CVID). The mean age at onset of neurological illness was 8.6 years (range: 2-28 years). Presenting features included seizures (n=7), neurodevelopmental delay (n=2), regression of milestones (n=1), and acute flaccid paralysis (n=1). Trough IgG levels were found to be low in 9 (81.8%) patients at the time of development of neurological symptoms. Herpes simplex virus (HSV), cytomegalovirus (CMV), and Streptococcus pneumoniae were isolated in 1 patient each. No etiological agent was identified in cerebrospinal fluid of 8 patients. Eight (72.7%) patients had altered signal hyperintensities in gray matter and deep white matter on magnetic resonance imaging (MRI), while 3 patients showed global cerebral atrophy. All patients were treated with high-dose intravenous immunoglobulin (IVIg). Fluoxetine was given to 2 patients. Eight (72.7%) patients in the present series have succumbed, while three have recovered with varying degrees of neurological sequelae. To conclude, meningoencephalitis is an uncommon complication in patients with PAD and is associated with high morbidity and mortality in our setting. Early diagnosis of immune deficiency and initiation of replacement immunoglobulin therapy may prevent the development of neurological complications.\u003c/p\u003e","manuscriptTitle":"Meningoencephalitis in Children with Primary Antibody Deficiency: A Single-Center Experience From Northwest India and Review of Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-11 19:14:35","doi":"10.21203/rs.3.rs-723651/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe6f14b1-82f7-4be5-b47c-259fe501c7a0","owner":[],"postedDate":"August 11th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":6380064,"name":"Clinical Pharmacology"},{"id":6380065,"name":"Immunology"}],"tags":[],"updatedAt":"2021-09-13T20:47:09+00:00","versionOfRecord":[],"versionCreatedAt":"2021-08-11 19:14:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-723651","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-723651","identity":"rs-723651","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}