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 10.3X109/L, and platelet count 356X109/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.