Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. OBJECTIVES: To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. METHODS: Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. RESULTS: Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. CONCLUSIONS: DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

Sex differences in cognitive function among people with HIV-1 clade C infection in Northern India.

Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

PURPOSE: To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. MATERIALS AND METHODS: Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. RESULTS: Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. CONCLUSION: These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Nutritional Recovery Batwing Dystonia in Infantile Vitamin B12 Deficiency.

The neurocutaneous syndrome of infantile B12 deficiency, more commonly called the infantile tremor syndrome, typically is characterized by developmental delay, sparse hair, hyperpigmentation, and tremors. When treated with injectable B12, the affected babies can develop a peculiar transient "batwing dystonia." This dystonia is possibly a nutritional recovery movement disorder due to basal ganglia dysfunction.

PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases.

BACKGROUND: Protein phosphatase 2 regulatory subunit B' delta (PPP2R5D)-related neurodevelopmental disorder is caused by pathogenic variations in the PPP2R5D gene, product of which is involved in dephosphorylation. This is a rare disorder with description limited to case reports. Its phenotypic spectrum has expanded over the last decade. METHODS: We report a child with a developmental and epileptic encephalopathy phenotype with a pathogenic PPP2R5D variant. This phenotype has not been previously reported. We also reviewed the previously published reports of patients with this disorder. RESULTS: Including the index child, 28 cases (15 girls) were identified from nine relevant research items for analysis. All patients had developmental delay. History of seizures was observed in seven patients while macrocephaly was seen in nearly 80% of patients. Nonneurological manifestations were observed in 13 patients with the most common one being ophthalmological manifestations. The most common genetic variation was c.G592A (p.E198K). The common phenotypic associations of this variation were developmental delay, macrocephaly (11/15), and epilepsy (6/15). CONCLUSION: PPP2R5D gene variations should be suspected in children with developmental delay, autistic features, macrocephaly with or without epilepsy in the absence of any clear etiology. Dysmorphic features might provide a diagnostic clue. DEE phenotype may also be the presenting feature and might be an underreported entity.

Seroprevalence of MOG and AQP4 Antibodies and Outcomes in an Indian Cohort of Pediatric Acquired Demyelinating Syndromes.

This study aimed to determine the seropositivity of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-4 antibodies (AQP4-Ab) and outcomes in children with acquired demyelinating syndromes (ADSs). Children (6 months-15 years) with suspected ADS were enrolled and tested for MOG-Ab and AQP4-Ab prospectively over 18 months at a tertiary care hospital in North India. Children with proven nonimmune-mediated neurological disorders were enrolled as controls. Of 79 children with suspected ADS, 66 were enrolled. Among the enrolled children with ADS, acute demyelinating encephalomyelitis (ADEM) (25) was the most common first clinical event followed by optic neuritis (ON) (20) and transverse myelitis (TM) (19; one child had ON and TM simultaneously [neuromyelitis optica spectrum disorders [NMOSDs]]), while two children had clinically isolated syndrome (CIS) apart from ON and TM. Fourteen (21.2%, confidence interval [CI] 11.3-31.1) tested positive for one antibody (12 [18.1%; 95% CI 10.5-25.5%] for MOG-Ab and 2 [3%; 95% CI 0-7.2%] for AQP4-Ab). None of the 62 controls tested positive for any antibody. The final diagnosis in those with the monophasic ADS was ADEM (21), ON (13), TM (16), and other CIS (1) while that in children with recurrent events was multiphasic disseminated encephalomyelitis (MDEM) (2), NMOSD (3), ADEM-ON (4), recurrent ON (4), and MS (2). Among those with the first event, 4/51 (7.8%; 95% CI 0.5-15.2%) were MOG-Ab positive and 2 AQP4-Ab positive, whereas 8/15 (53.3% [95% CI 28.1-78.6%]) with recurrent events (MDEM [2], ADEM-ON [4], recurrent ON [1], and recurrent TM [1]) were MOG-Ab positive. Hence, MOG-Abs are the most common antibodies detected in one in five children with pediatric ADS, especially in relapsing disease. AQP4-Abs are rare in children with ADS.

MR vessel wall imaging in cerebral bacterial and fungal infections.

PURPOSE: Central nervous system (CNS) bacterial and fungal infections can cause secondary vasculitis which worsens the prognosis due to development of complications like infarctions or hemorrhages. In this prospective study, we aim to study intracranial vessel wall imaging findings in bacterial and fungal infections. METHODS: We included 12 cases of nontubercular bacterial and fungal CNS infections each, in whom definitive microbiological diagnosis could be made. High-resolution vessel wall imaging (VWI) and time of flight MR angiography (TOF MRA) were incorporated in the routine imaging protocol. All cases were evaluated for the presence of vascular enhancement, pattern of enhancement, and stenosis on VWI. Statistical analysis was done to evaluate association between findings of vessel wall imaging and infarctions. RESULTS: We found infarctions in 5 out of 12 cases (41.7%) of the bacterial group and 7 out of 12 cases (58.3%) of the fungal group. Vessel wall enhancement was seen in 5 cases (41.7%) of the bacterial group and 9 cases (75%) of the fungal group. There was a significant association between infarctions and vessel wall enhancement in the fungal group. However, pattern of enhancement or stenosis on VWI was not significantly associated with presence of infarction. VWI detected more cases of vascular involvement than TOF MRA. CONCLUSION: Secondary infectious vasculitis in bacterial and fungal infections can be detected by VWI, which can play an important role in better patient management as detection of vascular involvement can prompt early treatment to prevent complications like infarctions or hemorrhages.

High-resolution intracranial vessel wall imaging in cerebral viral infections evaluations.

PURPOSE: Vascular complications can be seen in various viral CNS infections. Variable neuro-imaging findings have been described in the literature elucidating the parenchymal changes with vascular involvement. Vessel wall imaging (VWI) can help to detect these vascular involvements. We aimed to describe the role and usefulness of VWI in the evaluation of various viral CNS infections. METHODS: In this prospective study, we included 15 cases of various diagnosed viral CNS infections (varicella, HIV encephalopathy, HSV encephalitis, Japanese encephalitis, dengue, COVID-19). VWI and time-of-flight MR angiography (TOF MRA) were included in imaging protocol. All cases were evaluated for the presence of cerebral parenchymal changes, vascular enhancement, and vascular stenosis. RESULTS: We found infarctions in all 5 cases of varicella, 1 case of HIV encephalopathy, and 1 case of COVID-19 encephalopathy. All these cases also showed vascular enhancement and stenosis on VWI. The rest of the cases, including 1 case of HIV encephalopathy, 3 cases of herpes encephalitis, 2 cases of dengue, and 2 cases of Japanese encephalitis did not have any vascular complication, and also did not show vascular enhancement or stenosis. CONCLUSION: VWI can be useful in the detection of vascular involvement in various viral infections of CNS which show a relatively higher cerebrovascular complication rate like varicella, HIV encephalopathy, and COVID-19. However, VWI may not be useful in the routine evaluation of other viral infections like herpes, dengue, and Japanese encephalitis, which have a very low rate of cerebrovascular complication rate.

Neuroimaging Spectrum of Severe Hypernatremia in Infants with Neurological Manifestations.

BACKGROUND: Variable neurological manifestations and imaging findings have been described in children with severe hypernatremia. We aimed to describe the spectrum of neuroimaging changes in infants with severe hypernatremia. METHODS: This retrospective study included infants with severe hypernatremia (serum sodium >160 mEq/L), abnormal neurological examination, and an abnormal magnetic resonance imaging (MRI) of the brain over a period of 2 years in a tertiary care hospital. Relevant clinical data, including the feeding practices, clinical features, complications, and biochemical and radiological parameters, were entered in a structured pro forma. MRI findings were classified as vascular (hemorrhages and cerebral sinus venous thrombosis), osmotic demyelination syndrome (pontine and extrapontine myelinolyses), and white matter changes. RESULTS: The common clinical features in the neonates were poor feeding (n = 4) and decreased urine output (n = 4); the older infants presented with gastrointestinal losses (n = 5). All cases had dehydration with encephalopathy. The patterns of radiological injury were vascular (hemorrhages, n = 5 and venous thrombosis, n = 3), osmotic demyelination (n = 8), and white matter changes (n = 7). Coagulopathy was correlated with the vascular complications (r = 0.8, p < 0.0001); the degree of dehydration was correlated with the venous thrombosis (r = 0.7, p < 0.04) and acute kidney injury (r = 0.8, p < 0.001). Neurological sequelae were seen in four cases and correlated with hypernatremia (r = 0.6, p = 0.03) and hyperosmolarity (r = 0.6, p = 0.03). CONCLUSION: Characteristic neuroimaging findings are vascular changes in the form of venous thrombosis and hemorrhages, osmotic demyelination and white matter tract injury, and/or mostly combinations of these findings. Severe hypernatremia and resulting hyperosmolarity frequently cause neurological sequelae in neonates and infants.

MR vessel wall imaging in tubercular meningitis.

PURPOSE: Tubercular meningitis (TBM) has the propensity to cause secondary vasculitis through various mechanisms leading to development of cerebrovascular complications. These vascular involvements can be detected by vessel wall imaging (VWI). In this study, we aimed to study detailed findings of vessel wall imaging in cases of tubercular meningitis. METHODS: All consecutive patients of suspected tubercular meningitis in whom diagnosis of TBM could be made according to diagnostic criteria given by Ahuja et al. were included in the study. High-resolution MR VWI and time of flight (TOF) magnetic resonance angiography (MRA) were done along with routine MRI sequences. Arteries up to second-order branches were studied, and statistical analyses were done with respect to stage of tubercular meningitis, infarctions and TOF MRA findings. RESULTS: Out of all 101 cases of TBM, infarctions were found in 49 cases (48.5%), and vessel wall enhancement was seen in 67 cases (66.3%). With increasing severity of disease, more severe vascular involvement was seen on VWI. There was significant association between enhancement of individual arteries and infarctions in their territories. VWI had better sensitivity than the MRA, while MRA had better specificity than VWI for detection of vascular complications. CONCLUSION: Tubercular vasculitis can be detected by VWI in the form of nodular or smooth segmental enhancement of vessel wall with or without stenosis. Incorporation of VWI in routine MR imaging can play a greater role in early detection and management of cerebrovascular complications which can help to improve prognosis of the disease.

Primitive Neuroectodermal Tumor in a Child with Human Immunodeficiency Virus Infection: A Rare Association.

Children with human immunodeficiency virus (HIV) infection are reported to have various malignancies, most common being Non-Hodgkin lymphoma. Despite higher risk of malignancies, brain tumors are infrequently described in these children. We report Primitive Neuroectodermal tumor (PNET) in a young boy with HIV infection. PNET has never been described in association with HIV infection. Though a causative association cannot be established, it does emphasize that with longer survivals on effective antiretroviral therapy, we may see a wide range of malignancies more frequently.

Percutaneous glue embolization as a primary treatment for visceral pseudoaneurysms.

Aim: To evaluate the feasibility and outcome of percutaneous glue embolisation as primary treatment for pseudoaneurysms in selective patients.Material and methods: A review of the pseudoaneurysm cases managed with percutaneous glue at our institute was analyzed in this study. A total of 21 patients over a period of last one year who were treated for pseudoaneurysm at varied sites primarily with percutaneous n-butyl cynoacrylate were retrospectively evaluated. Site of pseudoaneurysm was Pulmonary (seven cases), renal (four cases), pelvic (4four cases) and miscellaneous abdomen (six cases). Combined ultrasound and fluoroscopy approach was used in 17 cases, CT guidance in three cases and combined ultrasound and CT guidance in one case. Patients were evaluated for therapeutic response (radiological and clinical) and procedure related complications.Results: Complete occlusion of the pseudoaneurysm was seen in all patients. Two patients showed mild pneumothorax and one patient showed reflux into the intercostal artery. All the patients showed symptomatic improvement and discharged in stable condition.Conclusions: Percutaneous glue embolisation of the pseudoaneurysms as a primary treatment is feasible and can be safely carried out in select group of patients with good therapeutic response and minimal complications.

Perfusion magnetic resonance imaging in differentiation of neurocysticercosis and tuberculoma.

PURPOSE: Tuberculoma and neurocysticercosis (NCC) are two of the most common intracranial infections in developing countries and cause of seizures or focal neurological deficit. They often present on neuroimaging as ring-enhancing lesions, and in absence of typical imaging features, can cause significant diagnostic dilemma. Differentiation is extremely important to avoid empirical exposure to anti-tubercular treatment or nonspecific treatment causing disease progression. The aim our study was to evaluate the MR perfusion characteristics of brain tuberculoma and NCC and to assess the potential role of the perfusion in differentiating the two entities. METHODS: Fifty untreated patients (20 tuberculoma and 30 NCC) were prospectively evaluated by using conventional imaging and dynamic susceptibility contrast (DSC) MR perfusion. Relative cerebral blood volume (rCBV) values were calculated from the wall and core of the lesion and were compared with contralateral normal white matter. RESULTS: rCBV values from the wall of the lesion were significantly different in tuberculoma and NCC (P < 0.05). Tuberculomas showed high mean rCBV values than NCC (3.3 and 1.3 respectively). The core of these lesions showed lower rCBV values in both the lesions which were lower than normal white matter. A cutoff value of rCBV from the wall of the lesion 1.965 for tuberculoma showed 90% sensitivity and 100% specificity. CONCLUSION: Perfusion MRI in combination with conventional sequences can better characterize and differentiate similar-appearing tuberculoma and NCC and may be incorporated in routine protocol which may help in avoiding brain biopsy and empirical therapy.

Isolated Congenital Absence of Cranial Nerves: Report of Two Cases.

Isolated cranial nerve absence is a rare condition that can be diagnosed using high-resolution cranial nerve magnetic resonance (MR) imaging. Thorough clinical examination with proper knowledge of the course of cranial nerves may help diagnose this rare condition. We describe two cases, one each of, isolated congenital absence of the third and seventh cranial nerve with their clinical presentation. High-resolution T2-weighted MR imaging was done in both patients which revealed absence of cisternal segment of the right-sided third nerve and cisternal with canalicular segment of the right-sided facial nerve.

Tuberculous meningitis: Challenges in diagnosis and management: Lessons learnt from Prof. Dastur's article published in 1970.

It has been approximately five decades since Dastur et al., published their seminal work on pathology of tuberculous meningitis (TBM). Though most of their findings find relevance in today's era, there is an important difference; these findings can now be replicated during life using modern day technology. In this article, we review the seminal words of Professor Dastur and colleagues, analyse their findings, interpret how these revolutionized our understanding of TBM and highlight their relevance in today's era. We also discuss challenges in the management of TBM, which we continue to face today and the various options required to overcome these challenges.

Endovascular management of internal carotid artery pseudoaneurysms: A single-centre experience of 20 patients.

BACKGROUND: Pseudoaneurysms (PSAs) of the internal carotid artery (ICA) are uncommon lesions. Various surgical and endovascular options are available for the management of these lesions. We describe our experience in using a spectrum of endovascular management strategies for ICA-PSA and present their outcome. AIMS: To evaluate the role and efficacy of endovascular intervention in the management of ICA PSA. MATERIALS AND METHODS: The clinical and angiographic data of 20 ICA PSAs from January 2008 till July 2016 were reviewed retrospectively. A meticulous evaluation of all the patients regarding their clinical symptoms, imaging findings (Ultrasound Doppler/CTA/MRI) and the endovascular techniques was performed. Clinical and imaging follow up for at least 1 year was also assessed. RESULTS: There were 15 (75%) male and 5 (25%) female patients, with their age ranging from 11 months to 60 years. Eleven patients (55%) were of the paediatric age group. PSAs were seen in the cervical ICA in 12 patients (60%) and in the intracranial ICA in 8 patients (40%). The most common causes of PS formation were iatrogenic (n = 8), followed by trauma (n = 7), and infection (n = 5). Parent artery occlusion was performed in 10 patients (50%), stenting in 7 patients (35%), and PSA coiling in 3 patients (15%). Immediate and complete obliteration of the PSAs was achieved in all cases without any major procedural complication. Recurrence was diagnosed at 2 years, in one patient who had undergone parent artery occlusion. This was successfully retreated. None of our patients had immediate or delayed major neurological deficits. CONCLUSIONS: Endovascular treatment provides a safe and minimally invasive management option in patients with ICA PSA. It helps in the prevention of rupture of the PS and also its thromboembolic complications.