Severe Central Nervous System Involvement Research Articles

P44 An acutely unwell and rare presentation of systemic lupus erythematosus; a case report

Abstract Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement. The condition has varying clinical presentations from mild mucocutaneous manifestations to severe multiorgan and central nervous system involvement. It is challenging to diagnose someone with SLE during acute admission. Apart from infection and malignancies, autoimmune and connective tissue diseases should always be one of our differentials in an acutely unwell patient with multisystem involvement. This case demonstrates how unwell and rare a patient with SLE can present. We also acknowledge the need to further understand and raise awareness of this uncommon condition. Case description A 48 year old Thai lady with no known medical illness presented with 2-3 weeks history of viral like illness. On admission, she was tachycardic, hypotensive and hypoxic. Clinical examination revealed bi-basal crepitations and elevated JVP. Her ECG showed sinus tachycardia. Admission bloods showed anemia, raised white cell count, lymphopenia, thrombocytopenia, raised inflammatory markers and acute kidney injury (AKI). CT scan revealed evidence of pericardial effusion with small free fluid in abdomen and pelvis. ECHO showed large pericardial effusion and pericardiocentesis was performed which drained purulent fluid. Blood culture was positive for E. Coli. 3rd Day blood tests were strongly positive for CTD screening. She was reviewed by the rheumatology team and was diagnosed as acute presentation of SLE causing serositis having fulfilled the SLICC criteria with E. Coli bacteremia. SLE DAI – 2K score was 11. She reported history of Raynaud’s since moving to UK, hair loss and two miscarriages in the past. She denied history of oral ulcers, facial rash or significant joint involvement. Renal team advised that AKI was due to infection rather than lupus. She was commenced on high dose oral prednisolone (40 mg/day) and antibiotics. Her condition responded to steroids and subsequently was commenced on mycophenolate as outpatient. Discussion SLE is an autoimmune disease that affects multiple organ systems. Symptoms and signs can vary although majority of patients present with cutaneous manifestation. Most of the clinical manifestations of the disease are due to abnormal inflammatory response. Patients with SLE are usually diagnosed at outpatient settings although they can present acutely unwell as seen in this patient. Serositis refers to inflammation of serous tissue which includes pleura, pericardium and peritoneum. It is considerably a rare condition which is only seen in only around 10% of patients with SLE. Patients can present with shortness of breath, abdominal pain, diarrhoea, fatigue chest pain and even cardiac tamponade. Due to the heterogeneity of SLE presentations, it is challenging for clinicians to diagnose and manage the symptoms. Besides infection and malignancies, it is always important to consider connective tissue disease as one of the differentials in an acutely unwell patient presenting with multisystem involvement. SLICC criteria can be used as a diagnosing tool for SLE which includes clinical and immunological criteria. SLEDAI-2K score can be used to assess disease activity. Her biochemical parameters as well as clinical symptoms drastically improved following steroid initiation. Early recognition and treatment initiation can improve mortality and morbidity significantly. Despite how unwell she was during admission; she improved quickly and was discharged relatively early. Her condition continues to improve on DMARDs, and she is on regular clinic follow up. Key learning points • A good clinical history and examination is essential and aids reaching a diagnosis. As reflected in this case, our patient was a female at childbearing age, south Asian (non-Caucasian ethnicity) who presented with multisystem involvement. Her initial finding of serositis, acute kidney injury, anemia, raised ESR and E. coli bacteremia were not fitting with a typical sepsis picture. There should be strong grounds for considering SLE during such clinical presentations. Suspecting SLE in an acute setting is really challenging due to various reasons, like wide symptomology of SLE, minimal exposure of SLE to physicians and their tendency of leaning towards other common conditions, like sepsis. As SLE is mostly diagnosed as outpatient, inpatient presentations are rare. Furthermore, blood results for connective tissue disease which is a major criteria for diagnosis, can take between 3 to 5 working days to be reported. However, early and appropriate consideration of autoimmune conditions as differentials of an acutely ill patient with multisystem involvement can expedite the process of diagnosis, involvement of related specialty and commencement of appropriate treatment. This approach will benefit patients producing favourable outcomes and minimal hospital stay.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease

IntroductionThe standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. MethodWe identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. ResultsAll six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DiscussionAmong a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Central nervous system manifestations of monogenic autoinflammatory disorders and the neurotropic features of SARS-CoV-2: Drawing the parallels.

Central nervous system (CNS) involvement in monogenic autoinflammatory disorders (AID) is increasingly recognized and can be life threatening. Therefore, a low threshold to consider CNS disease should be maintained in patients with systemic inflammation. Hyperinflammation is also a key feature of severe acute COVID-19 and post COVID-19 entities such as multisystem inflammatory syndrome in children. Like AID, COVID-19 patients can present with severe CNS involvement. The impact of COVID-19 on AID and CNS involvement in particular is still obscure, nevertheless dreaded. In the current review, we synthesize the spectrum of CNS manifestations in monogenic AID. We explore common pathophysiological and clinical features of AID and COVID-19. Moreover, we assess the impact of immune dysregulation associated with SARS-CoV-2 infections and post COVID-19 hyperinflammation in AID. The striking commonalities found between both disease entities warrant caution in the management of AID patients during the current pandemic.

Exosomes as Crucial Players in Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects multiple systems. Its clinical manifestation varies across patients, from skin mucosa to multiorgan damage to severe central nervous system involvement. The exosome has been shown to play an important role in the pathogenesis of autoimmune diseases, including SLE. We review the recent knowledge of exosomes, including their biology, functions, mechanism, and standardized extraction and purification methods in SLE, to highlight potential therapeutic targets for SLE.

Ocular involvement in STEC-associated hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a systemic thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and variable kidney involvement. Extrarenal thrombotic microangiopathy occurs in central nervous system (CNS), colon, and other organ systems, but ocular involvement is rarely recognized. This study aimed to analyze frequency and severity of ocular involvement in STEC-HUS, and the relationship between ocular involvement and disease severity, with emphasis on CNS, kidney, and colonic disease. Prospective, longitudinal, observational study. STEC-HUS patients September 2014-January 2019. Funduscopic examination (FE) was performed within 48h of admission. We evaluated severity of CNS disease, kidney involvement, and presence of hemorrhagic colitis (HC). Ninety-nine patients were included (female 52), mean age 39.4months (DE: 29.8; range 9-132). Thirteen patients (13.1%) had abnormal FE, 10 showing variable degrees of hemorrhagic exudates and 2 with typical Purtscher-like retinopathy. Other findings included tortuous vascularity, cotton wool spots, and transient retinal edema. CNS involvement was present in 16/99 patients, severe in 12 (75%). Abnormal FE occurred in 5/12 (31%) patients with severe CNS involvement vs. 8/87 (9.2%) with mild, moderate, or no CNS disease (p = 0.0191). Abnormal FE was present in 2/33 (6%) patients without dialysis vs. 11/66 (16.6%) requiring dialysis (p = 0.20). Finally, there were FE abnormalities in 6/20 patients with HC vs. 7/79 without HC (p = 0.012). FE abnormalities were present in 13% of HUS patients. Abnormal FE significantly associated with more severe disease, including severe CNS involvement and HC. We suggest FE should be performed in severe HUS, especially in cases with severe CNS disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical significance of cerebrospinal fluid soluble CD25 in pediatric hemophagocytic lymphohistiocytosis with central nervous system involvement.

To analyze the clinical significance of soluble CD25 (sCD25) levels in cerebrospinal fluid (CSF) in pediatric hemophagocytic lymphohistiocytosis (HLH) with central nervous system (CNS) involvement. All patients diagnosed with HLH admitted to Beijing Children's Hospital, Capital Medical University between January 1, 2017 and October 31, 2021 who received a measurement of their HLH-related parameters and CSF sCD25 levels at admission were enrolled in this study. CSF sCD25 levels in patients with primary HLH were higher than those in patients with Epstein-Barr virus infection-associated HLH, and the median level was 444pg/ml. The difference in CSF sCD25 levels between the non-CNS group and the CNS group was statistically significant (591 [259-33,643] pg/ml vs. 123 (36-437) pg/ml, p<.001). The best cutoff value of CSF sCD25 was 273.5pg/ml (AUC = 0.987, 95% CI: 0.972-1.000), with sensitivity, specificity, positive predictive values, and negative predictive values of 96.4%, 92.8%, 81.8%, and 98.7%, respectively. CSF sCD25 in the severe CNS involvement group was significantly higher than that in the nonsevere CNS involvement group (p=.014). The 3-year overall survival (OS) of patients with high CSF sCD25 levels was lower than that of patients with low CSF sCD25 levels(71.6% ± 8.1% vs. 93.3% ± 2.9%, hazard ratio [HR] = 3.637, p=.003). Increased CSF sCD25 levels in active disease can predict CNS-HLH. Primary HLH has a higher CSF sCD25 level than Epstein-Barr virus infection-associated HLH. Patients who are diagnosed with CNS-HLH with CSF sCD25 levels higher than 273.5pg/ml are more likely to develop severe CNS involvement, suggesting a poor prognosis.

Meningo-Encephalitis due to Spotted Fever Group Rickettsia––A Rare Case Report with Serial Follow up MRI

Spotted fever group (SFG) Rickettsial infection has rarely been reported to develop severe central nervous system involvement. We report a case of meningoencephalitis presenting with fever, headache, drowsiness, seizures, and a skin rash, showing ELISA IgM positivity to SFG Rickettsia group. MRI brain showed multifocal bilateral asymmetric patchy areas of T2W/FLAIR hyperintensity with significant diffusion restriction. Treatment with doxycycline resulted in clinical & radiological improvement. Rickettsial meningoencephalitis is a relatively under-diagnosed entity, probably due to the low index of suspicion and the lack of definitive diagnostic facilities in developing countries. This case was presented to highlight the importance of clinical suspicion mainly in endemic areas, the potential severity of the disease, and the need of early initiation of therapy to prevent mortality and long term neurological morbidity.

Neurocognitive deficits and sequelae following severe hand, foot, and mouth disease from 2009 to 2017, in JiangSu Province, China: a long-term follow-up study

BackgroundThe aim of this study was to evaluate the long-term sequelae and cognitive profiles resulting from severe hand, foot, and mouth disease (HFMD) with central nervous system (CNS) involvement. Methods294 HFMD cases were included in a retrospective follow-up study. Physical examinations were conducted. The Chinese Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was used to assess intelligence. Results58 mild HFMD cases and 99 severe HFMD cases with mild CNS involvement did not present any neurological sequelae. In comparison, the sequelae incidence for severe HFMD with more severe CNS complications was 50.0%. The proportion of full-scale intelligence quotient (FSIQ) impairment was 45.0%. In the 2:6–3:11 age group, severe HFMD with more severe CNS complications and lower maternal education level were risk factors for verbal comprehension disorder. Urban–rural residence and lower paternal education level were risk factors for FSIQ disorder. Furthermore, in the 4:0–6:11 age group, severe HFMD with more severe CNS complication was a risk factor for visual spatial disorder and fluid reasoning disorder. Lower paternal education level was a risk factor for FSIQ disorder. ConclusionEarly assessment and intervention among severe HFMD patients with more severe CNS involvement at a very young age will prove beneficial for their future performance.

Focal Seizures and Posterior Reversible Encephalopathy Syndrome as Presenting Signs of IgA Vasculitis/Henoch-Schoenlein Purpura-An Educative Case and Systematic Review of the Literature.

Background: IgA vasculitis/Henoch-Schoenlein purpura (IgAV/HSP) is a systemic small vessel vasculitis of unknown pathogenesis predominantly affecting children. While skin, GI tract, joints, and kidneys are frequently affected and considered, central nervous system (CNS) involvement of this disease is underestimated.Methods: We provide a case report and systematically review the literature on IgAV, collecting data on the spectrum of neurological manifestations.Results: We report on a 7-year-old girl with IgAV who presented with diplopia and afebrile focal seizures, which preceded the onset of purpura. Cranial magnetic resonance imaging was consistent with posterior reversible encephalopathy syndrome (PRES), showing typical focal bilateral parietal swelling and cortical and subcortical high signal intensities on T2-fluid attenuated inversion recovery (FLAIR) images predominantly without diffusion restriction. Cerebrospinal fluid analysis and blood tests excluded systemic inflammation or vasculitis. Interestingly, hypertension was not a hallmark of the developing disease in the initial phase of PRES manifestation. Renal disease and other secondary causes for PRES were also excluded. Supportive- and steroid treatment resulted in restitution ad integrum. Reviewing the literature, we identified 28 other cases of IgAV with CNS involvement. Severe CNS involvement includes seizures, cerebral edema, or hemorrhage, as well as PRES. Thirteen patients fulfilled all diagnostic criteria of PRES. The mean age was 11.2 years (median 8.0, range 5-42 years), with no reported bias toward gender or ethnic background. Treatment regimens varied from watchful waiting to oral and intravenously steroids up to plasmapheresis. Three cases showed permanent CNS impairment.Conclusion: Collectively, our data demonstrate that (I) severe CNS involvement such as PRES is an underappreciated feature of IgAV, (II) CNS symptoms may precede other features of IgAV, (III) PRES can occur in IgAV, and differentiation from CNS vasculitis is challenging, (IV) pathogenesis of PRES in the context of IgAV remains elusive, which hampers treatment decisions. We, therefore, conclude that clinical awareness and the collection of structured data are necessary to elucidate the pathophysiological connection of IgAV and PRES.

Successful rescue of a lethal Griscelli syndrome type 2 presenting with neurological involvement and hemophagocytic lymphohistiocytosis: a case report

BackgroundGriscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in RAB27A gene. It is primarily characterized by a combination of partial albinism, hemophagocytic lymphohistiocytosis (HLH) or other immunodeficiency. However, neurological involvement at onset in GS2 and treatment has rarely been described.Case presentationWe describe a 3-year-old boy with GS2 in an Asian Chinese family. He presented with progressive neurological abnormalities following unremitting fever at onset. He developed HLH during the clinical course. A novel homozygous mutation (c.1 A > G) in RAB27A gene was subsequently identified. He was then treated by HLH-1994 protocol combined with ruxolitinib and experienced a dramatic remission. He subsequently underwent a successful haploidentical hematopoietic stem cell transplantation and stayed at a good condition.ConclusionsWe reported an atypical form of GS2 manifesting as severe central nervous system involvement at onset and subsequent HLH, which was successfully rescued in time. This case also highlights the need for early consideration of immunologic and genetic evaluation for HLH in unexplained neuroinflammation in the diagnostic work up.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

Letter: May Cooler Heads Prevail During a Pandemic: Stroke in COVID-19 Patients or COVID-19 in Stroke Patients?

To the Editor: Along with the novel coronavirus (COVID-19) pandemic comes a growing public fear of its severe complications and possible central nervous system involvement.1 Neurointerventionalists in COVID-19 prevalent regions raised an alarm toward an increased risk of acute large-vessel-occlusion stroke in COVID-19 patients. It has been proposed that large-vessel stroke could be the presenting symptom of COVID-19 in younger patients.2 This has brought upon heightened fear and anxiety among younger adults. Yet, the scientific literature lacks evidence supporting a higher risk of stroke with COVID-19 in mildly symptomatic patients, or providing a causal link between COVID-19 and large-vessel stroke in younger adults. Systemic inflammation that may occur after severe COVID-19 infection promotes a prothrombotic state that may predispose to thrombotic events, including stroke. However, stroke as the presenting complaint of COVID-19 patients with otherwise mild or no systemic disease raises concerns over COVID-19 being a bystander given its high prevalence in reporting regions.2 In a report of 5 patients younger than 50 yr, 2 of whom were underscored for having no stroke comorbidities, stroke was described as a presenting symptom of young COVID-19 patients.2 This led to a robust news coverage to alarm young healthy adults of stroke secondary to COVID-19. We find this alarm unfounded. Stroke is less common, but not rare, in young adults. The findings presented remain anecdotal and lack the methodological and statistical rigor to claim that COVID-19 infection increases stroke risk in the youth or that stroke could be the presenting symptom of COVID-19. In fact, our Stroke Thrombectomy and Aneurysm Registry reports that 12% of 5000 patients undergoing thrombectomy are younger than 50 yr.3,4 Of young adults, 47% had no stroke comorbidity. Similarly, 8% of patients from the stroke thrombectomy trials were under 50 yr.5 Therefore, anecdotal reports of small case series of stroke in younger adults with COVID-19 do not reach the threshold, to date, to raise public fear among young adults. Although sounding early alarms during outbreaks may prevent delayed responses to novel threats, sufficient evidence is required to limit unnecessary burdens of the alarm itself on the healthcare system and public. Efforts to increase stroke awareness are always commended to avoid delay in patient presentation; however, in times of uncertainty and anxiety, it is critical to minimize misinformation that can have profound ramifications, even if it were well intended. Physicians are encouraged to seek sound medical evidence during care for patients and news appearances. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Human iPSC-Based Models for the Development of Therapeutics Targeting Neurodegenerative Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) are a group of rare genetic conditions. The absence or deficiency of lysosomal proteins leads to excessive storage of undigested materials and drives secondary pathological mechanisms including autophagy, calcium homeostasis, ER stress, and mitochondrial abnormalities. A large number of LSDs display mild to severe central nervous system (CNS) involvement. Animal disease models and post-mortem tissues partially recapitulate the disease or represent the final stage of CNS pathology, respectively. In the last decades, human models based on induced pluripotent stem cells (hiPSCs) have been extensively applied to investigate LSD pathology in several tissues and organs, including the CNS. Neural stem/progenitor cells (NSCs) derived from patient-specific hiPSCs (hiPS-NSCs) are a promising tool to define the effects of the pathological storage on neurodevelopment, survival and function of neurons and glial cells in neurodegenerative LSDs. Additionally, the development of novel 2D co-culture systems and 3D hiPSC-based models is fostering the investigation of neuron-glia functional and dysfunctional interactions, also contributing to define the role of neurodevelopment and neuroinflammation in the onset and progression of the disease, with important implications in terms of timing and efficacy of treatments. Here, we discuss the advantages and limits of the application of hiPS-NSC-based models in the study and treatment of CNS pathology in different LSDs. Additionally, we review the state-of-the-art and the prospective applications of NSC-based therapy, highlighting the potential exploitation of hiPS-NSCs for gene and cell therapy approaches in the treatment of neurodegenerative LSDs.

Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants

BackgroundNeurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined.MethodsWe assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV- and TNFRSF1A low-penetrance variants from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations.ResultsThe genetic distribution comprised 36 patients (23%) with NLRP3- and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in the MEFV gene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n = 51; 46%) followed by the Q703K NLRP3 variant (n = 15; 14%) and the E148Q substitution (n = 9; 8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n = 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n = 19, 43%) followed by NLRP3- (n = 17, 39%) and TNFRSF1A (n = 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p = 0.0228) and motor symptoms (p = 0.0455). Elevated acute-phase reactants were detected in all patients, and fever episodes were present in up to 50%. Arthralgias were the most frequently identified constitutional symptom among all subgroups.ConclusionsOur data highlight the high prevalence of neurological manifestations, including concomitant MS, among NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants. In particular, patients carrying the Q703K NLRP3 variant are at risk for severe CNS inflammation and CN affection.

FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome

BackgroundCharcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. ObjectivesTo analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. MethodsPhenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. ResultsNext generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. ConclusionThis study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

OAS1 gene polymorphism is associated with central nervous system involvement in children with enterovirus 71 infection

We investigated the association between OAS1 gene polymorphism and susceptibility to central nervous system (CNS) involvement of enterovirus (EV)71 infection. This case-control study was conducted among 180 children with EV71 infection, including 72 with mild infections without any complications and 108 with severe infections and CNS involvement; 201 children undergoing routine physical examination served as the healthy controls. For all the participants, the single nucleotide polymorphisms (SNPs) at OAS1 rs2660 and rs1131454 were analyzed using SNPscan multiple SNP typing methods. No significant differences were found between the case and control groups in genotype or allele distributions of rs2660 and rs1131454. OAS1 rs2660 polymorphism was significantly different between the children with CNS involvement and those with mild EV71 infection, and the genotype AG frequency was higher and the genotype GG frequency was lower in children with CNS involvement. No significant difference was found in the distribution of genotypes or alleles of rs1131454 between the children with CNS involvement and those with mild EV71 infection. OAS1 gene rs2660 and rs1131454 SNPs are not associated with the susceptibility to or CNS involvement of EV71 infection, but OAS1 rs2660 SNPs are significantly correlated with the susceptibility to CNS involvement in EV71 infection. Children carrying OAS1 rs2660 AG genotype are more likely to have CNS involvement after EV71 infection.

Kerosene, Camphor, and Naphthalene Poisoning in Children.

ABSTRACTKerosene poisoning is one of the most common accidental poisoning in children in developing countries due common use of kerosene in house-hold and unsafe storage practices. Aspiration pneumonitis is the most common manifestation of kerosene ingestion due to its low viscosity, high volatility, and low surface tension. The treatment of aspiration pneumonitis due to kerosene poisoning is symptomatic including oxygen support, respiratory monitoring, and careful monitoring of fluid balance. Children with severe respiratory distress and hypoxemia unresponsive to supplemental oxygen and/or severe central nervous system involvement require early intubation and mechanical ventilation. Transfer to the pediatric intensive care unit (PICU) is required at this stage. Emesis, gastric lavage, and administration of activated charcoal are contraindicated due to risk of aspiration. There is no clear benefit of using corticosteroids or prophylactic antibiotics. Asymptomatic children should be kept under observation for atleast 6 hours after exposure. The mortality rate is low and death occurs due to pneumonitis. Camphor is used in house-hold items including vaporized or topical cold preparations, liniments, moth repellents, for performing rituals in religious ceremonies, and in antimicrobial preparations. Camphor poisoning is not very common in childhood. Even small doses of camphor can cause serious toxicity and is potentially fatal. The onset of action is very rapid (5–15 minutes). The common manifestations are confusion, restlessness, delirium, and hallucinations, muscle twitching, myoclonus, ataxia, hyperreflexia, fasciculations, and seizures. Seizures are common and serious complication in camphor toxicity. The treatment is supportive including decontamination, gastric lavage, activated charcoal, and seizure control. Naphthalene is a major constituent of mothballs which are commonly used in household to protect clothes from moths. Though the poisoning with naphthalene is uncommon in children, most of the cases with naphthalene poisoning occur in developing countries where mothballs are still commonly used. The manifestations of naphthalene toxicity are predominantly due to acute intravascular hemolysis leading to anemia, hemoglobinuria, methemoglobinemia, and acute kidney injury (AKI). The treatment of naphthalene toxicity is supportive in form of transfusion of the packed red blood cells, monitoring of fluid and electrolyte balance, administration of alkalis in presence of hemoglobinuria, and renal replacement therapy. Prevention is better than cure. The strategies should be adopted to prevent children being exposed to these toxic compounds in the house-hold. Safe storage of toxic compounds away from the reach of children, avoiding storing kerosene in cold drink and beverage bottles, community education, provision of electricity in rural areas, safe cooking practices, and parental supervision are important interventions to prevent accidental poisoning among children.How to cite this articleKumar S, Kavitha TK, Angurana SK. Kerosene, Camphor, and Naphthalene Poisoning in Children. Indian J Crit Care Med 2019;23(Suppl 4):S278–S281.

Polymorphisms in enterovirus 71 receptors associated with susceptibility and clinical severity.

ObjectiveTo evaluate the association of enterovirus 71 (EV71) susceptibility and clinical severity with polymorphisms in EV71 receptors, including human scavenger receptor class B member 2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), and annexin II (ANXA2).MethodsWe enrolled laboratory-confirmed EV71 cases and healthy age- and gender-matched controls in Taiwan from 2000 to 2012. We detected genetic polymorphisms in SCARB2, PSGL-1, and ANXA2 and correlated the results with EV71 susceptibility and severity.ResultsWe collected 599 EV71 cases and 98 controls. Among EV71 patients, the male to female ratio was 1.61, and the mean age was 2.99±2.47 years. For clinical severity, 117 (19.6%) had severe central nervous system involvement with or without cardiopulmonary failure. For outcomes, 46 (7.7%) had sequelae, and 14 (2.3%) died. SCARB2 polymorphisms (rs6824953 and rs11097262) were associated with susceptibility to EV71 infection (OR 1.60, 95% CI 1.07–2.39; and OR 1.64, 95% CI 1.09–2.47, respectively). PSGL-1 polymorphisms (rs7137098 and rs8179137) were significantly associated with severe EV71 infection (OR 1.46, 95% CI 1.1–1.96; and OR 1.47, 95% CI 1.07–2.03, respectively).ConclusionsSCARB2 polymorphisms (rs6824953 and rs11097262) might be associated with EV71 susceptibility. PSGL-1 polymorphisms (rs7137098 and rs8179137) were associated with severe EV71 infection.

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement

Thrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC). TMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab. The great clinical variability of brain injury in our cohort has led us to retrospectively build a "neurological score" useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI). A "neurological score" may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

Characteristics and Outcomes of Patients with Systemic Lupus Erythematosus-associated Thrombotic Microangiopathy, and Their Acquired ADAMTS13 Inhibitor Profiles.

To investigate the characteristics and outcomes of patients with systemic lupus erythematosus (SLE)-associated thrombotic microangiopathy (TMA) based on their ADAMTS13 inhibitor profiles. The medical data of 31 SLE patients with clinically diagnosed TMA were analyzed. ADAMTS13 activity and ADAMTS13 inhibitor were measured in all patients. TMA was attributable to active SLE in 19 patients. ADAMTS13 inhibitor and severe ADAMTS13 deficiency were detected in 6 of them. Patients with ADAMTS13 inhibitor (n = 6) exhibited a lower platelet count (7.3 ± 5.1 vs 25.0 ± 17.8 × 109/l, p = 0.005) and more prevalent central nervous system (CNS) involvement (100.0% vs 23.1%, p = 0.003) than patients without ADAMTS13 inhibitor (n = 13). Patients with ADAMTS13 inhibitor also had mild renal involvement characterized by a higher estimated glomerular filtration rate (112.7 ± 18.0 vs 21.6 ± 12.0, p < 0.001), lower proteinuria level [0.6 (0.2-2.5) vs 8.1 (5.2-14.0) g/d, p = 0.011], and lower mean arterial pressure (95.3 ± 13.6 vs 117.5 ± 13.1 mmHg, p = 0.008) than was observed in patients without ADAMTS13 inhibitor. All patients with ADAMTS13 inhibitor achieved complete remission within 18.6 ± 8.7 days, while 3 patients (23.1%) without ADAMTS13 inhibitor achieved complete remission during a median followup of 5.0 months, even though more patients in this group received therapeutic apheresis (100.0% vs 50.0%, p = 0.021). The chance of complete remission increased by 10.8-fold (HR 10.8, 95% CI 1.8-65.5, p < 0.001) when ADAMTS13 inhibitor was present in SLE-associated TMA. Acquired ADAMTS13 deficiency is associated with more severe thrombocytopenia and CNS involvement, mild renal involvement, rapid resolution, and relatively good treatment response in SLE-associated TMA.