Case Report: Interest of Positron Emission Tomography in Pediatric Small Vessel Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare inflammatory disease affecting central nervous system vessels. The diagnosis, which requires confirmation by brain biopsy, remains challenging due to unspecific clinical presentation and low specificity of imaging and laboratory exams. In these two pediatric biopsy-proven cases of svPACNS we demonstrate that brain positron emission tomography (PET) show a high metabolic activity that extends beyond brain MRI abnormalities. Therefore, combining MRI and PET abnormalities to adequately guide brain biopsy might increase the diagnostic yield of this rare condition.

Hippocampal sclerosis and epilepsy surgery in neurofibromatosis type 1: case report of a 3-year-old child explored by SEEG and review of the literature.

PURPOSE: Epilepsy associated with neurofibromatosis type 1 (NF1) is infrequent and usually controlled with anti-epileptic drugs. However, in some drug-resistant patients a presurgical evaluation should be considered. Hippocampal sclerosis (HS) is one of the rare causes of epilepsy in neurofibromatosis type 1, which can lead to surgery. METHODS: We present a three-year-old child with refractory epilepsy associated with several structural brain abnormalities but normal hippocampi on brain MRI and a heterozygous variant in the NF1 gene (c.2542G > A). A complete presurgical evaluation was performed including stereo-electroencephalography (SEEG). RESULTS: Usual seizures were recorded, and the seizure onset zone was delineated in the anterior hippocampus. Pathological examination performed after a tailored mesio-temporal resection confirmed hippocampal sclerosis, and the child achieved seizure freedom with 2 years of follow-up. CONCLUSION: This rare pediatric case illustrates that NF1 may be associated with early-onset refractory epilepsy secondary to MRI-negative HS, supporting the major role of SEEG in the presurgical evaluation of patients with extended cortical malformations.

Novel homozygous variant of carbonic anhydrase 8 gene expanding the phenotype of cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3.

We report the case of an 11-year-old Syrian girl born to consanguineous parents, who presents an ataxic gait from early childhood. On clinical examination, she presented a severe static - kinetic cerebellar syndrome, walking without support is possible for short distances only. Strikingly, three consecutive MRIs did not show any sign of cerebellar abnormalities, but a brain positron emission tomography (PET) using [18F]-fluorodeoxyglucose (FDG) demonstrated a clear decrease in glucose metabolism in the cerebellum as well as the anterior and medial temporal lobe bilaterally. A clinical exome analysis identified a novel homozygous c.251A > G (p.Asn84Ser) likely pathogenic variant in the carbonic anhydrase 8 (CA8) gene. CA8 mutations cause cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3 (CAMRQ3), a rare genetically autosomal recessive disorder, only described in four families, so far with the frequent observation of quadrupedal gait. The proband differed with other reported CA8 mutations by the absence of clear cerebellar signs on brain MRI and the presence of focal seizures. This report expands the clinical spectrum associated with mutations in CA8 and illustrates the possible discrepancy between (mild) neuro-radiological images (MRI) and (severe) clinical phenotype in young individuals. In contrast, the observation of clear cerebellar abnormal metabolic findings suggests that the FDG-PET scan may be used as an early marker for hereditary ataxia.

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING: European Union's Seventh Framework Programme; European Research Council.

Primary angiitis of the central nervous system: neurologic deterioration despite treatment.

Primary angiitis of the central nervous system (PACNS) is an idiopathic vasculitis confined to the central nervous system. In children with PACNS, small-vessel (SV) involvement is characterized clinically by progressive neurologic symptoms, multifocal lesions on brain imaging, occasional pseudo-tumor presentation, and normal angiogram results in most patients. Small case series of patients with SV PACNS with short follow-up usually reveal favorable outcomes in children treated with immunosuppressive therapy. We report here the cases of 3 children with biopsy-confirmed SV PACNS and long-term follow-up who developed different patterns of neurologic deterioration despite immunosuppressive therapy. One patient had transient ischemic attacks shortly after initiation of corticosteroid treatment. Early ischemic events probably result from residual thrombogenicity or residual inflammation of recently affected vessels, which supports the use of antiplatelet agents and suggests potential benefits of stronger immunosuppressive therapy. In contrast, the other 2 patients had later neurologic deterioration after corticosteroid withdrawal, which suggests failure of initial immunosuppressant treatment and the need for stronger agents, longer treatment duration, or both. All patients responded to long-term treatment with corticosteroids combined with cytotoxic agents. This particular combination is probably indicated in many cases of SV PACNS, including those with neurologic deterioration that occurs during maintenance corticotherapy or after corticosteroid withdrawal. In 1 case, SV PACNS recurred several years after discontinuation of combination therapy. Long-term relapses may reflect intrinsic predispositions to SV PACNS rather than treatment failure. These cases highlight different chronological patterns of neurologic deterioration despite immunosuppressive therapy, which supports the relevance of monitoring clinical, laboratory, and radiologic responses to treatment and of long-term follow-up of patients with SV PACNS.

Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Persistent hydrocephalus after early surgical management of posterior fossa tumors in children: is routine preoperative endoscopic third ventriculostomy justified?

OBJECT: The authors evaluate the incidence of persistent hydrocephalus after early surgical management of pediatric posterior fossa tumors and the indicators for routine preoperative endoscopic third ventriculostomy (ETV). METHODS: Between 1989 and 2004, 160 children with a posterior fossa tumor were treated at Erasme Hospital in Brussels, Belgium. Hydrocephalus was present at admission in 114 of the patients. Thirty-one patients had severe hydrocephalus (Evans index [EI] > 0.4). Twenty-four of these and the 83 patients with mild hydrocephalus (EI between 0.3 and 0.4) were treated with early posterior fossa surgery (Group 1; 107 patients). In this group, 93 patients underwent a total or subtotal tumor resection associated with external ventricular drainage (Group 1A), and 14 underwent a stereotactic biopsy associated with an ETV (Group 1B). The 53 remaining patients underwent elective posterior fossa surgery (Group 2). Early tumor resection (Group 1A) resolved hydrocephalus in 85 (91%) of 93 patients, whereas an ETV resolved intracranial hypertension in 11 patients (Group 1B). In Group 1, persistent hydrocephalus affected 11 (10%) of 107 patients, seven of whom had symptoms and were treated (three with shunts and four with ETVs). Persistent hydrocephalus was more frequent in children with severe preoperative hydrocephalus (p = 0.002) and with medulloblastomas (p = 0.0154). A total of 22 technically successful ETV procedures were performed. The ETV success rate for controlling hydrocephalus was 81% (18 of 22) and the rate of severe complications was 9% (two of 22). CONCLUSIONS: An ETV is an efficient procedure for controlling hydrocephalus associated with posterior fossa tumor. The authors confirm that a routine postoperative ETV is indicated for treating persistent hydrocephalus. For preventing it, however, they recommend early posterior fossa surgery whenever possible. The low rate of persistent hydrocephalus does not justify adopting routine preoperative ETVs.