Automated Brain Perfusion Imaging in Acute Ischemic Stroke: Interpretation Pearls and Pitfalls.

Recent advancements in computed tomography technology, including improved brain coverage and automated processing of the perfusion data, have reinforced the use of perfusion computed tomography imaging in the routine evaluation of patients with acute ischemic stroke. The DAWN (Diffusion Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) and DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trials have established the benefit of endovascular thrombectomy in patients with acute ischemic stroke with anterior circulation large vessel occlusion up to 24 hours of last seen normal, using perfusion imaging-based patient selection. The compelling data has prompted stroke centers to increasingly introduce automated perfusion computed tomography imaging in the routine evaluation of patients with acute ischemic stroke. We present a comprehensive overview of the acquisition and interpretation of automated perfusion imaging in patients with acute ischemic stroke with a special emphasis on the interpretation pearls, pitfalls, and stroke mimicking conditions.

Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients.

PURPOSE: Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. METHODS: A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. RESULTS: Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. CONCLUSION: This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.

The neuroimaging findings of monocarboxylate transporter 1 deficiency.

Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections. Patients with homozygous mutations are known to have a more severe phenotype with mild to moderate developmental delay and an increased prevalence of epilepsy. There is only one recent report of the neuroimaging findings of this disorder as reported by Al-Khawaga et al. (Front Pediatr. 7:299, 2019). We report the neuroimaging abnormalities in two siblings with similar clinical presentation of recurrent ketoacidosis, seizures, and developmental delay. Whole exome sequencing in the younger sibling confirmed a known pathogenic homozygous mutation in MCT1, also known as SLC16A1 gene. Brain MRI showed a similar very distinctive pattern of signal abnormality at the gray-white matter junction, basal ganglia, and thalami in both patients. Both siblings had agenesis of the corpus callosum. Knowledge of this pattern of brain involvement might contribute to an earlier diagnosis and timely management of this rare and under recognized disorder.

Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.

We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann-Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene.

Tectocerebellar dysraphia with occipital encephalocele: a phenotypic variant of the TMEM231 gene mutation induced Joubert syndrome.

There are few reported cases of tectocerebellar dysraphia with occipital encephalocele (TCD-OE) in the literature. This malformation was first described by Padget and Lindburg in 1972 and consists of an occipital encephalocele, a cerebellar midline defect, inverted cerebellum, and deformity of the tectum. Occurrence is believed to be sporadic with a male predominance and a usually poor prognosis. We report a patient with brain MRI findings compatible with tectocerebellar dysraphia and occipital encephalocele. Additional features consistent with Joubert syndrome including deepened interpeduncular fossa, as well as elongated, thickened, and anteroposteriorly oriented superior cerebellar peduncles, were noted. The patient's evaluation also revealed a homozygous mutation of the TMEM231 gene, known to cause Meckel-Gruber and Joubert syndromes. Our case represents the first reported genetic confirmation that tectocerebellar dysraphia with occipital encephalocele is not a distinct nosological entity but likely a phenotypic variation of Joubert syndrome.

Mucopolysaccharidoses: overview of neuroimaging manifestations.

The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have autosomal-recessive transmission with the exception of mucopolysaccharidosis II, which is X-linked. Each individual disorder has a wide spectrum of phenotypic variation, depending on the specific mutation, from very mild to very severe. The skeletal and central nervous systems are particularly affected. The typical clinical presentation includes organomegaly, dysostosis multiplex with short trunk dwarfism, mental retardation and developmental delay. In this article, we review the neuroimaging manifestations of the different types of mucopolysaccharidoses including the dysostosis multiplex of the skull and spine as well as the various central nervous system complications. These include white matter injury, enlargement of the perivascular spaces, hydrocephalus, brain atrophy, characteristic enlargement of the subarachnoid spaces as well as compressive myelopathy. The correlation between several of the neuroimaging features and disease severity remains controversial, without well-established imaging biomarkers at this time. Imaging has, however, a crucial role in monitoring disease progression, in particular craniocervical junction stenosis, cord compression and hydrocephalus, because this allows for timely intervention before permanent damage occurs.

Imaging features of mucopolysaccharidoses in the head and neck.

Ear, Nose and Throat (ENT) involvement by mucopolysaccharidoses is very common, affecting over 90% of patients, and occurs early in the course of the disease. Airway narrowing secondary to glycosaminoglycan deposition results in greatly increased morbidity, mortality and risk of anesthetic complications in these patients. Macroglossia, restricted mouth opening, tracheobronchomalacia, adenotonsillar hypertrophy along with other factors such as a short, rigid and unstable cervical spine, cardiac disease and increased susceptibility to respiratory infections result in a high perioperative mortality and morbidity. Imaging is most beneficial for evaluation of the airway, in particular in patients with obstructive symptoms and prior to intubation. We review the ENT manifestations of mucopolysaccharidoses including airway involvement, otological, oral and dental complications. 3-D reconstructions of the trachea, which is routinely captured on CT imaging of the spine, can be of great value for planning intubation in this patient population.

Diffuse necrotising leukoencephalopathy with microhaemorrhages in a patient with severe COVID-19 disease.

A wide range of neurological complications of coronavirus disease 2019 (COVID-19) is increasingly recognised. Although the majority of these remain ischaemic and haemorrhagic events, various disorders are being reported. In particular, several cases of diffuse acute leukoencephalopathy have been observed in critically ill patients with COVID-19 disease. We report the case of a 59-year-old man with multiple comorbidities and severe COVID-19 pneumonia who developed a diffuse leukoencephalopathy with microhaemorrhages and extensive associated white matter necrosis. Although this is the first documented case of extensive COVID-19-associated white matter necrosis, we highlight the relatively constant features of this injury similar to previously reported cases, including symmetrical involvement of the supratentorial white matter, sparing of the peripheral subcortical regions except in the precentral gyri, frequently associated microhaemorrhages, relative sparing of the deep gray matter structures and infratentorial structures, and lack of enhancement.

Recessive congenital methemoglobinemia type II: Hypoplastic basal ganglia in two siblings with a novel mutation of the cytochrome b5 reductase gene.

Recessive congenital methemoglobinemia type II is a very rare autosomal recessive hematologic disorder due to NADH-cytochrome b5 reductase deficiency, usually caused by full-stop mutations or deletions. This disease classically presents with mild neonatal cyanosis, early onset severe progressive developmental delay, movement disorders, and progressive microcephaly. We report two siblings with recessive congenital methemoglobinemia type II whose evaluation revealed a novel p.Arg92Trp missense mutation of the CYB5R3 gene and a peculiar imaging finding of basal ganglia hypoplasia. Brain magnetic resonance imaging was performed at age 10 months in the older sibling and at age three months in the younger sibling. It revealed similar findings of bilateral small size of the lentiform and caudate nuclei and reduced frontotemporal brain volume. Our patient cases highlight that basal ganglia hypoplasia is an interesting clue to the very rare and frequently unsuspected diagnosis of recessive congenital methemoglobinemia type II, that may explain the associated movement disorders. The novel missense mutation is one of very few identified missense mutations known to cause severe type II recessive congenital methemoglobinemia.