Novel partial deletions, frameshift and missense mutations of CSF1R in patents with CSF1R-related leukoencephalopathy.

BACKGROUND AND PURPOSE: Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: CSF1R mutations were identified in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C-terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. CONCLUSIONS: Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

Venous Sinus Stenting for Transverse Sinus Stenosis Associated with Leptomeningeal Carcinomatosis in a Patient with Epidermal Growth Factor Receptor-Mutated Lung Cancer: A Case Report.

BACKGROUND Cerebral venous sinus obstruction associated with leptomeningeal carcinomatosis is an extremely rare complication of advanced non-small-cell lung cancer. There is little information available on the efficacy of therapeutic options because of its rarity and extremely poor prognosis. CASE REPORT A 57-year-old man presented with severe headache, vomiting, and visual loss for 1 month. Head magnetic resonance venography (MRV) showed occlusion of the left transverse sinus. Gd-enhanced MRI showed no abnormal enhancement. Lumbar puncture intracranial pressure was higher than 40 cmH2O. Positive cerebrospinal fluid tumor cytology confirmed the diagnosis of leptomeningeal carcinomatosis (LC). The headache was relieved by repeated lumbar punctures, and ventriculo-peritoneal shunt was performed. Cerebral angiography showed severe stenosis of the left transverse sinus without thrombosis, and significant delay of cerebral circulation. The transverse sinus stenosis was judged to be contributing to raised intracranial pressure, and the patient underwent left transverse sinus stent placement. After the procedure, his visual acuity improved, the visual field was enlarged, and his headache could be controlled by medication. Follow-up Gd-enhanced MRI showed dural enhancement and spinal dissemination. Because molecular biology of the surgical specimen showed epidermal growth factor receptor (EGFR)-activating mutations, he was treated with osimertinib for 2 months. He survived for 8 months following the diagnosis of LC and left transverse sinus stenosis. CONCLUSIONS Venous sinus stenting can offer an effective palliative interventional option for symptom relief of severe headache and visual symptoms, even in the end stage of malignancy.

The relationship between progressive motor deficits and lesion location in patients with single infarction in the lenticulostriate artery territory.

As the corticospinal tracts cross the lenticulostriate artery (LSA) territory at the posterior segment, we hypothesized that posteriorly located infarctions of the LSA may be associated with progressive motor deficits. We prospectively studied 519 consecutive patients with LSA infarctions who entered our hospital within 24 h after onset. We categorized patients into two groups in terms of progress: no progress and progress. Progress was defined as worsening by 1 point or more in the National Institutes of Health Stroke Scale (NIHSS), some of which recovered afterward or thoroughly progressed. LSA infarctions on the first DWI were divided into proximal type and distal (group 1) type. The proximal type was further divided into anterior (group 2), intermediate (group 3) and posterior (group 4) type according to the middle point of antero-posterior diameter of the lateral ventricle. There were 109 patients who showed progress that accounted for 21.0% of all patients. The number of patients who progressed is as follows: distal type 65 (23.8%), anterior type 31 (36.0%), intermediate type 26 (56.5%) and posterior type 97 (85.0%). The Cochran-Armitage test showed a significant increase through group 1 to group 4 (p < 0.0001). Independent predictive factors for progress were male (OR 0.57, p = 0.0107), higher NIHSS on admission (≥4) (OR 3.02, p < 0.0001), intermediate proximal type (OR 3.3, p = 0.0007) and posterior proximal type (OR 16.4, p < 0.0001). The more posterior the infarct location, the more frequent was the progress that occurred, probably due to the anatomical fact that corticospinal tracts crossed the LSA territory at the posterosuperior quadrant.