Many reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been ...given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition “Dark White Matter” (DWM) is more frequently associated with. This is the first systematic review on DWM.
PubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated.
56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data.
DWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.
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•Dark White Matter (Subcortical White Matter Hypointensity on T2/FLAIR) is frequently under-recognized.•This sign can exist alone and it is not merely a consequence of cortical involvement.•The most frequently DWM-associated condition was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma.•DWM has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment.•In the context of seizures DWM is highly indicative of NKH as the underlying disorder (in 51.4% of cases) followed by Encephalitis (in 26.4% of cases) mostly MOGAD.
Background
Many patients treated with Natalizumab experience wearing-off symptoms (WoS) towards the end of the administration cycle. During the pandemic we advised and asked patients undergoing ...treatment with Natalizumab if they wanted to be shifted from a standard interval dosing (StID of 4 weeks) to an extended interval dosing (ExID of 5–6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of WoS when ExID was adopted.
Methods
We enrolled 86 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on WoS, Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and MRI.
Results
Among the 86 patients, 32 (37.2%) reported WoS. Most common one was fatigue (93.7%). Mean EDSS was higher in the group reporting WoS (3.8 WoS vs 3.1 non-WoS,
p
< 0.05).
Sphincterial function
was the EDSS item that significantly differed between the WoS group and the non-WoS group (1.4 WoS vs 0.6 non-WoS,
p
< 0.001). WoS correlate with the FSS scale (
p
< 0.001).
Conclusion
Adopting an extended interval dosing does not result in significantly different occurrence of WoS between the ExID and the StID populations, in our cohort of patients. Interestingly, there is a strong correlation between WoS and a higher EDSS and FSS. Safety and efficacy of Natalizumab with ExID are relatively preserved in our study.
Background
Hereditary cranial hyperostosis is a rare disease never described in Italy, so the neurological manifestations in patients and carriers of the disease have been little studied.
Methods
We ...describe the neurological and neuroimaging features of patients and carriers of the gene from a large Italian family with sclerosteosis.
Results
In this family, genetic testing detected the homozygous p.Gln24X (c.70C > T) mutation of the SOST gene in the proband and a heterozygous mutation in 9 siblings. In homozygous adults, severe craniofacial hyperostosis was manifested by cranial neuropathy in childhood, chronic headache secondary to intracranial hypertension, and an obstructive sleep apnea syndrome in adults. In one of the adult patients, there was a compressible subcutaneous swelling in the occipital region caused by transosseous intracranial-extracranial occipital venous drainage, a compensation mechanism of obstructed venous drainage secondary to cranial hyperostosis. Mild cranial hyperostosis causing frequent headache and snoring was evident in the nine heterozygous subjects.
Conclusions
Multiple cranial neuropathies and headache in children, while severe chronic headache and sleep disturbances in adults, are the neurological manifestations of the first Italian family with osteosclerosis. It is reasonable to extend neurological and neuroimaging evaluation to gene carriers as well.
Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related ...toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.
•Functional genomic screens reveal SHMT2 as a drug target in BL, and SHMT2 inhibitors synergize with methotrexate to induce anti-BL effects.•SHMT2 inhibition disrupts the BL survival program by triggering autophagic degradation of TCF3 and a subsequent collapse of BCR signaling.
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Background Influence of tumor subtype, radiological sign and prognostic factors on tumor size discrepancies between DBT and final histology has not been completely investigated so far. Purpose To ...study the influence of tumor subtype, radiological sign and prognostic factors on tumor size discrepancies between digital breast tomosynthesis and final histology. Material and methods This is a retrospective study conducted between January 2015 and December 2016. After IRB approval, 130 consecutive patients with breast cancer diagnosed with digital breast tomosynthesis (DBT) were evaluated. A discrepancy between DBT and final histology was considered present if the difference was above the cut-off of 5 mm. Tumor subtype, radiological sign and prognostic factors were evaluated in patients with discrepancies. Descriptive statistic and non-parametric tests were used. Results A total of 105 cases of cancer, in 96 patients, all female, were included. Mean age was 61 years (range: 35-82 yrs). In 19 (18.1%) cases, discrepancies were found: 13 (68.4%) were underestimated by DBT. For tumor subtype, 10 (52.6%) were infiltrating lobular carcinomas (ILC) (p < 0.01). Fourteen (73.7%) discordant cases were architectural distortions (p < 0.01). Prognostic factors did not affect tumor size discrepancies. Conclusion ILC or an architectural distortion represents the majority of cases of tumor size discrepancies between DBT and final histology.
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