Epilepsia partialis continua revealing idelalisib-associated PML-IRIS: clinical and pathological features.

Idelalisib, a selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is a newly approved second-line drug for patients with chronic lymphocytic leukemia. Recent clinical trials have suggested a possible association between idelalisib treatment and development of progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus (JCV) reactivation. Nevertheless, clinical course and radiological and pathological features of idelalisib-induced PML still need to be clarified. We provide here the first clinicopathological description of idelalisib-associated PML in a patient who developed epilepsia partialis continua (EPC) as the first manifestation of the disease. Since EPC could present without electroencephalogram alterations, it is crucial to recognize the clinical features of this epileptic condition. EPC is characterized by the presence of repetitive, irregular, clonic jerking, often associated with hemiparesis and involvement of distal rather than proximal muscle groups. Moreover, we highlight the importance of brain biopsy in selected cases when there is a high clinical suspicion of PML, despite negative JCV testing in the cerebrospinal fluid. The pathological finding of prominent inflammatory infiltrate observed here was consistent with a diagnosis of immune reconstitution inflammatory syndrome (IRIS). IRIS is often associated with PML as a paradoxical worsening of clinical symptoms due to an overreacting immune response, in the context of previous immunosuppression. The unprecedented pathologic observation of IRIS in idelalisib-associated PML provides further insights into the pathogenesis of this rare neurological side effect.

Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients' Plasma.

The pathogenesis of cerebral small vessel disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study, we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from three groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormalities at MRI scanning); BDs (blood donors). Human Brain Endothelial Cells 5i (HBEC5i) were treated with plasma and total RNA was extracted. RNAs were pooled to reduce gene expression-based variability and NGS analysis was performed. Differentially expressed genes were highlighted comparing PTs, CTRLs and BDs with HBEC5i untreated cells. No significantly altered pathway was evaluated in BD-related treatment. Regulation of p38 MAPK cascade (GO:1900744) was the only pathway altered in CTRL-related treatment. Indeed, 36 different biological processes turned out to be deregulated after PT treatment of HBEC5i, i.e., the cytokine-mediated signaling pathway (GO:0019221). Endothelial cells activate inflammatory pathways in response to stimuli from CSVD patients' plasma, suggesting the pathogenetic role of neuroinflammation from the early asymptomatic phases of cerebrovascular disease.

Amplifying the spectrum of SPAST gene mutations.

Hereditary spastic paraplegias (HSPs) include a group of neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities, caused by axon degeneration of corticospinal tracts. Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant form of HSP and is caused by mutations in the SPAST gene. SPAST gene encodes for the protein spastin, a member of the ATPases Associated with a variety of cellular Activity (AAA) family.We describe a newly variant in SPAST gene, within an Italian family affected by pure HSP. In particular, we found a heterozygous intragenic microdeletion of 3T in exon 13 of SPG4 gene. The 3T deletion results in a mutated protein with a unique leucine residues deletion at the protein position 508, in the AAA ATPase domain. This variant is not registered in any public database either as rare normal variant nor as mutation in SPAST gene and the importance of this aminoacid is confirmed by the absolute conservation in multiple alignments with diverse species. We conclude that the novel SPAST gene variant identified is probably pathogenic and destabilizes the precise arrangement of the nucleotide binding domain, with a consequent loss-of-function of the mutated spastin protein.

ADMA as a possible marker of endothelial damage. A study in young asymptomatic patients with cerebral small vessel disease.

Sporadic small vessel disease (SVD) has high prevalence in aging population and stroke patients, but also in younger asymptomatic subjects. In this last group it can represents a prelude to stroke and cognitive impairment. Still nowadays, its pathogenesis is unclear. 35 consecutive patients with SVD at brain MRI and 35 age- and sex-matched controls, between January 2016 and February 2018, underwent an extended screening for thrombophilia, autoimmunity and evaluated levels of blood markers of inflammation and endothelial activation. Asymmetric DiMethyl Arginine (ADMA) levels proved higher in patients (70.44 ± 36.25 ng/ml vs. 46.58 ± 30.67 ng/ml; p = 0.004), also after controlling for confounding factors. ADMA levels showed positive correlation with Fazekas score (r = 0.304; p = 0.01). ROC curve analysis showed a moderate accuracy in discriminating patients and controls (AUC = 0.70; CI 0.57-0.82; p = 0.004): a cut-off of 46 ng/ml is associated with 80% sensitivity, but limited (54%) specificity. Higher ADMA levels characterize selected subjects with sporadic SVD, asymptomatic for vascular diseases and without latent inflammatory conditions or coagulopathy. This reinforces the hypothesis of the key role of endothelial dysfunction in SVD. Further studies should explore the cause-effect relationship between ADMA pathway and SVD.

Electroencephalographic Evaluation for Early Diagnosis of Limbic Encephalitis.

Limbic encephalitis (LE) is an inflammation of structures of limbic system. It may be an autoimmune disease or secondary to a neoplasia. Onset is subacute within a few weeks and clinical presentation is characterized by behavioral changes, psychiatric symptoms, short-term memory loss, and epileptic seizures. Diagnosis is typically set after a magnetic resonance imaging (MRI) scan, revealing hyperintensity in limbic structures on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences or detection of antineuronal antibodies; EEG aspecific alterations on temporal areas usually match with MRI and laboratory findings. Specific diagnostic criteria are still under debate. We describe a case presenting with EEG alterations before MRI ones.A 36-year-old woman came to our attention for a first generalized tonic-clonic seizure, several episodes of likely epigastric auras and memory loss. Her clinical history was unremarkable. Neurological examination and brain MRI with gadolinium were normal. Electroencephalographic (EEG) recordings showed theta activity and sharp elements in frontotemporal regions. Therapy with levetiracetam 1000 mg/day was started, but she had another generalized seizure and episodes of epigastric auras increased to 10 per day. After 2 months, another cerebral MRI revealed areas of swelling and signal alteration in deep left temporal areas, especially in hippocampal and parahippocampal gyrus. A spectroscopic evaluation revealed decreased N-acetyl aspartate peak and increased choline and myo-inositol peaks in left frontotemporal areas. These findings were consistent with LE. Cerebrospinal fluid (CSF) analysis was normal; viral serology and onconeuronal antibodies on CSF and blood were negative. Patient was treated with high-dosage steroids, with improvement in memory, epileptic seizures and auras. A third MRI revealed no signal alterations.In conclusion, the clinical picture initially did not meet accepted diagnostic criteria for LE. Effective steroid therapy was consequently delayed. With this case report we would emphasize diagnostic relevance of EEG alterations early in suspected LE in order to start immunosuppressive therapy as soon as possible.