Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Objective: Many neurological manifestations are associated with COVID‐19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID‐19 patients. Cytokine storm is also associated with immune effector cell‐associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T‐cell (CAR‐T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID‐19‐related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings.Methods: Narrative literature review.Results: Comparisons between COVID‐19‐related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection‐associated encephalopathies.Interpretation: COVID‐19‐related encephalopathy and ICANS are characterized by a predominant electro‐clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm‐associated encephalopathy (CySE), and its diagnostic criteria.

Introduction: Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making.Methods: Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar.Discussion: Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month.There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated.Conclusion: Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine.Graphical

Background: Medication overuse headache significantly contributes to the chronification process and treatment refractoriness of migraine. Currently, abrupt discontinuation of the overused medication still represents the best management strategy for these patients, challenging public health system resources. Methods: In this prospective study, chronic migraine and medication overuse headache sufferers with at least 28 days of analgesic consumption per month were included. Assessment of efficacy outcomes at three months were compared among patients who underwent in-hospital abrupt discontinuation of overused acute medication (YES-DETOX group) and patients who did not (NO-DETOX group) before starting an anti-CGRP monoclonal antibody. Results: Of 401 patients who received either erenumab or galcanezumab, 28% (n = 111) satisfied inclusion criteria (YES-DETOX n = 28; NO-DETOX n = 83). After three months of treatment, 59% (n = 65; 47/83 YES-DETOX; 18/28 NO-DETOX) patients reverted from medication overuse headache and 51% (n = 57; 42/83 YES-DETOX; 15/28 NO-DEOTX) achieved ≥50% reduction in monthly headache days; yet no statistical differences were observed between the two groups (p = 0.4788 and p = 0.8393, respectively). Monthly consumption of pain medication was the only baseline prognostic factor in multivariate analysis in the overall cohort (p = 0.016). Conclusion: Our results support the emerging evidence that anti-CGRP monoclonal antibodies may be effective in medication overuse headache patients irrespective of detoxification, yet further studies are needed to draw definitive conclusions.