The transition of medication overuse status by acute medication categories in episodic or chronic migraine patients to non-overuse status after receiving anti-CGRP monoclonal antibodies: a systematic review and meta-analysis of phase 3 randomized control trial.

OBJECTIVE: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. METHODS: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. RESULTS: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. CONCLUSION: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters.

Medication "underuse" headache.

BACKGROUND: Many risk factors have been associated with migraine progression, including insufficient and ineffective utilization of migraine medications; however, they have been inadequately explored. This has resulted in suboptimal usage of medications without effective altering of prescribing recommendations for patients, posing a risk for migraine chronification. METHODS: Our aim is to conduct a comprehensive review of the available evidence regarding the underuse of migraine medications, both acute and preventive. The term "underuse" includes, but is not limited to: (1) ineffective use of appropriate and inappropriate medication; (2) underutilization; (3) inappropriate timing of usage; and (4) patient dissatisfaction with medication. RESULTS: The underuse of both acute and preventive medications has been shown to contribute to the progression of migraine. In terms of acute medication, chronification occurs as a result of insufficient drug use, including failure of the prescriber to select the appropriate type based on pain intensity and disability, patients taking medication too late (more than 60 minutes after the onset or after central sensitization has occurred as evidenced by allodynia), and discontinuation because of lack of effect or intolerable side effects. The underlying cause of inadequate effectiveness of acute medication lies in its inability to halt the propagation of peripheral activation to central sensitization in a timely manner. For oral and injectable preventive migraine medications, insufficient efficacy and intolerable side effects have led to poor adherence and discontinuation with subsequent progression of migraine. The underlying pathophysiology here is rooted in the repetitive stimulation of afferent sensory pain fibers, followed by ascending brainstem pain pathways plus dysfunction of the endogenous descending brainstem pain inhibitory pathway. Although anti-calcitonin gene-related peptide (CGRP) medications partially address pain caused by the above factors, including decreased efficacy and tolerability from conventional therapy, some patients do not respond well to this treatment. Research suggests that initiating preventive anti-CGRP treatment at an early stage (during low frequency episodic migraine attacks) is more beneficial than commencing it during high frequency episodic attacks or when chronic migraine has begun. CONCLUSIONS: The term "medication underuse" is underrecognized, but it holds significant importance. Optimal usage of acute care and preventive migraine medications could potentially prevent migraine chronification and improve the treatment of migraine attacks.

A SUNCT-like headache associated with lateral pontine infarction - case series and systematic review.

BACKGROUND AND AIM: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and autonomic symptoms (SUNA) are trigeminal autonomic cephalalgias (TACs). The study explores the potential association between SUNCT/SUNA-like headaches and lateral pontine infarctions. METHODS: Case series and systematic review. RESULTS: We present three cases diagnosed with SUNCT following lateral pontine infarction on magnetic resonance imaging (MRI), along with a review of these cases and 10 others from the literature. DISCUSSION AND CONCLUSION: This review suggests a connection between SUNCT/SUNA-like symptoms and lateral pontine infarctions. The section also delves into the anatomy and pathophysiology of these symptoms, proposing a mechanism involving neural pathway remodelling in the lateral brainstem.

Neurofilament light chain for classifying the aetiology of alteration of consciousness.

Neurofilament light chain has become a promising biomarker for neuroaxonal injury; however, its diagnostic utility is limited to chronic disorders or specific contexts. Alteration of consciousness is a common clinical problem with diverse aetiologies, many of which require timely diagnoses. We evaluated the value of neurofilament light chain alone, as well as creating diagnostic models, in distinguishing causes of alteration of consciousness. Patients presenting with alteration of consciousness were enrolled. Initial clinical data of each participant were evaluated by a neurologist to give a provisional diagnosis. Each participant subsequently received advanced investigations and follow-up to conclude the final diagnosis. All diagnoses were classified into a structural or non-structural cause of alteration of consciousness. Plasma and cerebrospinal fluid levels of neurofilament light chain were measured. Cerebrospinal fluid neurofilament light chain and other clinical parameters were used to develop logistic regression models. The performance of cerebrospinal fluid neurofilament light chain, the neurologist's provisional diagnosis, and the model to predict the final diagnosis were compared. For the results, among 71 participants enrolled, 67.6% and 32.4% of their final diagnoses were classified as structural and non-structural, respectively. Cerebrospinal fluid neurofilament light chain demonstrated an area under the curve of 0.75 (95% confidence interval 0.63-0.88) which was not significantly different from a neurologist's provisional diagnosis 0.85 (95% confidence interval 0.75-0.94) (P = 0.14). The multivariable regression model using cerebrospinal fluid neurofilament light chain and other basic clinical data achieved an area under the curve of 0.90 (95% confidence interval 0.83-0.98). In conclusion, neurofilament light chain classified causes of alteration of consciousness with moderate accuracy. Nevertheless, including other basic clinical data to construct a model improved the performance to a level that was comparable to clinical neurologists.

The current state of artificial intelligence-augmented digitized neurocognitive screening test.

The cognitive screening test is a brief cognitive examination that could be easily performed in a clinical setting. However, one of the main drawbacks of this test was that only a paper-based version was available, which restricts the test to be manually administered and graded by medical personnel at the health centers. The main solution to these problems was to develop a potential remote assessment for screening individuals with cognitive impairment. Currently, multiple studies have been adopting artificial intelligence (AI) technology into these tests, evolving the conventional paper-based neurocognitive test into a digitized AI-assisted neurocognitive test. These studies provided credible evidence of the potential of AI-augmented cognitive screening tests to be better and provided the framework for future studies to further improve the implementation of AI technology in the cognitive screening test. The objective of this review article is to discuss different types of AI used in digitized cognitive screening tests and their advantages and disadvantages.

Fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome: a case report.

BACKGROUND: Fluorouracil-induced leukoencephalopathy is a rare complication and has been reported to present as confusion, oculomotor abnormality, ataxia, and parkinsonism; however, there is no previous report of a presentation mimicking neuroleptic malignant syndrome. Acute cerebellar syndrome may occur, which can be explained by the extremely high accumulation of the drug in the cerebellum. However, presentation mimicking neuroleptic malignant syndrome similar to our case has never been reported. CASE PRESENTATION: Here, we describe a 68-year-old Thai male presenting with advanced-stage cecal adenocarcinoma, as well as symptoms and signs indicative of neuroleptic malignant syndrome. He received two doses of intravenous metoclopramide 10 mg 6 hours before his symptoms occurred. Magnetic resonance imaging scan revealed signal hyperintensity within the bilateral white matter. Further evaluation showed that his thiamine level was extremely low. Thus, he was diagnosed with fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome. The concomitant fluorouracil-induced thiamine deficiency eventually leads to rapid depletion of thiamine and was considered a risk factor for fluorouracil-induced leukoencephalopathy. CONCLUSION: Fluorouracil-induced leukoencephalopathy is believed to be caused by insult causing mitochondrial dysfunction. However, the exact mechanism remains unknown, but our finding suggests that thiamine deficiency plays a crucial role in fluorouracil-induced leukoencephalopathy. Diagnosis is usually delayed due to a lack of clinical suspicion and results in significant morbidity requiring unnecessary investigations.

Neurofilament light is associated with clinical outcome and hemorrhagic transformation in moderate to severe ischemic stroke.

Background: Ischemic stroke is a leading cause of morbidity and mortality worldwide. One possible predictor is the use of biomarkers especially neurofilament light chain (NFL). Objectives: To explore whether NFL could predict clinical outcome and hemorrhagic transformation in moderate to severe stroke. Design: Single center prospective cohort study. Methods: Fifty-one moderate to severe ischemic stroke patients were recruited. Blood NFL was obtained from patients at admission (First sample) and 24-96 hours later (Second sample). NFL was analyzed with the ultrasensitive single molecule array (Simoa). Later, we calculated incremental rate NFL (IRN) by changes in NFL per day from baseline. We evaluated National Institute of Health stroke scale (NIHSS), modified Rankins score (mRs), and the presence of hemorrhagic transformation (HT). Results: IRN was found to be higher in patients with unfavorable outcome (7.12 vs 24.07, P = .04) as well as Second sample (49.06 vs 71.41, P = .011), while NFL First sample was not significant. IRN had a great correlation with mRS (r = .552, P < .001). Univariate logistic regression model showed OR of IRN and Second sample to be 1.081 (95% CI 1.016-1.149, P = .013) and 1.019 (1.002-1.037, P = .03), respectively. Multiple logistic regression model has shown to be significant. In receiver operating analysis, IRN, Second sample, combined IRN with NIHSS and combined Second sample with NIHSS showed AUC (.744, P = .004; 0.713, P = .01; 0.805, P < .001; 0.803, P < .001, respectively). For HT, First sample and Second sample had significant difference with HT (Z = 2.13, P = .033; Z = 2.487, P = .013, respectively). Conclusion: NFL was found to correlate and predict clinical outcome. In addition, it was found to correlate with HT.

Unusual thalamic mass and subsequent gelatinous pseudocysts in an immunocompetent host: A case report.

Cryptococcal meningoencephalitis often occurs in an immunocompromised host with several known neurological manifestations including space-occupying lesions, meningitis or meningoencephalitis. Here, we describe a 38-year-old previously healthy durian farm owner with cryptococcoma and subsequent development of cryptococcus gelatinous pseudocyst after receiving high doses of intravenous dexamethasone to treat mass lesion presumed to be a malignant process. An MRI scan of the head demonstrated a 2-cm heterogeneous solitary enhancing cystic lesion at the right thalamus. Progression of neurological deficit and another repeat imaging showing typical appearance of gelatinous pseudocyst. Lumbar puncture found markedly elevated pressure and cryptococcal antigen strongly positive confirming the diagnosis. He was immediately started on amphotericin B and flucytosine for cryptococcus meningoencephalitis with partial improvement in his vision. This report highlights consideration of cryptococcal infection in an immunocompetent host to avoid delays in diagnosis and treatment.

COVID-19 related acute necrotizing encephalopathy with extremely high interleukin-6 and RANBP2 mutation in a patient with recently immunized inactivated virus vaccine and no pulmonary involvement.

BACKGROUND: We report the first case of COVID-19 associated acute necrotizing encephalopathy (ANE) without pulmonary disease in a patient with an extremely high interleukin-6 (IL-6) level and Ran Binding Protein 2 (RANBP2) mutation. CASE PRESENTATION: A 29-year-old woman recently immunized with inactivated viral vaccine-BBIBP32-CorV (Sinopharm) presented with alteration of consciousness. Her body temperature was 37° Celsius, blood pressure 42/31 mmHg, heart rate 130 bpm, respiratory rate 20 per minute, and oxygen saturation 98%. Respiratory examination was unremarkable. Neurological examination revealed stupor but preserved brainstem reflexes. Non-contrast computerized tomography of the brain showed symmetrical hypodense lesions involving bilateral thalami and cerebellar hemispheres characteristic of ANE. No pulmonary infiltration was found on chest radiograph. SARS-CoV-2 was detected by PCR; whole genome sequencing later confirmed the Delta variant. RANBP2 gene analysis revealed heterozygous Thr585Met mutation. Serum IL-6 was 7390 pg/mL. Urine examination showed pyelonephritis. Her clinical course was complicated by seizure, septic shock, acute kidney injury, and acute hepatic failure. She later developed coma and passed away in 6 days. CONCLUSIONS: ANE is caused by cytokine storm leading to necrosis and hemorrhage of the brain. IL-6 was deemed as a prognostic factor and a potential treatment target of ANE in previous studies. RANBP2 missense mutation strongly predisposes this condition by affecting mitochondrial function, viral entry, cytokine signaling, immune response, and blood-brain barrier maintenance. Also, inactivated vaccine has been reported to precipitate massive production of cytokines by antibody dependent enhancement (ADE). The true incidence of COVID-19 associated ANE is not known as were the predictors of its development. We proposed these potential two factors (RANBP2 mutation and ADE) that could participate in the pathogenesis of ANE in COVID-19 apart from SARS-CoV2 infection by itself. Further study is needed to confirm this hypothesis, specifically in the post-vaccination period. Role of RANBP2 mutation and its application in COVID-19 and ANE should be further elaborated.

Neurobiology of migraine progression.

Chronic migraine is one of the most devastating headache disorders. The estimated prevalence is 1.4-2.2% in the population. The factors which may predispose to the process of migraine progression include high frequency of migraine attacks, medication overuse, comorbid pain syndromes, and obesity. Several studies showed that chronic migraine results in the substantial anatomical and physiological changes in the brain. Despite no clear explanation regarding the pathophysiologic process leading to the progression, certain features such as increased sensory sensitivity, cutaneous allodynia, impaired habituation, identify the neuronal hyperexcitability as the plausible mechanism. In this review, we describe two main mechanisms which can lead to this hyperexcitability. The first is persistent sensitization caused by repetitive and prolonged trigeminal nociceptive activation. This process results in changes in several brain networks related to both pain and non-pain behaviours. The second mechanism is the decrease in endogenous brainstem inhibitory control, hence increasing the excitability of neurons in the trigeminal noceptive system and cerebral cortex. The combination of increased pain matrix connectivity, including hypothalamic hyperactivity and a weak serotonergic system, may contribute to migraine chronification.

A case of successive development of possible acute necrotizing encephalopathy after COVID-19 pneumonia.

COVID-19 infection often results in an excessive inflammatory response with a spectrum of neurological manifestations. Here, we describe an 81-year-old female with severe COVID-19 pneumonia and subsequent alteration of consciousness after high-dose intravenous dexamethasone and remdesivir. A non-contrast head computed tomography (CT) demonstrated bilateral hypodensities involving bilateral cerebellar hemispheres, thalami, cerebral peduncles and medial parieto-occipital areas. There was no improvement and repeat CT showed progression with findings suggestive of acute necrotizing encephalopathy. Interleukin-6 levels were initially normal; however, subsequent levels were found to be markedly elevated. Acute necrotizing encephalopathy associated with COVID-19 may occur in the setting of severe pneumonia and may represent an immune-mediated process involving inflammatory cytokines such as interleukin-6.

Prolonged migraine aura resembling ischemic stroke following CoronaVac vaccination: an extended case series.

BACKGROUND: After the initiation of the COVID-19 vaccination program in Thailand, thousands of patients have experienced unusual focal neurological symptoms. We report 8 patients with focal neurological symptoms after receiving inactivated virus vaccine, CoronaVac. CASE SERIES: Patients were aged 24-48 years and 75% were female. Acute onset of focal neurological symptoms occurred within the first 24 h after vaccination in 75% and between 1-7d in 25%. All presented with lateralized sensory deficits, motor deficits, or both, of 2-14 day duration. Migraine headache occurred in half of the patients. Magnetic resonance imaging of the brain during and after the attacks did not demonstrate any abnormalities suggesting ischemic stroke. All patients showed moderately large regions of hypoperfusion and concurrent smaller regions of hyperperfusion on SPECT imaging while symptomatic. None developed permanent deficits or structural brain injury. DISCUSSIONS: Here, we present a case series of transient focal neurological syndrome following Coronavac vaccination. The characteristic sensory symptoms, history of migraine, female predominant, and abnormal functional brain imaging without structural changes suggest migraine aura as pathophysiology. We propose that pain related to vaccine injection, component of vaccine, such as aluminum, or inflammation related to vaccination might trigger migraine aura in susceptible patients.

Acute prolonged motor aura resembling ischemic stroke after COVID - 19 vaccination (CoronaVac): the first case report.

BACKGROUND: We report the first case of a patient who suffered transient focal neurological deficit mimicking stroke following CoronaVac vaccination. However, instead of an ischemic stroke, motor aura was suspected. CASE PRESENTATIONS: A 24 year-old Thai female presented with left hemiparesis fifteen minutes after receiving CoronaVac. She also had numbness of her left arm and legs, flashing lights, and headaches. On physical examination, her BMI was 32.8. Her vital signs were normal. She had moderate left hemiparesis (MRC grade III), numbness on her left face, arms, and legs. Her weakness continued for 5 days. A brain CT scan was done showing no evidence of acute infarction. Acute treatment with aspirin was given. MRI in conjunction with MRA was performed in which no restricted diffusion was seen. A SPECT was performed to evaluate the function of the brain showing significant hypoperfusion of the right hemisphere. The patient gradually improved and was discharged. DISCUSSIONS: In this study, we present the first case of stroke mimic after CoronaVac vaccination. After negative imaging studies had been performed repeatedly, we reach a conclusion that stroke is unlikely to be the cause. Presumably, this phenomenon could possibly have abnormal functional imaging study. Therefore, we believed that it might be due to cortical spreading depression, like migraine aura, which we had conducted a literature review.

The Evolution of Medication Overuse Headache: History, Pathophysiology and Clinical Update.

Medication overuse headache (MOH), the development or worsening of chronic headache resulting from frequent and excessive intake of medications used for acute treatment of headache, is a common secondary headache disorder and is associated with significant personal and societal burdens. The plausible physiologic mechanism is that chronic exposure to acute care migraine treatment leads to suppression of endogenous antinociceptive systems, consequently facilitating the trigeminal nociceptive process via up-regulation of the calcitonin gene-related peptide (CGRP) system. Recognizing and preventing its development is an integral aspect of migraine management, as medication overuse is a modifiable risk factor in the progression from episodic to chronic migraine. Over the years, MOH has been difficult to treat and has generated much controversy. Ongoing debates exist over the diagnostic criteria and treatment strategies, particularly regarding the roles of formal detoxification and preventive treatment. The arrival of the anti-CGRP monoclonal antibodies has also challenged our views of MOH and its treatment. This review outlines the evolution of MOH diagnostic criteria, presents the current understanding of MOH pathogenesis and discusses the debates over its development and treatment. Data on the efficacy of anti-CGRP monoclonal antibodies in the setting of medication overuse is also presented. These results indicate that patients with medication overuse, who are treated with these new medications, may not need to be detoxified in order to treat MOH. In light of these developments, it is likely that in the future MOH will be more readily diagnosed and treatment will result in better outcomes.