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2023 VA/DoD Clinical Practice Guidelines for the Management of Headache

3 Nov, 2024 | 18:45h | UTC

Introduction: Headache disorders, notably migraine and tension-type headache (TTH), are among the most prevalent and disabling neurological conditions globally, significantly impacting individuals’ quality of life and imposing substantial societal costs. This 2023 guideline provides primary care clinicians with evidence-based recommendations for the evaluation, treatment, and prevention of migraine and TTH, aiming to enhance patient care and outcomes.

Key Recommendations:

  1. Acute Migraine Treatment:
    • Triptans (eletriptan, frovatriptan, rizatriptan, sumatriptan, zolmitriptan) are strongly recommended for short-term migraine relief. (Strength: Strong for)
    • Aspirin–Acetaminophen–Caffeine combination is strongly recommended for acute migraine treatment. (Strength: Strong for)
    • Gepants (ubrogepant, rimegepant) are suggested as options for acute migraine management. (Strength: Weak for)
    • NSAIDs (aspirin, ibuprofen, naproxen) and acetaminophen are suggested for acute migraine relief. (Strength: Weak for)
  2. Preventive Migraine Therapy:
    • CGRP Monoclonal Antibodies (erenumab, fremanezumab, galcanezumab) are strongly recommended for preventing episodic or chronic migraine. (Strength: Strong for)
    • Angiotensin Receptor Blockers (candesartan, telmisartan) are recommended for episodic migraine prevention. (Strength: Strong for)
    • Topiramate and valproate are suggested for migraine prevention. (Strength: Weak for)
    • Lisinopril, magnesium, memantine, and atogepant are suggested for preventing episodic migraine. (Strength: Weak for)
    • OnabotulinumtoxinA injections are suggested for preventing chronic migraine but not episodic migraine. (Strength: Weak for chronic migraine; Weak against for episodic migraine)
    • Gabapentin is not recommended for preventing episodic migraine. (Strength: Weak against)
  3. Tension-Type Headache Management:
    • For acute TTH, ibuprofen (400 mg) or acetaminophen (1000 mg) are suggested. (Strength: Weak for)
    • Amitriptyline is suggested for preventing chronic TTH. (Strength: Weak for)
  4. Nonpharmacologic Interventions:
    • Physical Therapy is suggested for managing TTH and migraine. (Strength: Weak for)
    • Aerobic Exercise or progressive strength training is suggested for preventing TTH and migraine. (Strength: Weak for)
  5. Injections and Procedures:
    • Greater Occipital Nerve Block is suggested for short-term migraine treatment. (Strength: Weak for)

Conclusion: The 2023 VA/DoD Clinical Practice Guideline provides updated, evidence-based recommendations for managing migraine and TTH, incorporating new pharmacologic agents and nonpharmacologic interventions. The inclusion of newer medications, such as CGRP inhibitors, offers additional options for patients who may not respond to traditional therapies.

Reference: Sico JJ, et al. 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline for the Management of Headache. Annals of Internal Medicine. 2023. DOI: http://doi.org/10.7326/ANNALS-24-00551

 

 


Review: Chronic Low-Level Lead Poisoning

3 Nov, 2024 | 01:15h | UTC

Introduction: Lead poisoning, historically known as plumbism, remains a significant health concern despite reductions in lead use. Chronic low-level lead exposure has been identified as a critical risk factor for cardiovascular disease in adults and cognitive deficits in children, even at blood lead concentrations previously deemed safe. This review by Lanphear et al. explores the multifaceted effects of chronic, low-level lead poisoning, emphasizing its impact on neurodevelopment, kidney function, and cardiovascular health, and underscores the urgent need for effective prevention strategies.

Key Findings:

  1. Exposure and Absorption: Lead exposure occurs primarily through ingestion and inhalation, with children absorbing lead more readily than adults. Absorption is enhanced in the presence of iron or calcium deficiency. Once absorbed, lead is predominantly stored in the skeleton, and factors altering bone metabolism can mobilize lead back into the bloodstream.
  2. Neurodevelopmental Effects: Lead exposure is linked to preterm birth, cognitive deficits, attention deficit–hyperactivity disorder (ADHD), and behavioral disorders in children. Notably, cognitive deficits are proportionately larger at lower blood lead levels, with significant IQ reductions observed even at the lowest measurable concentrations.
  3. Kidney Disease: Chronic lead exposure is a risk factor for chronic kidney disease. Higher blood lead levels are associated with reduced glomerular filtration rates and an increased risk of developing chronic kidney conditions.
  4. Cardiovascular Disease: Lead induces hypertension and atherosclerosis through mechanisms such as oxidative stress and endothelial dysfunction. It is a leading risk factor for mortality from cardiovascular disease, with substantial risk increases even at low blood lead concentrations. Studies indicate that lead exposure may have contributed to historical trends in coronary heart disease mortality.
  5. Global Burden: In 2019, lead exposure accounted for approximately 5.5 million deaths from cardiovascular disease and the loss of 765 million IQ points in children globally. The economic cost associated with lead-related health outcomes is estimated at $6 trillion annually, representing about 7% of the global gross domestic product.
  6. Screening and Treatment: Screening high-risk populations is recommended, including children in older housing and workers in certain industries. While chelation therapy can reduce body lead burden, its effects on health outcomes are inconsistent, highlighting the importance of primary prevention.
  7. Prevention Strategies: Eliminating environmental sources of lead through government-funded population strategies is essential. This includes replacing lead-containing infrastructure like water service lines, banning leaded aviation fuel, reducing lead in consumer products, and remediating contaminated soils and older housing with lead-based paints.

Conclusion: Chronic low-level lead poisoning continues to pose a significant global health threat, contributing to cardiovascular disease and neurodevelopmental deficits. The disproportionate effects at even the lowest exposure levels underscore the necessity for robust, population-wide prevention strategies. Implementing stringent regulatory actions to eliminate sources of lead exposure is imperative to reduce the substantial morbidity, mortality, and economic burdens associated with lead poisoning.

Reference: Lanphear B, Navas-Acien A, Bellinger DC. Lead Poisoning. New England Journal of Medicine. 2024;391(17):1621–1631. DOI: http://doi.org/10.1056/NEJMra2402527

 


RCT: Vitamin K2 Reduces Nocturnal Leg Cramps in Older Adults

28 Oct, 2024 | 18:59h | UTC

Background Nocturnal leg cramps (NLCs) affect 50% to 60% of adults, causing significant discomfort, sleep disturbances, and reduced quality of life. Current treatments lack robust evidence for efficacy and safety, with quinine no longer recommended due to severe adverse effects. Vitamin K2 has shown promise in reducing muscle cramps in dialysis patients, suggesting potential benefits for managing NLCs.

Objective To evaluate whether vitamin K2 supplementation reduces the frequency, duration, and severity of nocturnal leg cramps in older adults compared with placebo.

Methods In this multicenter, double-blind, placebo-controlled randomized clinical trial conducted in China from September 2022 to December 2023, 199 community-dwelling individuals aged 65 years or older with at least two episodes of NLCs over a two-week screening period were enrolled. Participants were randomly assigned in a 1:1 ratio to receive daily oral vitamin K2 (menaquinone-7, 180 μg) or placebo for eight weeks. The primary outcome was the mean number of NLCs per week. Secondary outcomes included cramp duration and severity, measured on a 1 to 10 analog scale.

Results Of the 199 participants (mean age 72.3 ± 5.5 years; 54.3% female), 103 received vitamin K2 and 96 received placebo. Baseline weekly cramp frequency was similar between groups (vitamin K2: 2.60 ± 0.81; placebo: 2.71 ± 0.80). Over eight weeks, the vitamin K2 group experienced a significant reduction in mean weekly cramps to 0.96 ± 1.41, while the placebo group increased to 3.63 ± 2.20 (between-group difference: −2.67; 95% CI, −2.86 to −2.49; P < .001). The vitamin K2 group also showed greater reductions in cramp severity (mean decrease of 2.55 ± 2.12 points vs 1.24 ± 1.16 points in placebo) and duration (mean decrease of 0.90 ± 0.88 minutes vs 0.32 ± 0.78 minutes in placebo). No adverse events related to vitamin K2 were reported.

Conclusions Vitamin K2 supplementation significantly reduced the frequency, severity, and duration of nocturnal leg cramps in older adults, demonstrating both efficacy and safety.

Implications for Practice Vitamin K2 may offer an effective and safe therapeutic option for managing NLCs in older individuals, addressing a significant unmet clinical need in primary care.

Study Strengths and Limitations Strengths include the randomized, double-blind design and focus on an older population; limitations involve the relatively mild symptoms of participants and lack of assessment of quality of life or sleep improvements.

Future Research Further studies should assess the impact of vitamin K2 on sleep quality and quality of life in patients with more severe NLCs and explore the underlying mechanisms of its muscle-relaxing effects.

Reference Tan J, Zhu R, Li Y, et al. Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial. JAMA Internal Medicine. Published online October 28, 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5726


RCT: Early DOACs Safe and Non-Inferior to Delayed Initiation Post-Stroke with Atrial Fibrillation

28 Oct, 2024 | 17:52h | UTC

Background: Atrial fibrillation increases ischaemic stroke risk, and patients are prone to recurrence. Prompt anticoagulation post-stroke is critical, but optimal timing is unclear due to bleeding concerns. Guidelines often delay DOAC initiation without strong evidence.

Objective: To determine if early DOAC initiation (≤4 days) is non-inferior to delayed initiation (7–14 days) in preventing recurrent ischaemic events without increasing intracranial haemorrhage risk in patients with acute ischaemic stroke and atrial fibrillation.

Methods: In this multicentre, open-label, blinded-endpoint, phase 4 randomised controlled trial at 100 UK hospitals, 3,621 adults with atrial fibrillation and acute ischaemic stroke were randomised to early or delayed DOAC initiation. Eligibility required physician uncertainty about timing. Participants and clinicians were unmasked; outcomes were adjudicated by a masked committee. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism within 90 days.

Results: Among 3,621 patients (mean age 78.5; 45% female), the primary outcome occurred in 59 patients (3.3%) in both early and delayed groups (adjusted risk difference 0.0%, 95% CI –1.1 to 1.2%). Upper confidence limit below the 2% non-inferiority margin (p=0.0003) confirmed non-inferiority. Symptomatic intracranial haemorrhage rates were similar (0.6% early vs 0.7% delayed; p=0.78). No significant differences in mortality or heterogeneity across subgroups.

Conclusions: Early DOAC initiation within 4 days is non-inferior to delayed initiation in preventing recurrent events without increasing intracranial haemorrhage risk. Findings challenge guidelines advising delayed anticoagulation and support early initiation regardless of stroke severity.

Implications for Practice: Clinicians should consider starting DOACs within 4 days post-stroke in atrial fibrillation patients. Early initiation is safe and effective, potentially improving outcomes and suggesting guidelines may need revision.

Study Strengths and Limitations: Strengths include large sample size and masked outcome adjudication. Limitations include exclusion of patients with very severe strokes and low event rates, potentially limiting detection of rare adverse events.

Future Research: Further studies should explore optimal DOAC timing within 4 days and assess safety in patients with severe strokes or extensive haemorrhagic transformation.

Reference: Werring DJ, Dehbi HM, Ahmed N, et al. Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial. Lancet. 2024; DOI: http://doi.org/10.1016/S0140-6736(24)02197-4

 


Cohort Study: GIP/GLP-1 Receptor Agonist Prescriptions Linked to Reduced Opioid Overdose and Alcohol Intoxication

20 Oct, 2024 | 18:36h | UTC

Background: Opioid use disorder (OUD) and alcohol use disorder (AUD) are prevalent conditions leading to significant morbidity and mortality, including overdose and intoxication. Current pharmacotherapies for OUD and AUD are underutilized due to barriers like access and stigma. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used for type 2 diabetes and obesity, have shown potential in modulating reward pathways associated with substance use, suggesting a possible role in reducing substance-related harms.

Objective: To estimate the association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or GLP-1 receptor agonists and the incidence of opioid overdose and alcohol intoxication in patients with OUD and AUD, respectively, and to assess this association among patients with comorbid type 2 diabetes and obesity.

Methods: This retrospective cohort study analyzed de-identified electronic health record data from 136 U.S. health systems in the Oracle Cerner Real-World Data, covering over 100 million patients from January 2014 to September 2022. Adults aged 18 years or older with a history of OUD (n = 503,747) or AUD (n = 817,309) were included. The exposure was defined as having one or more prescriptions of GIP/GLP-1 RAs after the first OUD or AUD diagnosis. The primary outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort.

Results: Patients with GIP/GLP-1 RA prescriptions had significantly lower rates of opioid overdose (aIRR in OUD patients: 0.60; 95% CI, 0.43–0.83) and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI, 0.40–0.63) compared to those without such prescriptions. The protective association remained significant among patients with comorbid type 2 diabetes and obesity.

Conclusions: Prescriptions of GIP and/or GLP-1 receptor agonists are associated with lower rates of opioid overdose and alcohol intoxication in patients with OUD and AUD. These protective effects persist across various subgroups, including those with comorbid type 2 diabetes and obesity.

Implications for Practice: GLP-1 RAs show promise for reducing substance-related harms in patients with OUD and AUD. Clinicians may consider the potential benefits of GIP/GLP-1 RA prescriptions in this population, while recognizing the need for further research to establish causality and understand underlying mechanisms.

Study Strengths and Limitations: Strengths include a large, diverse patient population and adjustment for multiple confounders. Limitations involve the retrospective observational design limiting causal inference and reliance on data from Cerner-affiliated health systems, which may affect generalizability.

Future Research: Prospective clinical trials are needed to validate these findings, elucidate underlying mechanisms, and assess the efficacy and safety of GIP/GLP-1 RAs as treatments for substance use disorders.

Reference: Qeadan F, et al. (2024). The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction. DOI: http://doi.org/10.1111/add.16679

 


Psychedelic-Assisted Therapy May Reduce Anxiety and Depression in Patients with Life-Threatening Diseases

20 Oct, 2024 | 18:02h | UTC

Background: Anxiety, depression, and existential distress are prevalent among individuals facing life-threatening illnesses, significantly impacting their quality of life. Traditional treatments often have limited efficacy in this population. Psychedelic-assisted therapy, involving substances like psilocybin and LSD under professional supervision, has been proposed as a potential intervention. However, these substances are illegal in most countries and pose potential risks.

Objective: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators in treating anxiety, depression, and existential distress in people with life-threatening diseases.

Methods: This Cochrane systematic review included six randomized controlled trials conducted in the USA and Switzerland between 2011 and 2022. A total of 149 participants (140 analyzed), aged 36 to 64 years with life-threatening illnesses (e.g., cancer), were randomized to receive psychedelic-assisted therapy using classical psychedelics (psilocybin or LSD) or MDMA. Interventions included preparatory sessions, the psychedelic experience, and integration sessions. Comparators were active placebos (e.g., low-dose psychedelic or niacin) or placebo. Primary outcomes were anxiety, depression, and existential distress measured 1 to 12 weeks post-intervention.

Results: Psychedelic-assisted therapy with classical psychedelics may reduce anxiety and depression compared to active placebo:

  • Anxiety: Mean difference (MD) of −8.41 points on the STAI-Trait scale (20–80 range; 95% CI, −12.92 to −3.89; 5 studies, 122 participants; low-certainty evidence).
  • Depression: MD of −4.92 points on the Beck Depression Inventory (0–63 range; 95% CI, −8.97 to −0.87; 4 studies, 112 participants; low-certainty evidence).

The effect on existential distress was mixed and very uncertain. No treatment-related serious adverse events or grade 3/4 adverse events were reported. Common mild to moderate adverse events included elevated blood pressure, nausea, anxiety, and transient psychotic-like symptoms, which resolved shortly after the sessions.

Conclusions: Psychedelic-assisted therapy with classical psychedelics may reduce symptoms of anxiety and depression in patients with life-threatening diseases, but the evidence is of low certainty due to methodological limitations and small sample sizes. The effects of MDMA-assisted therapy are very uncertain.

Implications for Practice: While findings are promising, clinicians should exercise caution due to the low certainty of evidence and legal restrictions surrounding psychedelic substances.

Study Strengths and Limitations: Strengths include randomized designs and standardized therapeutic protocols involving preparation and integration sessions. Limitations are high risk of bias due to unblinding, small sample sizes, potential expectation bias, and cross-over designs with carry-over effects.

Future Research: Larger, well-designed RCTs with rigorous blinding are needed to confirm these findings. Future studies should explore long-term outcomes, diverse patient populations, and strategies to mitigate bias, such as using active placebos and measuring expectancy effects.

Reference: Schipper S, et al. (2024). Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases. Cochrane Database of Systematic Reviews. DOI: https://doi.org/10.1002/14651858.CD015383.pub2

 


Review: Endovascular Management of Acute Stroke

20 Oct, 2024 | 14:43h | UTC

Introduction: Stroke due to large vessel occlusion (LVO) remains a leading cause of disability and mortality worldwide. Endovascular therapy has revolutionized acute ischemic stroke management by enhancing recanalization rates and improving patient outcomes. This review outlines the evolution of endovascular treatments, expansion of therapeutic indications, current best practices, and ongoing research in the endovascular management of acute stroke.

Key Recommendations:

  1. Early Time Window Therapy (0–6 Hours): Robust evidence from randomized controlled trials demonstrates that mechanical thrombectomy significantly improves functional outcomes in patients with anterior circulation LVO presenting within 6 hours of symptom onset. Patients are selected based on moderate-to-severe neurological deficits and small infarct cores identified via imaging.
  2. Extended Time Window Therapy (6–24 Hours): Trials such as DAWN and DEFUSE3 have extended thrombectomy benefits to patients up to 24 hours after symptom onset. Advanced imaging techniques, like CT perfusion and MRI, identify patients with substantial penumbral tissue, indicating potential for recovery.
  3. Large Ischemic Core Infarcts: Recent studies (e.g., SELECT2, ANGEL-ASPECT) suggest that patients with large core infarcts can benefit from endovascular therapy, challenging previous contraindications. Individualized patient selection is crucial to balance risks and benefits.
  4. Basilar Artery Occlusion: New evidence supports thrombectomy for basilar artery occlusions, especially in patients with moderate-to-severe symptoms. This intervention improves outcomes in a condition historically associated with high morbidity and mortality.
  5. Bridging Thrombolysis: The necessity of intravenous thrombolysis before thrombectomy in patients directly admitted to endovascular centers is under debate. Meta-analyses indicate that omitting thrombolysis may not adversely affect outcomes, although it remains standard for patients at non-thrombectomy centers.
  6. Simplified Imaging for Patient Selection: The use of non-contrast CT and CT angiography alone has proven effective for patient selection, reducing treatment delays and expanding access to thrombectomy, particularly in resource-limited settings.

Conclusion: Advancements in endovascular therapy have markedly improved outcomes for patients with acute ischemic stroke due to LVO. Expanded treatment indications and simplified imaging protocols have broadened patient eligibility for thrombectomy. Ongoing research into adjunctive therapies and optimization of management strategies holds promise for further reducing stroke-related disability and mortality.

Reference: Nguyen TN, et al. (2024) Endovascular management of acute stroke. Lancet. DOI: http://doi.org/10.1016/S0140-6736(24)01410-7

 


Meta-Analysis: Topiramate and CGRP Monoclonal Antibodies Effective in Medication Overuse Headache

13 Oct, 2024 | 14:07h | UTC

Background: Medication overuse headache (MOH) results from frequent intake of acute pain medications, leading to increased headache frequency and severity. There is ongoing debate regarding the necessity and optimal choice of prophylactic drugs in MOH treatment, with previous studies lacking clear guidance.

Objective: To determine the comparative efficacy and safety of available pharmacological therapies for MOH, including their ability to eliminate medication overuse (MO).

Methods: A systematic review and network meta-analysis of randomized controlled trials were conducted, comparing different pharmacological treatments for MOH. Primary outcomes included the responder rate (≥50% reduction in headache frequency), proportion of patients reverting to no medication overuse (nMO), and reductions in monthly headache days and acute medication intake frequency. The certainty of evidence was assessed using the GRADE framework.

Results: Twenty-eight studies involving 5,527 patients were included. Topiramate demonstrated significant benefits in increasing responder rates (odds ratio [OR] 4.93), reducing headache frequency (weighted mean difference [WMD] –5.53), and decreasing acute medication intake frequency (WMD –6.95), but was associated with more adverse events compared to placebo (OR 0.20). Fremanezumab, galcanezumab, and botulinum toxin type A (BTA) were effective in increasing responder rates (ORs 2.57 to 3.46). For reversion to nMO, eptinezumab, fremanezumab, and BTA were superior to placebo (ORs 1.55 to 2.75). Eptinezumab, fremanezumab, erenumab 140 mg, and BTA were more efficacious than erenumab 70 mg without significant differences in safety and tolerability.

Conclusions: Topiramate likely has large beneficial effects on increasing responder rates and reducing headache frequency but is associated with lower safety and greater intolerability. Fremanezumab, galcanezumab, and eptinezumab show promise in increasing responder rates. Eptinezumab has a large beneficial effect on reversion to nMO, with fremanezumab and BTA having smaller effects.

Implications for Practice: Clinicians should balance efficacy and tolerability when selecting pharmacological treatments for MOH. While topiramate is effective, its adverse event profile may limit its use. CGRP monoclonal antibodies, such as eptinezumab and fremanezumab, offer promising efficacy with acceptable safety profiles and may be preferred options for some patients.

Study Strengths and Limitations: Strengths include a comprehensive network meta-analysis of multiple pharmacological therapies and the use of GRADE for assessing evidence certainty. Limitations involve variability among included studies, small sample sizes, and heterogeneity in study populations and methodologies, which may affect the generalizability of the findings.

Future Research: High-quality randomized controlled trials are needed to confirm these findings and directly compare different pharmacological treatments in MOH. Future studies should focus on long-term efficacy, safety of newer therapies, and their impact on patient-centered outcomes.

Reference: Kong, F., Buse, D.C., Zhu, G., & Xu, J. (2024). Comparative efficacy and safety of different pharmacological therapies to medication overuse headache: a network meta-analysis. Journal of Headache and Pain. https://doi.org/10.1186/s10194-024-01878-0

 


Meta-analysis: Colchicine Reduces Ischemic Stroke and MACE in Patients with Prior Stroke or Coronary Disease

13 Oct, 2024 | 12:10h | UTC

Background: Colchicine is recommended for secondary prevention in cardiovascular disease, but its efficacy in preventing ischemic stroke and benefits in key patient subgroups remain uncertain. Inflammation plays a significant role in stroke and cardiovascular events, and colchicine’s anti-inflammatory properties may confer additional protective effects.

Objective: To evaluate the efficacy of colchicine for secondary prevention of ischemic stroke and major adverse cardiovascular events (MACE) in patients with prior stroke or coronary disease, and to assess its safety profile across key clinical subgroups.

Methods: A trial-level meta-analysis was conducted, including six randomized controlled trials with a total of 14,934 patients with prior stroke or coronary disease. Trials comparing colchicine with placebo or no colchicine for at least three months were included. The primary efficacy outcomes were ischemic stroke and MACE, defined as a composite of ischemic stroke, myocardial infarction, coronary revascularization, or cardiovascular death. Secondary outcomes included serious safety events and mortality.

Results: Colchicine reduced the risk of ischemic stroke by 27% (1.8%] vs. 186 events [2.5%]; RR 0.73, 95% CI 0.58–0.90; P = .004) and MACE by 27% (505 events [6.8%] vs. 693 events [9.4%]; RR 0.73, 95% CI 0.65–0.81; P < .001). The efficacy was consistent across key subgroups, including sex, age (<70 vs. ≥70 years), diabetes status, and statin use at baseline. Colchicine was not associated with an increase in serious safety outcomes, all-cause mortality (201 deaths [2.7%] vs. 181 deaths [2.4%]; RR 1.09, 95% CI 0.89–1.33; P = .39), cardiovascular death, or non-cardiovascular death.

Conclusions: In patients with prior stroke or coronary disease, colchicine significantly reduces the risk of ischemic stroke and MACE without increasing serious adverse events or mortality. These findings support the use of low-dose colchicine as an effective secondary prevention therapy in a broad cardiovascular patient population.

Implications for Practice: Clinicians should consider incorporating low-dose colchicine into secondary prevention regimens for patients with prior stroke or coronary disease, given its demonstrated efficacy and acceptable safety profile. Its affordability and widespread availability make it a practical option for diverse healthcare settings, including low- and middle-income countries.

Study Strengths and Limitations: Strengths include a large pooled sample size and inclusion of multiple trials across various patient populations, enhancing generalizability. Limitations involve potential performance bias in non-placebo-controlled trials, differences in stroke outcome definitions among studies, and the inability to perform individual patient data analyses.

Future Research: Further studies are needed to evaluate the long-term effects of colchicine on vascular events and cognitive decline in stroke patients, assess safety in patients with renal impairment, and explore its impact on non-cardiovascular mortality.

Reference: Fiolet A.T.L., et al. (2024). Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials. eClinicalMedicine. DOI: https://doi.org/10.1016/j.eclinm.2024.102835

 


RCT: Liberal Transfusion Strategy Reduced Unfavorable Neurological Outcomes in Acute Brain Injury

12 Oct, 2024 | 11:01h | UTC

Background: Patients with acute brain injury frequently develop anemia, and the optimal hemoglobin threshold for red blood cell transfusion in this population remains uncertain. Previous studies have shown conflicting results regarding the benefits of liberal versus restrictive transfusion strategies on neurological outcomes.

Objective: To determine whether a liberal transfusion strategy (hemoglobin threshold <9 g/dL) reduces the occurrence of unfavorable neurological outcomes at 180 days compared to a restrictive strategy (hemoglobin threshold <7 g/dL) in patients with acute brain injury.

Methods: The TRAIN trial, a multicenter, phase 3, randomized clinical trial, was conducted across 72 ICUs in 22 countries. It included patients with traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage, who had hemoglobin levels below 9 g/dL within the first 10 days post-injury. Participants were randomized to a liberal strategy (transfusion triggered by hemoglobin <9 g/dL) or a restrictive strategy (transfusion triggered by hemoglobin <7 g/dL), with primary outcomes measured by the occurrence of an unfavorable neurological outcome, defined by a Glasgow Outcome Scale Extended score of 1-5 at 180 days.

Results: Among 820 patients who completed the trial (mean age 51 years; 45.9% women), 806 had data on the primary outcome (393 liberal, 413 restrictive). The liberal group received a median of 2 units of blood (IQR, 1–3), while the restrictive group received a median of 0 units (IQR, 0–1), with an absolute mean difference of 1.0 unit (95% CI, 0.87–1.12 units). At 180 days, 62.6% of patients in the liberal group had an unfavorable neurological outcome compared to 72.6% in the restrictive group (absolute difference –10.0%; 95% CI, –16.5% to –3.6%; adjusted relative risk 0.86; P = .002). The effect was consistent across prespecified subgroups. Cerebral ischemic events were lower in the liberal group (8.8% vs 13.5%; relative risk 0.65; 95% CI, 0.44–0.97). No significant differences were observed in 28-day survival or other secondary outcomes.

Conclusions: In patients with acute brain injury and anemia, a liberal transfusion strategy resulted in a lower rate of unfavorable neurological outcomes at 180 days compared to a restrictive strategy.

Implications for Practice: A liberal transfusion threshold of 9 g/dL may improve neurological outcomes in patients with acute brain injury by reducing cerebral ischemic events. Clinicians should consider adopting a higher hemoglobin threshold for transfusion in this population, weighing the benefits against potential risks associated with transfusions, such as infection or lung injury.

Study Strengths and Limitations: Strengths include the large, multicenter international design and blinding of outcome assessors. Limitations involve the open-label nature, potential detection bias in assessing cerebral ischemic events, lack of standardized neuroprognostication, and incomplete assessment of concomitant interventions.

Future Research: Further studies are needed to confirm these findings in specific subgroups of acute brain injury, to explore optimal transfusion strategies, and to assess long-term outcomes and potential risks associated with liberal transfusion thresholds.

Reference: Taccone FS, et al. (2024) Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. JAMA. DOI: http://doi.org/10.1001/jama.2024.20424

 


Summary of the review “Neuroleptic Malignant Syndrome”

6 Oct, 2024 | 16:20h | UTC

In a comprehensive review published in the New England Journal of Medicine, Wijdicks and Ropper discuss neuroleptic malignant syndrome (NMS), a rare but potentially fatal complication of antipsychotic therapy characterized by fever, muscle rigidity, and autonomic dysfunction. Given the widespread use of dopamine-blocking agents across various medical specialties, it is crucial for practicing physicians to recognize and manage this syndrome promptly to improve patient outcomes.

Key Aspects Influencing Patient Care:

  • Epidemiology and Risk Factors:
    • NMS occurs in approximately 0.02 to 3% of patients exposed to dopamine-blocking agents.
    • Risk factors include dehydration, high doses of antipsychotics, rapid dose escalation, intramuscular administration, and prior episodes of NMS.
    • Both first-generation (typical) and second-generation (atypical) antipsychotics can cause NMS, though it may be less severe with atypical agents.
  • Clinical Presentation:
    • Hyperthermia: Elevated temperatures often exceeding 40°C.
    • Muscle Rigidity: Lead-pipe rigidity leading to rhabdomyolysis and elevated creatine kinase levels.
    • Autonomic Dysfunction: Tachycardia, fluctuating blood pressure, diaphoresis.
    • Altered Mental Status: Ranges from agitation to stupor or catatonia.
    • Laboratory Findings: Leukocytosis, electrolyte imbalances, and signs of renal impairment.
  • Diagnosis:
    • Based on clinical criteria including recent exposure to dopamine antagonists and presence of key symptoms.
    • Important to differentiate from serotonin syndrome, malignant hyperthermia, heat stroke, and severe catatonia.
  • Management:
    • Immediate Discontinuation of the offending agent.
    • Supportive Care in ICU:
      • Stabilize vital signs and manage autonomic instability.
      • Aggressive hydration to prevent renal failure from rhabdomyolysis.
      • Cooling measures for hyperthermia.
    • Pharmacologic Interventions:
      • Dantrolene: Reduces muscle rigidity and hyperthermia.
      • Dopamine Agonists: Bromocriptine or amantadine may reverse dopamine blockade.
      • Benzodiazepines: Lorazepam for sedation and muscle relaxation.
    • Monitoring for Complications:
      • Watch for respiratory failure, renal dysfunction, electrolyte disturbances, and cardiac arrhythmias.
    • Electroconvulsive Therapy (ECT):
      • Considered in refractory cases unresponsive to medical management.
  • Outcome and Prognosis:
    • Recovery typically occurs within 7 to 11 days with appropriate treatment.
    • Mortality rates have decreased but can reach up to 15% within one year due to complications.
    • Rechallenge with Antipsychotics:
      • If necessary, reintroduce antipsychotics cautiously after full recovery, using low doses and slow titration.
      • Prefer atypical agents and monitor closely for recurrence.

Clinical Implications:

  • Early Recognition: Timely identification of NMS is critical for initiating life-saving interventions.
  • Interdisciplinary Approach: Collaboration among psychiatrists, intensivists, neurologists, and other specialists enhances patient care.
  • Education and Prevention:
    • Educate healthcare providers about the signs and risk factors of NMS.
    • Monitor patients on antipsychotics closely, especially during dose changes or when using high-potency agents.

Reference: Wijdicks, E. F. M., & Ropper, A. H. (2024). Neuroleptic Malignant Syndrome. New England Journal of Medicine, 391(12), 1130–1138. DOI: 10.1056/NEJMra2404606

 


Network Meta-Analysis: Eletriptan, Rizatriptan, Sumatriptan, and Zolmitriptan Most Effective for Acute Migraine Episodes

23 Sep, 2024 | 22:34h | UTC

Background: Migraine, a highly prevalent neurological disorder, is a leading cause of disability, especially among women aged 15 to 49. Effective acute management is critical, with current guidelines recommending non-steroidal anti-inflammatory drugs (NSAIDs) and triptans for moderate to severe episodes. However, the relative efficacy of various drug interventions remains unclear, especially with newer treatments like lasmiditan and gepants entering the market.

Objective: To evaluate and compare the efficacy and tolerability of all licensed oral drugs for the acute treatment of migraine episodes in adults.

Methods: A systematic review and network meta-analysis was conducted, including 137 randomized controlled trials (RCTs) involving 89,445 participants. The study analyzed 17 drug interventions, including NSAIDs, triptans, ditans, and gepants, and compared them with placebo. Primary outcomes included pain freedom at two hours post-dose and sustained pain freedom from two to 24 hours post-dose. Certainty of evidence was assessed using the CINeMA framework, and sensitivity analyses were conducted to confirm the robustness of the findings.

Results: All active interventions outperformed placebo for pain freedom at two hours, with odds ratios ranging from 1.73 (95% CI 1.27 to 2.34) for naratriptan to 5.19 (4.25 to 6.33) for eletriptan. The most effective drugs for sustained pain freedom were eletriptan and ibuprofen. Among head-to-head comparisons, eletriptan was the most effective for pain freedom at two hours, followed by rizatriptan, sumatriptan, and zolmitriptan. Newer drugs like lasmiditan, rimegepant, and ubrogepant were less effective than the triptans and showed adverse effects like dizziness and nausea.

Conclusions: Triptans—specifically eletriptan, rizatriptan, sumatriptan, and zolmitriptan—demonstrated superior efficacy and tolerability profiles compared to newer treatments like lasmiditan and gepants. Given their efficacy, these triptans should be prioritized in acute migraine management. However, triptans are underused, and barriers to access should be addressed to ensure broader utilization. Lasmiditan and gepants may still serve as alternatives for patients contraindicated for triptans due to cardiovascular risks.

Implications for Practice: Clinicians should prioritize triptans, particularly eletriptan, rizatriptan, sumatriptan, and zolmitriptan, in managing acute migraine episodes due to their superior efficacy. Careful consideration is needed when selecting newer drugs like lasmiditan and gepants, as they may be less effective and have higher costs and adverse event risks. Cost-effectiveness and patient cardiovascular profiles should guide decision-making.

Study Strengths and Limitations: Strengths include the comprehensive inclusion of both published and unpublished data, as well as the large sample size and robust methodological framework. Limitations include moderate heterogeneity and low confidence in some comparisons due to reporting biases and imprecise treatment effects in older studies.

Future Research: Future studies should focus on re-evaluating the cardiovascular contraindications of triptans to ensure broader access. Additional research is also needed to assess the cost-effectiveness of newer treatments like lasmiditan and gepants, particularly in patients for whom triptans are unsuitable.

Reference: Karlsson WK, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis. BMJ. 2024; DOI: https://doi.org/10.1136/bmj-2024-080107

 


RCT: PACAP Monoclonal Antibody Lu AG09222 Reduced Migraine Days in Patients with Refractory Migraine

20 Sep, 2024 | 17:56h | UTC

Background: Migraine affects approximately 1 billion people worldwide and is a leading cause of disability. While calcitonin gene–related peptide (CGRP)-targeted therapies have advanced migraine prevention, many patients do not achieve sufficient benefit. Pituitary adenylate cyclase–activating polypeptide (PACAP) is implicated in migraine pathogenesis, and blocking its signaling may offer a new therapeutic target.

Objective: To assess the efficacy and safety of Lu AG09222, a monoclonal antibody against PACAP, for migraine prevention in adults who failed two to four prior preventive treatments.

Methods: In a phase 2, double-blind, randomized, placebo-controlled trial (HOPE), 237 adults aged 18–65 years with migraine (mean baseline of 16.7 migraine days per month) were randomized 2:1:2 to receive a single intravenous infusion of 750 mg Lu AG09222, 100 mg Lu AG09222, or placebo. The primary endpoint was the mean change from baseline in migraine days per month over weeks 1–4 in the 750 mg Lu AG09222 group compared to placebo. Secondary endpoints included the proportion achieving ≥50% reduction in migraine days per month and change in headache days per month.

Results: Of 237 participants, 97 received 750 mg Lu AG09222, 46 received 100 mg, and 94 received placebo. Over weeks 1–4, the 750 mg Lu AG09222 group had a mean reduction of 6.2 migraine days per month versus 4.2 days in the placebo group (difference –2.0 days; 95% CI, –3.8 to –0.3; P=0.02). A ≥50% reduction in migraine days per month was achieved by 32% in the 750 mg group versus 27% with placebo. The most common adverse events in the 750 mg group compared to placebo were COVID-19 (7% vs 3%), nasopharyngitis (7% vs 4%), and fatigue (5% vs 1%).

Conclusions: A single intravenous infusion of 750 mg Lu AG09222 significantly reduced migraine frequency over 4 weeks compared to placebo in patients with migraine refractory to prior preventive treatments.

Implications for Practice: Lu AG09222, by targeting PACAP signaling, may provide a novel preventive therapy for patients who have not responded to existing treatments, including CGRP antagonists.

Study Strengths and Limitations: Strengths include the randomized, double-blind, placebo-controlled design. Limitations encompass the short trial duration, small sample size, single-dose administration, predominantly White and European study population, and exclusion of patients with significant cardiovascular disease.

Future Research: Long-term studies are needed to evaluate the sustained efficacy and safety of Lu AG09222, optimal dosing strategies, and its effectiveness in diverse patient populations.

Reference: Ashina M., et al. (2024). A Monoclonal Antibody to PACAP for Migraine Prevention. New England Journal of Medicine. DOI: http://doi.org/10.1056/NEJMoa2314577

 


RCT: Tenecteplase Noninferior to Alteplase in Acute Ischemic Stroke

14 Sep, 2024 | 20:03h | UTC

Background: Acute ischemic stroke (AIS) is a leading cause of morbidity and mortality globally, with a particularly high burden in China. Intravenous thrombolysis with alteplase, administered within 4.5 hours of symptom onset, is the current standard of care. Tenecteplase, a genetically modified variant of alteplase with greater fibrin specificity and a longer half-life, allows for single-bolus administration, potentially simplifying and expediting treatment. Prior studies suggest tenecteplase may be as effective as alteplase in AIS, but data specific to Chinese patients are limited.

Objective: To determine whether tenecteplase is noninferior to alteplase in achieving excellent functional outcomes in Chinese patients with AIS treated within 4.5 hours of symptom onset.

Methods:

  • Design: Multicenter, randomized, open-label, blinded-endpoint, noninferiority trial conducted at 55 centers in China between July 2021 and July 2023.
  • Participants: 1,489 Chinese adults aged ≥18 years with AIS, National Institutes of Health Stroke Scale (NIHSS) scores of 1–25, measurable neurological deficits, and symptom onset within 4.5 hours.
  • Interventions: Patients were randomized 1:1 to receive either:
    • Tenecteplase: 0.25 mg/kg intravenous single bolus (maximum 25 mg).
    • Alteplase: 0.9 mg/kg intravenous (maximum 90 mg), with 10% as an initial bolus and the remainder infused over 1 hour.
  • Outcomes:
    • Primary Outcome: Proportion of patients achieving a modified Rankin Scale (mRS) score of 0 or 1 at 90 days (indicating no symptoms or no significant disability).
    • Secondary Outcomes: Major neurological improvement at 24 hours, mRS scores of 0–2 at 90 days, change in NIHSS score at 90 days, Barthel Index score ≥95 at 90 days.
    • Safety Outcomes: Symptomatic intracerebral hemorrhage (sICH) per ECASS III definition and all-cause mortality at 90 days.

Results:

  • Participants: 1,465 patients were included in the full analysis set (732 tenecteplase; 733 alteplase). Median age was 66 years, median NIHSS score was 6, and 30.4% were female.
  • Primary Outcome:
    • 72.7% in the tenecteplase group achieved mRS 0 or 1 at 90 days compared to 70.3% in the alteplase group.
    • Adjusted risk ratio (RR): 1.03 (95% CI, 0.97–1.09), meeting the predefined noninferiority margin (RR ≥0.937).
  • Secondary Outcomes:
    • Major Neurological Improvement at 24 Hours: 48.0% (tenecteplase) vs. 45.0% (alteplase); RR, 1.07 (95% CI, 0.96–1.19).
    • mRS 0–2 at 90 Days: 80.9% (tenecteplase) vs. 79.9% (alteplase); RR, 1.01 (95% CI, 0.96–1.06).
    • Change in NIHSS Score at 90 Days: Mean change of –3.70 (tenecteplase) vs. –3.02 (alteplase); adjusted difference, –0.45 (95% CI, –1.40 to 0.50).
    • Barthel Index ≥95 at 90 Days: 75.7% (tenecteplase) vs. 73.9% (alteplase); RR, 1.02 (95% CI, 0.96–1.08).
  • Safety Outcomes:
    • sICH: Occurred in 1.2% of patients in both groups; RR, 1.01 (95% CI, 0.37–2.70).
    • 90-Day Mortality: 4.6% (tenecteplase) vs. 5.8% (alteplase); RR, 0.80 (95% CI, 0.51–1.23).

Conclusions: Tenecteplase was noninferior to alteplase in achieving excellent functional outcomes (mRS 0 or 1) at 90 days in Chinese patients with AIS treated within 4.5 hours of symptom onset. Safety profiles, including rates of sICH and mortality, were similar between the two treatments. These findings support tenecteplase as a suitable alternative to alteplase for intravenous thrombolysis in AIS.

Implications for Practice:

  • Administration Advantage: Tenecteplase’s single-bolus administration could streamline treatment workflows and reduce door-to-needle times.
  • Efficacy and Safety: Comparable efficacy and safety profiles suggest tenecteplase can be confidently used in place of alteplase.
  • Patient Selection: Results are applicable to a broad range of AIS patients, including those with varying stroke severities and ages.

Study Strengths and Limitations:

  • Strengths: Large sample size, multicenter design, and inclusion of a real-world patient population enhance the generalizability of findings.
  • Limitations: Open-label design may introduce bias despite blinded endpoint assessments. The relatively low proportion of patients undergoing thrombectomy limits conclusions about combined therapy.

Future Research:

  • Further studies could explore the effectiveness of tenecteplase in specific subgroups, such as patients with large vessel occlusions or those requiring endovascular interventions.
  • Investigations into long-term outcomes beyond 90 days and real-world implementation strategies may provide additional insights.

Reference: Meng, X., et al. (2024). Tenecteplase vs alteplase for patients with acute ischemic stroke: The ORIGINAL randomized clinical trial. JAMA. DOI: https://doi.org/10.1001/jama.2024.14721

 


RCT: AF Screening Does Not Reduce Stroke Hospitalizations in Elderly Patients

6 Sep, 2024 | 22:18h | UTC

Study Design and Population: The GUARD-AF trial was a prospective, randomized controlled trial conducted across 149 primary care sites in the U.S. It enrolled 11,905 participants aged 70 and older, with a median age of 75 years, 56.6% of whom were female. Participants were randomized 1:1 to either screening for atrial fibrillation (AF) using a 14-day continuous electrocardiographic patch monitor or usual care. The primary outcome was all-cause stroke hospitalization, with bleeding as a key safety outcome.

Main Findings: After a median follow-up of 15.3 months, AF diagnosis was higher in the screening group (5%) compared to the usual care group (3.3%), and anticoagulation initiation was also more frequent (4.2% vs. 2.8%). However, the risk of stroke hospitalization was not significantly different between the screening and usual care groups (0.7% vs. 0.6%; HR: 1.10, 95% CI: 0.69-1.75). Similarly, there was no significant difference in bleeding risk (1.0% vs. 1.1%; HR: 0.87, 95% CI: 0.60-1.26).

Implications for Practice: The findings suggest that screening for AF using continuous electrocardiographic monitoring in elderly patients does not reduce stroke hospitalizations despite an increased detection of AF. Given the low event rates and premature termination of enrollment due to COVID-19, further studies are needed to confirm these results and explore alternative strategies for stroke prevention in this population.

Reference: Lopes RD, et al. (2024). Effect of screening for undiagnosed atrial fibrillation on stroke prevention. Journal of the American College of Cardiology. http://doi.org/10.1016/j.jacc.2024.08.019

 


Phase 2b Trial: Nicardipine Implants Show Promise in Reducing Vasospasm After Aneurysmal Subarachnoid Hemorrhage – JAMA Neurology

25 Aug, 2024 | 11:29h | UTC

Study Design and Population: This single-masked, multicenter, randomized clinical trial involved 41 patients with World Federation of Neurological Surgeons grade 3 or 4 aneurysmal subarachnoid hemorrhage (aSAH) from six neurovascular centers in Germany and Austria. The patients were randomized to either receive localized nicardipine release implants during microsurgical aneurysm repair plus standard care or standard care alone.

Main Findings: The incidence of moderate to severe angiographic vasospasm (aVS) between days 7 and 9 after aSAH was significantly lower in the implant group (20%) compared to the control group (58%; P = .02). Additionally, fewer patients in the implant group required vasospasm rescue therapy (10% vs. 58%; P = .002). However, at 52 weeks, no significant difference was observed in favorable outcomes between the groups (84% in the implant group vs. 67% in the control group; P = .27).

Implications for Practice: Nicardipine implants show promise in reducing vasospasm-related complications following aSAH, suggesting a potential benefit for early postoperative management. However, their impact on long-term clinical outcomes requires further investigation in larger phase 3 trials to determine the overall benefit and cost-effectiveness of this intervention.

Reference: Wessels L et al. (2024). Localized Nicardipine Release Implants for Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. JAMA Neurology. http://doi.org/10.1001/jamaneurol.2024.2564

 


Meta-Analysis: High-Dose Psilocybin Shows Small Advantage Over Escitalopram for Depression – The BMJ

24 Aug, 2024 | 16:41h | UTC

Study Design and Population: This systematic review and Bayesian network meta-analysis evaluated the effectiveness of oral monotherapy with psychedelics (psilocybin, LSD, MDMA, ayahuasca) compared to escitalopram in adults with depressive symptoms. The analysis included 15 trials with psychedelics and 5 trials with escitalopram, covering a total of 811 participants in psychedelic trials and 1968 in escitalopram trials.

Main Findings: The analysis revealed that only high-dose psilocybin demonstrated a significant improvement in depressive symptoms compared to placebo when considered in the context of antidepressant trials, but the effect size was small (standardized mean difference of 0.31). High-dose psilocybin also outperformed escitalopram (10 mg and 20 mg), with a mean difference exceeding the minimal important difference. However, the placebo response was generally lower in psychedelic trials compared to antidepressant trials, suggesting potential overestimation of effect sizes in psychedelic studies.

Implications for Practice: The findings suggest that while high-dose psilocybin may offer a small advantage over escitalopram for treating depression, the overall effect size is comparable to traditional antidepressants. The results highlight the importance of considering the impact of blinding and placebo response in psychedelic trials, and suggest that improved blinding and standardized psychotherapies could help better assess the true efficacy of these treatments.

Reference: Hsu, T.-W., Tsai, C.-K., Kao, Y.-C., Thompson, T., Carvalho, A. F., Yang, F.-C., Tseng, P.-T., Hsu, C.-W., Yu, C.-L., Tu, Y.-K., & Liang, C.-S. (2024). Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis. BMJ, 386, e078607. DOI: https://doi.org/10.1136/bmj-2023-078607

 


Cohort Study: One-Fourth of MS Relapses Occur Without MRI Activity, Highlighting ACES Phenomenon – JAMA Neurol

18 Aug, 2024 | 19:16h | UTC

Study Design and Population: This multicenter observational cohort study examined 637 clinical relapse events in 608 patients with relapsing-remitting multiple sclerosis (RRMS) from the French MS registry, spanning January 2015 to June 2023. The study included relapses with brain and spinal cord MRI performed within 12-24 months before and 50 days after the event.

Main Findings: Approximately 26% of relapses were classified as acute clinical events with stable MRI (ACES), showing no new T2 or gadolinium-enhanced T1 lesions. ACES were more likely in patients on highly effective disease-modifying therapies (DMTs), with longer disease duration, or with fatigue. ACES were associated with increased rates of relapse, confirmed disability accrual, and progression to secondary progressive MS, though their MRI stability was unaffected by DMTs.

Implications for Practice: The study suggests that MRI alone may not fully capture disease activity in RRMS, highlighting the need for comprehensive clinical assessment in therapeutic decision-making and clinical trial designs.

Reference: Gavoille, A., Rollot, F., Casey, R., et al. (2024). Acute clinical events identified as relapses with stable magnetic resonance imaging in multiple sclerosis. JAMA Neurology, 81(8), 814-823. DOI: 10.1001/jamaneurol.2024.1961.

 


Non-Inferiority Trial: Burr-Hole Drainage Without Irrigation Results in Higher Reoperation Rate in Chronic Subdural Hematoma – The Lancet

18 Aug, 2024 | 18:17h | UTC

Study Design and Population: This Finnish, nationwide, multicentre, randomised, controlled non-inferiority trial (FINISH) evaluated whether subdural irrigation during burr-hole drainage for chronic subdural haematoma could be omitted without compromising outcomes. The trial enrolled 589 adults (165 women, 424 men) requiring burr-hole drainage, randomly assigned to receive drainage with or without irrigation.

Main Findings: The study found a 6.0 percentage point higher reoperation rate within 6 months in the non-irrigation group (18.3%) compared to the irrigation group (12.6%). There were no significant differences in secondary outcomes, including the proportion of patients with an unfavorable functional outcome (13.1% vs. 12.6%) or mortality (6.1% vs. 7.1%). Adverse events were comparable between the groups.

Implications for Practice: The trial results suggest that omitting subdural irrigation during burr-hole drainage increases the risk of reoperation, without improving functional outcomes or reducing mortality. The findings support the continued use of subdural irrigation in this procedure.

Reference: Raj, R., Tommiska, P., Koivisto, T., Leinonen, V., Danner, N., & Posti, J. P., et al. (2024). Burr-hole drainage with or without irrigation for chronic subdural haematoma (FINISH): A Finnish, nationwide, parallel-group, multicentre, randomised, controlled, non-inferiority trial. The Lancet, 403(10446), 2798-2806. DOI: https://doi.org/10.1016/S0140-6736(24)00686-X.

 


Meta-Analysis: Effects of Psychological, Psychosocial, Pharmacological, Physical and Combined Treatments for Adults with a New Episode of Depression – eClinicalMedicine

17 Aug, 2024 | 19:49h | UTC

Study Design and Population: This systematic review and network meta-analysis examined 676 randomized controlled trials (RCTs) involving 105,477 participants, comparing psychological, psychosocial, pharmacological, physical, and combined treatments for adults with a new episode of unipolar depression. The study stratified interventions based on depressive symptom severity (less severe and more severe).

Main Findings: For less severe depression, group cognitive behavioral therapy (CBT) was the only treatment class that significantly improved depressive symptoms compared to treatment as usual (TAU). For more severe depression, effective interventions included combined individual CBT with antidepressants, individual behavioral therapies, and combined treatments like acupuncture or exercise with antidepressants. Notably, antidepressants alone did not show significant effects in less severe depression.

Implications for Practice: These findings suggest that group CBT may be an effective first-line treatment for less severe depression, while combined therapies, particularly those involving antidepressants and individual psychological interventions, are more effective in treating more severe depression. This evidence could guide clinical decision-making and inform updates to treatment guidelines.

Reference: Mavranezouli I et al. (2024). A systematic review and network meta-analysis of psychological, psychosocial, pharmacological, physical and combined treatments for adults with a new episode of depression. eClinicalMedicine, 75: 102780. DOI: 10.1016/j.eclinm.2024.102780.

 


Randomized Phase 2 Trial: Extended-Release Ketamine Tablets Reduce Depression Scores in Treatment-Resistant Depression Without Significant Adverse Effects – Nat Med

14 Aug, 2024 | 13:30h | UTC

Study Design and Population: This phase 2 multicenter, randomized, placebo-controlled trial evaluated the efficacy and safety of extended-release ketamine tablets (R-107) in adults with treatment-resistant depression (TRD). A total of 231 patients underwent an initial open-label phase where they received 120 mg of R-107 daily for 5 days. Responders, defined by a ≥50% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) scores, were randomized to receive one of four doses of R-107 (30, 60, 120, or 180 mg) or placebo twice weekly for 12 weeks.

Main Findings: The primary endpoint, change in MADRS score at week 13, showed a significant reduction of 6.1 points in the 180 mg R-107 group compared to placebo (P = 0.019). This dose also had the lowest relapse rate (42.9%) compared to 70.6% for placebo. Secondary outcomes, including response and remission rates, were generally higher for active treatment arms but reached statistical significance only in the 120 mg dose group for treatment response. The treatment was well-tolerated, with no significant increases in blood pressure or sedation.

Implications for Practice: Extended-release ketamine tablets could be a promising treatment for TRD, offering significant symptom improvement with minimal adverse effects, particularly at higher doses. The favorable safety profile and potential for at-home administration make this formulation a convenient option for wider use, though further research is needed to confirm these findings in broader populations.

Reference: Glue, P. et al. (2024). Extended-release ketamine tablets for treatment-resistant depression: A randomized placebo-controlled phase 2 trial. Nature Medicine, 30(7), 2004–2009. DOI: 10.1038/s41591-024-03063-x.

 


RCT: Tenecteplase Reduces Disability but Not Mortality in Ischemic Stroke 4.5 to 24 Hours Post-Onset – N Engl J Med

3 Aug, 2024 | 19:03h | UTC

Study Design and Population: This randomized clinical trial was conducted in China to assess the efficacy and safety of tenecteplase in patients with ischemic stroke caused by large-vessel occlusion. The study included 516 patients who were randomly assigned to receive either tenecteplase (264 patients) or standard medical treatment (252 patients) within 4.5 to 24 hours after stroke onset. All patients had salvageable brain tissue confirmed by perfusion imaging and did not have access to endovascular thrombectomy.

Main Findings: The primary outcome, absence of disability (modified Rankin scale score of 0 or 1) at 90 days, was achieved by 33.0% of patients in the tenecteplase group compared to 24.2% in the standard treatment group (relative rate, 1.37; 95% CI, 1.04 to 1.81; P=0.03). Mortality at 90 days was similar between the two groups (13.3% for tenecteplase vs. 13.1% for standard treatment). Symptomatic intracranial hemorrhage within 36 hours occurred in 3.0% of tenecteplase-treated patients compared to 0.8% of those receiving standard treatment.

Implications for Practice: The study suggests that tenecteplase administered 4.5 to 24 hours post-stroke onset can reduce disability in patients with large-vessel occlusion who do not have access to endovascular thrombectomy. However, the increased risk of symptomatic intracranial hemorrhage warrants cautious consideration. Further research may be needed to optimize patient selection and timing of administration to balance benefits and risks.

Reference: Xiong Y et al. (2024). Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy. New England Journal of Medicine, 390(24), 2980-2992. DOI: 10.1056/NEJMoa2402980.


RCT: Reteplase More Likely to Achieve Excellent Functional Outcome Than Alteplase in Acute Ischemic Stroke – N Engl J Med

3 Aug, 2024 | 19:00h | UTC

Study Design and Population: This randomized clinical trial compared the efficacy and safety of reteplase versus alteplase in patients with acute ischemic stroke. The study involved 1,412 patients who presented within 4.5 hours of symptom onset. Patients were randomly assigned in a 1:1 ratio to receive either intravenous reteplase or intravenous alteplase.

Main Findings: The primary efficacy outcome, an excellent functional outcome (modified Rankin scale score of 0 or 1) at 90 days, was achieved in 79.5% of the reteplase group compared to 70.4% of the alteplase group (risk ratio, 1.13; 95% CI, 1.05 to 1.21; P<0.001 for noninferiority and P=0.002 for superiority). The primary safety outcome, symptomatic intracranial hemorrhage within 36 hours, was similar between groups (2.4% for reteplase vs. 2.0% for alteplase; risk ratio, 1.21; 95% CI, 0.54 to 2.75). However, reteplase was associated with a higher incidence of any intracranial hemorrhage at 90 days (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51) and more adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20).

Implications for Practice: Reteplase shows superior efficacy in achieving excellent functional outcomes compared to alteplase in acute ischemic stroke, making it a viable alternative thrombolytic agent. However, the higher risk of intracranial hemorrhage and adverse events necessitates careful patient selection and monitoring. Further research may be needed to refine dosage and administration protocols to mitigate these risks.

Reference: Li, S., Gu, H-Q., Li, H., Wang, X., Jin, A., Guo, S., Lu, G., et al. (2024). Reteplase versus Alteplase for Acute Ischemic Stroke. New England Journal of Medicine, 390(24), 2264-2273. DOI: 10.1056/NEJMoa2400314.


Randomized Controlled Trial: Mixed results with Andexanet Alfa for Factor Xa inhibitor-associated acute intracerebral hemorrhage – N Engl J Med

27 May, 2024 | 20:26h | UTC

Study Design and Population: This randomized controlled trial involved 530 patients with acute intracerebral hemorrhage who had taken factor Xa inhibitors within 15 hours before the event. They were randomly assigned to receive either andexanet alfa or usual care.

Main Findings: Hemostatic efficacy was achieved in 67% of patients receiving andexanet compared to 53.1% receiving usual care. Andexanet significantly reduced anti-factor Xa activity by 94.5%, compared to 26.9% with usual care. However, thrombotic events were more frequent in the andexanet group, including ischemic stroke.

Implications for Practice: Andexanet alfa is effective in controlling hematoma expansion in patients with factor Xa inhibitor-associated intracerebral hemorrhage but has an increased risk of thrombotic events. Further research is needed to balance efficacy and safety.

 

Reference (link to abstract – $ for full-text):

Connolly SJ, Sharma M, Cohen AT, et al. (2024). Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. New England Journal of Medicine, 390(19), 1745-1755. DOI: 10.1056/NEJMoa2313040.

 


AAN updated practice guidelines for epilepsy and pregnancy – Neurology

27 May, 2024 | 20:23h | UTC

Introduction:

The American Academy of Neurology (AAN), the American Epilepsy Society (AES), and the Society for Maternal-Fetal Medicine (SMFM) have published a comprehensive guideline focusing on the management of epilepsy in individuals of childbearing potential. This guideline addresses the use of antiseizure medications (ASMs) and the impact of folic acid supplementation on major congenital malformations (MCMs), perinatal outcomes, and neurodevelopmental outcomes.

 

Key Points:

  1. Optimizing ASM Therapy Preconceptionally: Clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, ideally starting this process preconceptionally.
  2. Minimizing Convulsive Seizures During Pregnancy: It is crucial to minimize convulsive seizures in pregnant individuals to reduce risks to both the parent and the fetus.
  3. Monitoring and Adjusting ASM Levels: ASM levels should be monitored throughout pregnancy, and doses should be adjusted based on serum levels and seizure control.
  4. Preferred ASMs for Pregnancy: Lamotrigine, levetiracetam, and oxcarbazepine are recommended when appropriate, as they are associated with lower risks of MCMs compared to other ASMs.
  5. Avoiding Certain ASMs: Valproic acid should be avoided to minimize risks of MCMs, neural tube defects, and poor neurodevelopmental outcomes. Topiramate should also be avoided due to risks of offspring being born small for gestational age.
  6. Folic Acid Supplementation: At least 0.4 mg of folic acid should be prescribed daily preconceptionally and during pregnancy to decrease the risk of neural tube defects and possibly improve neurodevelopmental outcomes.
  7. Counseling on Risks and Monitoring: Clinicians must counsel patients on the potential risks associated with different ASMs and ensure regular fetal screenings to detect congenital malformations early.

 

Conclusion:

These guidelines provide essential, evidence-based recommendations for managing epilepsy in individuals of childbearing potential, emphasizing the importance of preconception planning, careful medication selection, and ongoing monitoring to optimize both maternal and fetal health outcomes.

 

Guideline Reference (link to free full-text):

Pack, A.M., et al. (2024). Practice Guideline From the AAN, AES, and SMFM: Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication. Neurology, 102, e209279. Available at: https://doi.org/10.1212/WNL.0000000000209279​​.

 


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