Neurology

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28 Jan, 2025 | 00:54h | UTC

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Phase 2b RCT: Abelacimab Significantly Reduces Bleeding Events Compared with Rivaroxaban in Patients with Atrial Fibrillation

27 Jan, 2025 | 11:00h | UTC

Background: Atrial fibrillation (AF) elevates stroke risk roughly fivefold, necessitating anticoagulation therapy to reduce embolic events. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the preferred agents, given their comparable efficacy and lower risk of intracranial hemorrhage. However, significant bleeding—especially gastrointestinal bleeding—still occurs with DOACs, prompting ongoing efforts to develop safer anticoagulants. Abelacimab, a fully human monoclonal antibody targeting factor XI (and its active form, XIa), is hypothesized to “uncouple” thrombosis from hemostasis, potentially lowering bleeding risk. Early data in knee arthroplasty prevention suggested reduced venous thromboembolism (VTE) without increased bleeding. This trial (AZALEA–TIMI 71) aimed to compare the bleeding rates of monthly subcutaneous abelacimab with once-daily rivaroxaban in patients with AF and moderate-to-high stroke risk.

Objective: To evaluate whether subcutaneous abelacimab at two doses (150 mg or 90 mg monthly) leads to fewer major or clinically relevant nonmajor bleeding events than rivaroxaban (20 mg or 15 mg daily) in patients with AF.

Methods: In this phase 2b, parallel-group, partially blind, randomized trial, 1287 adults with AF (CHA2_22​DS2_22​-VASc ≥3–4 and moderate/high stroke risk) were assigned 1:1:1 to abelacimab 150 mg, abelacimab 90 mg, or open-label rivaroxaban. Treatment continued for a median of 2.1 years. The primary endpoint was major or clinically relevant nonmajor bleeding, adjudicated by a blinded events committee. Levels of free factor XI were measured to gauge abelacimab’s pharmacodynamics. The trial was halted early based on a recommendation from the independent data monitoring committee due to unexpectedly large reductions in bleeding with abelacimab.

Results: Median age was 74 years, and 44% of participants were female. In the final analysis of the complete dataset, major or clinically relevant nonmajor bleeding occurred at rates of 3.2 and 2.6 events per 100 person-years for abelacimab 150 mg and 90 mg, respectively, versus 8.4 per 100 person-years for rivaroxaban. Corresponding hazard ratios were 0.38 (95% CI, 0.24–0.60) for the 150-mg dose and 0.31 (95% CI, 0.19–0.51) for the 90-mg dose (P<0.001 for both comparisons). The incidence of major gastrointestinal bleeding was notably lower with abelacimab (0.5% in both arms) compared with rivaroxaban (4.2%). Although not powered for stroke prevention, ischemic stroke rates were numerically higher with abelacimab, underscoring the need for larger efficacy trials.

Conclusions: Monthly abelacimab led to substantial and sustained reduction of free factor XI and demonstrated significantly lower bleeding rates than rivaroxaban in patients with AF. While these findings suggest a potentially safer profile for abelacimab, definitive conclusions about stroke prevention require phase 3 studies.

Implications for Practice: Should abelacimab maintain efficacy in preventing thromboembolism in forthcoming trials, it may offer an alternative to existing DOACs, particularly for patients at elevated bleeding risk (e.g., gastrointestinal). However, clinicians must consider real-world factors such as possible high drug cost, insurance coverage, and the logistics of monthly subcutaneous injections. Abelacimab is investigational and not yet approved; its role will depend on phase 3 efficacy and cost-effectiveness outcomes.

Study Strengths and Limitations: Strengths include randomized design, relatively long follow-up (median 2.1 years), and direct comparison to an established DOAC. The major limitation is that the trial was not sufficiently powered to evaluate stroke or systemic embolism. Moreover, the open-label design between abelacimab and rivaroxaban could introduce bias, partly mitigated by blinded dose assignments for abelacimab and blinded endpoint adjudication. The predominantly White population may limit generalizability.

Future Research: Ongoing phase 3 studies (e.g., LILAC–TIMI 76) will clarify abelacimab’s efficacy and safety in larger cohorts, particularly regarding stroke prevention. Comparative cost analyses, real-world adherence, and exploration of subcutaneous administration logistics will be crucial in determining abelacimab’s long-term clinical value. Additional investigations into factor XIa inhibitors (e.g., small molecules, antisense oligonucleotides) may further expand this therapeutic class.

Reference:

1. Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. “Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation.” New England Journal of Medicine. 2025;392:361–371. DOI: https://doi.org/10.1056/NEJMoa2406674
2. Angiolillo DJ, Capodanno D. “Uncoupling Thrombosis and Hemostasis by Inhibiting Factor XI.” New England Journal of Medicine. 2025;392:400–403. DOI: https://doi.org/10.1056/NEJMe2414209
3. Mandrola JM. “Factor XI Inhibitors May Not Be Dead.” This Week in Cardiology Podcast. January 24, 2025. https://www.medscape.com/viewarticle/1002184#vp_3

 

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2024 VA/DOD Clinical Practice Guideline for Stroke Rehabilitation

26 Jan, 2025 | 17:07h | UTC

Introduction:
This document summarizes the updated 2024 clinical practice guideline (CPG) jointly developed by the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DOD). It addresses stroke rehabilitation across inpatient, outpatient, and community settings, emphasizing an interdisciplinary approach. The main objective is to provide evidence-based recommendations to guide clinical decision-making and improve functional outcomes and quality of life for adult stroke survivors.

Key Recommendations:

1. Transition to Community
   • Case Management: Suggest using case management services at discharge to enhance activities of daily living (ADLs) and functional independence (“weak for”).
   • Behavioral/Psychosocial Interventions: Recommend psychosocial supports, such as stress management and motivational interviewing, to improve patient and caregiver depression, family function, and overall quality of life (“weak for”).
   • Psychoeducation: Encourage structured education on stroke care and self-management for patients and their caregivers to boost functional independence and social support.
2. Motor Therapy
   • Task-Specific Practice: Strongly recommend repetitive or task-oriented practice to improve motor function, gait, posture, and ADLs (“strong for”).
   • Mirror Therapy: Suggest mirror therapy to improve motor outcomes, ADLs, and unilateral spatial neglect (“weak for”).
   • Rhythmic Auditory Stimulation: Suggest adding external auditory cues (e.g., music or metronome) to assist in gait training (“weak for”).
   • Neuromuscular Electrical Stimulation: Suggest neuromuscular electrical stimulation for enhancing upper- or lower-extremity motor recovery (“weak for”).
   • Botulinum Toxin for Spasticity: Suggest botulinum toxin for focal spasticity, considering patient-specific characteristics and preferences, though evidence shows comparable efficacy to oral baclofen except in ankle spasticity (“weak for”).
3. Dysphagia, Aphasia, and Cognition
   • Dysphagia Rehabilitation:
     • Chin tuck against resistance for swallowing impairment (“weak for”).
     • Respiratory muscle strength training (for those without tracheostomy) to reduce aspiration risk (“weak for”).
   • Aphasia Rehabilitation:
     • No specific intensity level of language therapy is proven superior; tailor therapy duration and frequency to individual needs (“neither for nor against”).
   • Cognitive Outcomes:
     • Current evidence does not support or refute SSRIs for cognitive recovery; consider other individualized cognitive rehabilitation strategies (“neither for nor against”).
   • Unilateral Spatial Neglect:
     • Mirror therapy may help address neglect and improve ADLs (“weak for”).
4. Mental Health
   • Depression Treatment:
     • Suggest SSRIs or SNRIs for patients with established poststroke depression (“weak for”).
     • Recommend psychotherapy (e.g., cognitive behavioral therapy) and consider mindfulness-based therapies for depression following stroke (“weak for”).
   • Prevention of Depression:
     • Suggest against prophylactic antidepressants for preventing poststroke depression due to risk of adverse effects, such as fractures (“weak against”).
5. Telehealth
   • Consider telerehabilitation as an alternative or adjunct to in-person therapy if it aligns with patient preferences and clinical feasibility (“weak for”).
   • Evidence is inconclusive regarding telerehabilitation for dysphagia, aphasia, or caregiver support; use individualized judgment (“neither for nor against”).
6. Noninvasive Brain Stimulation
   • Insufficient evidence to recommend for or against repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), or continuous theta burst stimulation to enhance motor recovery (“neither for nor against”).

Conclusion:
These updated 2024 VA/DOD stroke rehabilitation guidelines underscore the importance of an interdisciplinary and patient-centered approach that integrates medical, psychological, and rehabilitative strategies. Adopting these recommendations—particularly around early case management, targeted motor therapies (task-specific practice, mirror therapy, neuromuscular electrical stimulation), dysphagia interventions, and tailored mental health treatments—can improve functional outcomes, optimize quality of life, and reduce poststroke morbidity.

Reference:

• Eapen BC, Tran J, Ballard-Hernandez J, et al. Stroke Rehabilitation: Synopsis of the 2024 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-02205
• Cramer SC. Moving Stroke Rehabilitation Forward and Into the Future. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-03568

 

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Management of Cervical Artery Dissection: Key Points From the AHA Scientific Statement

21 Jan, 2025 | 11:05h | UTC

Introduction:
This document summarizes the American Heart Association (AHA) scientific statement on cervical artery dissection (CAD), an important cause of ischemic stroke, especially in younger and middle-aged adults. Cervical artery dissection often presents with nonspecific symptoms—such as headache, neck pain, or partial Horner syndrome—but can lead to serious neurological deficits. Early recognition, targeted imaging, appropriate acute treatment, and well-informed decisions on antithrombotic therapy are essential to optimize patient outcomes.

Key Recommendations:

• Epidemiology and Risk Factors
  • CAD accounts for up to 25% of ischemic strokes in adults under 50 years of age, with a slightly higher incidence in men but lower peak age in women.
  • Risk factors include genetic predispositions (eg, connective tissue disorders), anatomic variants (elongated styloid process, vascular tortuosity), minor cervical trauma, and comorbidities such as hypertension or fibromuscular dysplasia.
• Diagnosis and Imaging
  1. Clinical Suspicion
     • Suspect CAD in younger adults with new or worsening neck pain, headache, pulsatile tinnitus, partial Horner syndrome, or cranial nerve involvement, especially if there is a history of recent minor neck trauma or manipulation.
     • Up to 8%–12% of patients may have isolated neck or head pain with no initial ischemic signs.
  2. Imaging Modalities
     • Magnetic Resonance Imaging (MRI)/Magnetic Resonance Angiography (MRA): High-resolution, fat-suppressed T1-weighted sequences are useful for detecting intramural hematoma.
     • Computed Tomography Angiography (CTA): Good sensitivity and specificity for luminal abnormalities and can detect intraluminal thrombus. Avoid false positives by distinguishing imaging artifacts from true double lumens or intimal flaps.
     • Conventional Digital Subtraction Angiography (DSA): Historically the gold standard but reserved for equivocal cases because of procedure-related risks (eg, iatrogenic dissection).
     • Ultrasound with Color Doppler: Operator-dependent but helpful for serial follow-up of vessel remodeling.
  3. Additional Diagnostic Testing
     • Connective Tissue Disorders: Consider genetic counseling if physical exam, family history, or recurrent dissections suggest a monogenic disorder (eg, vascular Ehlers-Danlos).
     • Screening for Fibromuscular Dysplasia (FMD): Patients with CAD, especially those with hypertension or evidence of FMD in other vascular beds, may warrant renal artery imaging.
     • Aortic and Intracranial Imaging: Aortic root dilation and cerebral aneurysms may be more prevalent in CAD; consider advanced imaging (eg, MRA) based on clinical judgment.
• Hyperacute and Acute Stroke Management
  1. Intravenous Thrombolysis (IVT):
     • IVT (alteplase or tenecteplase) remains reasonable for otherwise eligible acute ischemic stroke patients, with no specific evidence of higher hemorrhagic risk in CAD. Caution is advised if there is intracranial extension of the dissection or other significant bleeding risk factors.
  2. Mechanical Thrombectomy:
     • Recommended for large-vessel occlusion in CAD patients who meet standard thrombectomy criteria. Tandem lesions (extracranial dissection and intracranial occlusion) can be addressed via retrograde (intracranial first) or antegrade (extracranial first) approach, with similar overall outcomes reported.
  3. Acute or Subacute Stenting:
     • May be considered in selected cases of severe flow-limiting stenosis leading to distal hypoperfusion or in persistent ischemia despite optimal medical therapy. Stenting in tandem occlusions can improve reperfusion but carries added risks (in-stent restenosis, stent thrombosis, or need for dual antiplatelet therapy).
• Antithrombotic Therapy for Secondary Stroke Prevention
  1. Rationale for Early Treatment:
     • Artery-to-artery embolization underpins most CAD-related ischemic events. Early initiation of antithrombotics (ideally within the first 24–72 hours) reduces further embolic risk.
  2. Choice of Agent: Antiplatelet vs Anticoagulant
     • When to Prefer Anticoagulation:
       • Patients with high-risk imaging features: severe stenosis (>50%–70%), intraluminal thrombus, occlusion, multiple or early recurrent dissections.
       • Traditional option is heparin bridging to Vitamin K antagonist (target INR ≈2–3), but direct oral anticoagulants (DOACs) can be considered based on patient profile and preference.
     • When to Prefer Antiplatelet Therapy:
       • Patients with lower stroke risk (no significant stenosis, no intraluminal thrombus) or higher bleeding risk (large infarct, hemorrhagic transformation, intradural extension).
       • Aspirin monotherapy is typical; a short course of dual antiplatelet therapy (aspirin + clopidogrel) for 21–90 days can be considered if minor stroke/TIA criteria apply and bleeding risk is acceptable.
  3. Practical Start-Up and Monitoring:
     • Begin therapy as soon as deemed safe, ideally after hemorrhagic complications are excluded.
     • For VKA: bridge with heparin (IV unfractionated or low–molecular-weight) for at least 5 days until INR is therapeutic for ≥24 hours.
     • Regularly monitor clinical response and, if relevant, INR in anticoagulated patients.
  4. Duration of Therapy:
     • Minimum 3–6 months of antithrombotics, with vessel imaging at follow-up (eg, 3 or 6 months) to assess for healing or persistent dissection.
     • Decisions to extend antithrombotic therapy past the 6-month mark may be considered in the context of an individual’s overall vascular risk factor profile and in the context of neuroimaging features as remodeling occurs.
     • Consider extended or indefinite therapy (often antiplatelet) if persistent stenosis, high-risk anatomic factors, or recurrent dissections occur.
• Risk of Recurrent Dissection and Lifestyle Precautions
  • Recurrence rates range from 1% to 2% per year but are higher in the first few months post-dissection. Fibromuscular dysplasia and younger age are associated with increased recurrence risk.
  • It is reasonable to advise patients to avoid high-risk neck activities (eg, contact sports, extreme neck manipulation) for 1–6 months or until imaging confirms vessel healing. In those with a known connective tissue disorder or recurrent dissection, lifelong caution is appropriate.
• Follow-Up Imaging and Management of Dissecting Aneurysms
  • Recanalization most often occurs by 6–12 months; persistent occlusions or stenoses beyond 12 months rarely recanalize further.
  • Dissecting aneurysms form or enlarge in some cases but seldom rupture. Antithrombotic choice does not appear to affect aneurysm resolution rates.
  • Endovascular or surgical interventions are reserved for enlarging or symptomatic aneurysms causing compression or other complications.

Conclusion: Cervical artery dissection warrants vigilant clinical recognition, prompt imaging, and individualized treatment strategies. Early antithrombotic therapy—whether anticoagulation or antiplatelet—plays a critical role in preventing stroke. Decisions should reflect both the patient’s hemorrhagic risk and the presence of imaging features predictive of stroke. Mechanical thrombectomy and, in selected cases, stenting are viable acute interventions for high-risk presentations. Although recurrences are uncommon, thoughtful follow-up imaging, patient education, and avoidance of high-risk neck activities are central to minimizing future dissections and optimizing outcomes.

Reference: Yaghi S, Engelter S, Del Brutto VJ, Field TS, Jadhav AP, Kicielinski K, Madsen TE, Mistry EA, Salehi Omran S, Pandey A, Raz E, on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease. Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association. Stroke. 2024;55(3). DOI: https://doi.org/10.1161/STR.0000000000000457

 

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Review: Identification and Treatment of Alcohol Use Disorder

19 Jan, 2025 | 11:41h | UTC

Introduction: This summary provides key insights from a comprehensive review published in the New England Journal of Medicine about the clinical identification and management of alcohol use disorder (AUD). The document highlights AUD’s chronic, relapsing course, its underdiagnosis in general practice, and its wide-ranging health and social impacts. Emphasis is placed on early recognition, the importance of nonjudgmental communication, and the potential for effective treatment across various medical settings.

Key Recommendations:

• Routine Screening and Assessment: Clinicians should routinely ask about alcohol use, employing validated tools (e.g., AUDIT, AUDIT-C, or CAGE) to gauge risk. When self-reporting is unreliable, biologic markers (e.g., γ-glutamyl transpeptidase or phosphatidylethanol) can help detect recent or chronic use.
• Nonjudgmental, Patient-Centered Approach: Engagement improves when patients feel supported rather than stigmatized. Collaboration in care planning can enhance adherence, especially for individuals who are ambivalent about changing their alcohol consumption patterns.
• Brief Interventions: Time-limited counseling, guided by motivational interviewing principles, is effective in reducing alcohol use. These interventions can be delivered by primary care professionals and may motivate further treatment or pharmacotherapy.
• Psychosocial Therapies: Multiple methods—including cognitive behavioral therapy, motivational enhancement, acceptance and commitment therapy, and peer-supported programs (e.g., Alcoholics Anonymous, SMART Recovery)—offer benefit. Clinicians are encouraged to adapt and integrate these treatments based on availability, patient preference, and severity of dependence.
• Pharmacologic Treatment: Medications such as naltrexone (once daily), acamprosate (three times daily), and supervised disulfiram are approved and effective for AUD. Naltrexone helps reduce craving and heavy drinking; acamprosate supports abstinence; and disulfiram, though aversive if alcohol is consumed, can reinforce abstinence in motivated patients. Other agents (e.g., topiramate, gabapentin) show promise but are not universally approved.
• Management of Withdrawal: Outpatient or inpatient treatment of withdrawal depends on clinical stability and coexisting conditions. Benzodiazepines remain first-line for symptom control, with close monitoring to prevent complications like seizures and delirium tremens. Nutritional support, particularly thiamine replacement, is essential to avert Wernicke–Korsakoff syndrome.
• Addressing Coexisting Conditions: AUD commonly co-occurs with mental health disorders (e.g., depression, anxiety) and other substance use (especially tobacco). Screening for suicidality and referring for specialized care can improve overall outcomes. Medical complications (e.g., alcoholic liver disease, hypertension) may also improve with sustained alcohol reduction or abstinence.
• Ongoing Support and Follow-up: AUD has a relapsing course, so long-term care, repeated assessments, and revisiting treatment goals are crucial. Follow-up visits can reinforce progress, manage relapses, and promote sustained recovery efforts.

Conclusion: Recognizing and treating alcohol use disorder significantly improves patient outcomes in both physical and mental domains. Generalist clinicians play a pivotal role in screening, initiating brief interventions, and coordinating care. Timely, evidence-based interventions and a supportive, empathetic stance can reduce the immense burden of AUD, enhance treatment retention, and improve quality of life for affected individuals.

Reference: Haber PS. Identification and Treatment of Alcohol Use Disorder. New England Journal of Medicine. 2025;392:258-266. DOI: http://doi.org/10.1056/NEJMra2306511

 

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Review: Management of Alcohol Withdrawal Syndromes in General Hospital Settings

14 Jan, 2025 | 12:33h | UTC

Introduction:
This summary provides an overview of a state-of-the-art review on identifying, assessing, and treating alcohol withdrawal syndromes among patients in general hospital settings. The rising prevalence of heavy alcohol use—and the sharp increase in hospital admissions for alcohol withdrawal during and after the COVID-19 pandemic—underscores the need for clear, evidence-based guidance. This review addresses the epidemiology, pathophysiology, clinical features, screening tools, and pharmacologic options for managing alcohol withdrawal. It also highlights nutritional considerations and the importance of preventing relapse to reduce readmissions and improve patient outcomes.

Key Recommendations:

1. Screening and Risk Stratification:
   • Use brief, validated questionnaires (eg, Single Alcohol Screening Question or AUDIT-C) to identify at-risk alcohol use.
   • Employ biomarker tests (eg, blood alcohol level, PEth, EtG) when possible to confirm recent intake and evaluate heavy use.
   • Consider standardized risk scales (eg, PAWSS) to identify patients likely to develop severe withdrawal and guide treatment intensity.
2. Symptom Severity Assessment:
   • Select a validated tool to monitor withdrawal progress (eg, CIWA-Ar).
   • For patients with altered mental status or unreliable self-report, consider alternative scales (eg, BAWS or GMAWS) that rely more on objective signs.
3. Benzodiazepine Therapy:
   • Continue to regard benzodiazepines (particularly long-acting agents like diazepam or chlordiazepoxide) as first-line therapy for prevention of seizures and delirium.
   • In patients with liver dysfunction or advanced age, short-acting options (eg, lorazepam, oxazepam) may be safer.
   • Symptom-triggered regimens can reduce total benzodiazepine exposure in lower-risk patients but require trained staff and structured protocols.
   • Fixed-schedule or loading-dose regimens may be warranted in severe withdrawal cases or when symptom-triggered approaches prove insufficient.
4. Alternative and Adjunctive Pharmacotherapies:
   • Phenobarbital: Offers GABA-enhancing and anti-glutamatergic effects, useful in severe or benzodiazepine-resistant withdrawal; consider ICU-level monitoring for high-risk patients.
   • Alpha-2 Adrenergic Agonists (clonidine, dexmedetomidine): Adjunctive benefit for persistent autonomic instability (tachycardia, hypertension), but these agents do not prevent seizures or delirium if used alone.
   • Antiseizure Medications (eg, carbamazepine, gabapentin, valproate): May aid in mild cases or adjunctively, but current evidence does not support them as stand-alone agents in severe withdrawal.
5. Nutritional Repletion and Thiamine Replacement:
   • Aggressively treat thiamine deficiency (eg, IV thiamine 200–500 mg daily) to prevent or halt Wernicke-Korsakoff syndrome.
   • Correct additional deficits (eg, folate, magnesium) for better overall recovery.
6. Relapse Prevention and Post-Acute Care:
   • Initiate FDA-approved medications (eg, naltrexone or acamprosate) during admission to reduce relapse risk after discharge.
   • Provide psychosocial support and referral to continuing addiction services (eg, specialty programs, peer support) to sustain recovery efforts.

Conclusion:
Effective management of alcohol withdrawal in hospital settings requires early recognition of at-risk patients, thoughtful risk stratification, and prompt pharmacologic intervention tailored to withdrawal severity and comorbid conditions. Benzodiazepines remain the mainstay therapy, though phenobarbital shows promise, particularly for resistant or severe cases. Adjunctive alpha-2 agonists help control hyperadrenergic symptoms, but do not replace core GABA-targeted therapies. By integrating nutritional repletion, addressing potential complications, and initiating relapse-prevention strategies, clinicians can reduce both the morbidity of acute withdrawal and the likelihood of future hospitalizations related to alcohol use.

Reference:
Kast KA, Sidelnik SA, Nejad SH, Suzuki J. Management of alcohol withdrawal syndromes in general hospital settings. BMJ 2025;388:e080461. https://doi.org/10.1136/bmj-2024-080461

 

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Managing Autonomic Dysfunction, Pain, and Sleep Disturbances in Parkinson’s Disease: Key Points from the German Society of Neurology Guideline

5 Jan, 2025 | 11:00h | UTC

Introduction: This text summarizes a practice-oriented 2023 guideline from the German Society of Neurology addressing non-motor manifestations of Parkinson’s disease (PD). The guideline focuses on evidence-based approaches for diagnosing and treating autonomic failure (including urogenital, cardiovascular, and gastrointestinal dysfunction), pain, and sleep disturbances—problems that often reduce quality of life and accelerate disease progression. The guideline was developed using PICO (Patient, Intervention, Comparison, Outcome) questions, comprehensive literature searches, and a consensus process among German Parkinson’s experts. By presenting stepwise recommendations, the guideline aims to help clinicians manage these non-motor aspects more effectively and improve patient outcomes.

Key Recommendations:

Autonomic Failure

• Bladder Dysfunction: Encourage behavioral modifications (e.g., timed fluid intake, bladder training) and, if necessary, consider antimuscarinics (e.g., solifenacin, trospium) or β3 agonists (e.g., mirabegron 50 mg once daily). Specifically, solifenacin 5 mg once daily, trospium 15–30 mg twice daily or darifenacin 7.5–15 mg once daily are preferred, due to their lower risk of cognitive side effects.
  • In patients who have responded inadequately to oral therapy, intravesical botulinum toxin A injection (200 U or customized) may be considered for treating severe urinary urge incontinence, if the individual motor and cognitive performance enables the subsequently likely necessary intermittent catheterization.
  • For nocturia, limit evening fluid intake and consider a 10°–20° head-up tilt in bed. In nocturnal polyuria, desmopressin (5–40 µg once daily nasal spray or 100–800 µg once daily per os) may be used with close monitoring of blood pressure, serum electrolytes and body weight.
• Orthostatic Hypotension (OH): Apply a four-step approach: (1) address aggravating factors (e.g., infections, dehydration); (2) review medications; (3) use non-pharmacological measures (increased fluid/salt intake if no contraindications, abdominal binders, head-up tilt sleeping); (4) add medications to raise blood pressure (e.g., midodrine 2.5–10 mg two to three times a day, fludrocortisone 0.1–0.3 µg once daily). For the diagnosis of OH, a Schellong test or tilt table examination should be performed.
  • Monitor for supine hypertension, which may require evening antihypertensives (e.g., low-dose losartan 25–100 mg or transdermal nitroglycerin 0.1–0.2 mg/h) and further adjustments. PD individuals with neurogenic OH should be screened for the presence of supine and nocturnal hypertension.
• Constipation: Follow the general German guideline on “Chronic Constipation.” Emphasize adequate hydration (1.5-2 L per day), fiber intake, and exercise.
  • First-line drug therapy is macrogol (polyethylene glycol, PEG, 13–26 g once daily). Consider bisacodyl (5–10 mg once daily), sodium picosulfate (5–10 mg once daily), or prucalopride (1–2 mg once daily) if needed.
• Male Erectile Dysfunction: First-line treatment involves phosphodiesterase type 5 (PDE-5) inhibitors (e.g., sildenafil 50–100 mg on demand), used cautiously in patients with orthostatic hypotension. A multidisciplinary approach with urologists is necessary.

Pain Management

• Classification: Differentiate PD-related pain (nociceptive, neuropathic, or nociplastic) from pain arising independently of PD. Use PD-specific scales, such as the King’s Parkinson’s Disease Pain Scale (KPPS) or the Parkinson’s Disease Pain Classification System (PD-PCS), to clarify pain etiology and guide therapy.
• Approach: Optimize dopaminergic therapy, especially if pain correlates with wearing-off.
  • Treat nociceptive pain per the WHO 3-step analgesic ladder (which recommends starting with non-opioid analgesics like acetaminophen or NSAIDs, then moving to mild opioids like codeine if needed, and finally to strong opioids like morphine for severe pain).
  • For neuropathic pain, preference is given to anticonvulsants (e.g., gabapentin 300–1800 mg, especially in case of concomitant restless legs syndrome) or antidepressants (e.g., duloxetine 60–120 mg, in case of concomitant depression).
  • Opioids (e.g., prolonged-release oxycodone/naloxone 5/2.5–20/10 mg, rarely up to 40/20 mg) may be considered in severe or refractory cases.

Sleep Disturbances

• Screening & Diagnosis: Use the Parkinson’s Disease Sleep Scale-2 (PDSS-2) to identify problems such as insomnia, nocturnal akinesia, restless legs, and REM sleep behavior disorder (RBD).
  • Objective tests—actigraphy, polygraphy, or video-polysomnography—are recommended for complex or treatment-refractory sleep issues.
• Treatment: Address comorbid conditions (e.g., restless legs syndrome, sleep apnea) following standard guidelines.
  • If motor fluctuations disturb sleep, adjust dopaminergic therapy (e.g., use long-acting levodopa or dopamine agonists at night).
  • RBD management typically includes creating a safe sleep environment and considering clonazepam (0.125–3 mg) or melatonin (2–9 mg).
  • Insomnia linked to circadian disruption may benefit from good sleep hygiene, bright light therapy, structured exercise, and (if indicated) low-dose agents such as eszopiclone (1 mg), doxepin (25 mg), zolpidem (5 mg), trazodone (50 mg), melatonin (2 mg), venlafaxine (37.5 mg, in case of comorbid depression), nortriptyline (25 mg) or mirtazapine (7.5 mg).
  • Excessive daytime sleepiness calls for an etiology-driven approach, with non-pharmacological strategies (e.g., scheduled naps, light therapy, exercise) and possible use of modafinil (200–400 mg) if needed. Driving should be reassessed if sleep attacks occur.

Clinical Impact: Poor sleep worsens cognitive decline, motor deficits, caregiver burden, and overall disease progression. RBD in early PD often predicts faster deterioration and earlier cognitive complications. The guideline also addresses the prognostic implications of sleep disturbances.

Conclusion: This guideline underscores the critical importance of identifying and managing non-motor symptoms in Parkinson’s disease. A structured, practice-oriented, etiology-driven stepwise approach to autonomic failure, pain, and sleep problems helps reduce the risk of dangerous complications, alleviates patient distress, and may delay the progression of both motor and cognitive domains. By integrating evidence-based recommendations into daily practice—focusing on precise assessment, tailored interventions, and regular follow-up—clinicians can improve outcomes and quality of life for individuals with PD and their caregivers.

Reference: Fanciulli A, Sixel-Döring F, Buhmann C, Krismer F, Hermann W, Winkler C, Woitalla D, Jost WH, German Parkinson’s Guideline Group, Trenkwalder C & Höglinger G (2025). Diagnosis and treatment of autonomic failure, pain and sleep disturbances in Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology. Journal of Neurology (2025). DOI: https://doi.org/10.1007/s00415-024-12730-5

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Meta-Analysis: Glutamatergic Agents May Improve Obsessive-Compulsive and Related Disorder Symptoms

4 Jan, 2025 | 12:08h | UTC

Background: Obsessive-compulsive and related disorders (OCRDs) affect approximately 2% to 3% of the general population and encompass conditions such as OCD, skin-picking disorder, and trichotillomania, leading to substantial distress and impaired daily functioning. Glutamatergic dysfunction within cortico-striatal-thalamo-cortical circuits has emerged as a potential target, prompting investigations into whether glutamatergic agents can enhance outcomes either alone or alongside selective serotonin reuptake inhibitors (SSRIs).

Objective: To determine whether glutamatergic medications, used as monotherapy or as augmentation to SSRIs, can improve clinical symptoms across different OCRDs compared to placebo, with emphasis on changes in standardized measures such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).

Methods: This systematic review and meta-analysis included 27 double-blind, placebo-controlled randomized clinical trials involving 1369 participants with OCRDs. Eligible studies examined agents including N-acetylcysteine (NAC), memantine, lamotrigine, riluzole, and topiramate, among others. Data extraction focused on changes in symptom severity, and pooled effect sizes were calculated using random-effects meta-analysis. Subgroup analyses evaluated potential moderators, such as disorder subtype, age group, refractoriness, and augmentation strategies, while sensitivity analyses and publication bias assessments (e.g. Egger test) were performed to ensure robustness.

Results: Overall, glutamatergic medications showed a large effect size in reducing OCRD symptoms (Cohen’s d = −0.80). Specifically for OCD (n=23 trials), a significant mean reduction in Y-BOCS scores (−4.17 points) indicated clinically meaningful improvement. Publication bias was detected in the broader OCRD meta-analysis but not in the OCD-specific analysis. Heterogeneity was high across studies, reflecting varied populations and treatment designs. Despite these findings, the certainty of evidence ranged from low to moderate, mandating cautious interpretation.

Conclusions: Glutamatergic interventions appear promising for OCRDs, particularly OCD, where moderate-certainty evidence suggests meaningful symptom improvement. Nevertheless, elevated heterogeneity and signs of publication bias highlight the need for larger, more rigorous trials to confirm optimal dosing parameters and elucidate which patient subsets may benefit most.

Implications for Practice: Clinicians might consider adding or switching to glutamatergic agents for individuals with inadequate response to SSRIs. However, these findings do not warrant unrestrained enthusiasm. Each case should be weighed individually, taking into account possible mild to moderate gastrointestinal side effects (particularly with NAC).

Study Strengths and Limitations: Strengths include the focus on double-blind RCTs, diverse glutamatergic agents, and robust statistical approaches. Limitations comprise high between-study heterogeneity, limited data for less common disorders (e.g., body dysmorphic disorder), and potential publication bias. Additionally, few trials specifically tested novel agents like ketamine.

Future Research: Studies with larger sample sizes, clearly defined outcomes, and detailed dose-response evaluations are needed. Future trials should explore underrepresented OCRDs, such as hoarding disorder, and newer glutamatergic compounds (e.g., troriluzole) to further optimize therapeutic strategies.

Reference: Coelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52963

 

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Cohort Study: One in Four Patients Demonstrates Covert Cognition Despite Behavioral Unresponsiveness

3 Jan, 2025 | 08:30h | UTC

Background: Cognitive motor dissociation (CMD) refers to the presence of specific neuroimaging or electrophysiological responses to commands in patients otherwise incapable of voluntary behavioral output. Detecting CMD is clinically relevant because its underdiagnosis may lead to premature decisions regarding goals of care, life-sustaining treatment, and rehabilitation efforts. Although several single-center studies have suggested that CMD may exist in 10–20% of patients with disorders of consciousness, larger multinational data were lacking, particularly using both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).

Objective: To determine how often CMD occurs in a large, multinational cohort of adults with impaired consciousness and to evaluate the clinical variables potentially associated with this phenomenon.

Methods: This prospective cohort study included 353 adults with disorders of consciousness recruited from six international centers between 2006 and 2023. Enrolled participants had at least one behavioral assessment using the Coma Recovery Scale–Revised (CRS-R) and underwent task-based fMRI, EEG, or both. Sites utilized validated analytic pipelines and automated data processing to minimize false positives. Participants were divided into two groups: those without observable responses to verbal commands (coma, vegetative state, or minimally conscious state–minus) and those with observable responses (minimally conscious state–plus or emerged). CMD was defined as the absence of any observable behavioral response to commands, combined with a positive command-following signal on fMRI or EEG.

Results: Among 241 participants with no overt command-following, 25% showed CMD through either fMRI alone, EEG alone, or both. CMD was more common in younger patients, those assessed later after injury, and those with traumatic brain injury. Interestingly, in 112 participants who did exhibit command-following on bedside exams, only 38% demonstrated confirmatory responses on fMRI or EEG. These findings support the notion that the tasks used for neuroimaging and electrophysiological assessments may require more sustained cognitive engagement than typical bedside evaluations.

Conclusions: CMD was identified in about one in four patients who lacked behavioral command-following. Combining fMRI with EEG likely increases detection rates compared to either modality alone. The results highlight the need for increased awareness of covert cognitive activity in this population, given potential ramifications for prognosis, family counseling, and clinical care.

Implications for Practice: Clinicians should consider the possibility of CMD in patients who appear unresponsive at the bedside. When feasible, employing both fMRI and EEG might reveal hidden cognitive capacities that can guide patient-centered decisions, encourage targeted therapies, and allow healthcare teams to respect potential consciousness and autonomy. However, such technologies remain limited to specialized centers.

Study Strengths and Limitations: Strengths include a diverse sample from multiple international sites and the integration of two complementary neurodiagnostic techniques. Limitations involve heterogeneous recruitment practices, variations in local data acquisition methods, and potential selection biases toward patients who survived until advanced testing was available. Additionally, the absence of standardized paradigms across sites reduced consistency of results.

Future Research: Further large-scale investigations should standardize fMRI and EEG protocols and determine whether earlier and more consistent identification of CMD affects functional outcomes. Efforts to refine and validate automated analytic pipelines could facilitate widespread adoption of these techniques in routine clinical settings.

Reference: Bodien YG, Allanson J, Cardone P, et al. Cognitive Motor Dissociation in Disorders of Consciousness. New England Journal of Medicine. 2024;391:598-608. DOI: http://doi.org/10.1056/NEJMoa2400645

 

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RCT: Discontinuing First-Line DMT in Long-Term Stable Relapsing MS Leads to Recurrence of Disease Activity

3 Jan, 2025 | 08:00h | UTC

Background: Increasing numbers of patients with relapsing-onset multiple sclerosis (MS) are receiving first-line disease-modifying therapies (DMTs) to control inflammatory lesions and reduce disability progression. Yet, extended therapy raises questions regarding overtreatment, adverse effects, and costs, especially in older or clinically stable individuals.

Objective: This randomized, multicenter, rater-blinded clinical trial (DOT-MS) assessed whether discontinuing first-line DMT in adults with MS who had at least five years of clinical and radiological stability is safe in terms of recurrence of significant inflammatory disease activity.

Methods: Eighty-nine participants (median age 54 years, 67% female) were randomly assigned 1:1 to either continue or discontinue their first-line DMT. Inclusion required relapse-onset MS without new, sizeable brain MRI lesions (≤1 new T2 lesion in the previous five years or ≤3 new T2 lesions in the past ten years). Follow-up included clinical evaluations, gadolinium-enhanced brain MRI at baseline and months 3, 6, 12, 18, and 24, and optional unscheduled visits. The primary endpoint was significant inflammatory disease activity, defined as clinical relapse and/or ≥3 new T2 lesions or ≥2 contrast-enhancing lesions. The trial was prematurely terminated by the data safety monitoring board due to higher-than-expected disease activity in the discontinue arm.

Results: After a median follow-up of 15.3 months, none of the 44 participants in the continue group had significant disease activity, versus 8 of 45 (17.8%) in the discontinue group (95% CI for difference, 0.09–0.32). Nearly all events were MRI-detected new or enhancing lesions, though two participants experienced clinical relapses. Most individuals with reactivation were able to regain stability upon DMT reintroduction. Serum neurofilament light levels rose during episodes of inflammatory activity, but neither NfL nor GFAP levels reliably predicted disease recurrence at baseline. No difference in serious adverse events emerged between groups.

Conclusions: In this trial, discontinuation of first-line DMT in long-term stable MS was associated with a significant risk (about 20%) of inflammatory reactivation, particularly noted in participants under 55 years old. As a result, close clinical and MRI monitoring should be mandatory if discontinuation is attempted, with early DMT reinitiation if necessary.

Implications for Practice: Clinicians may consider stopping first-line DMT in select patients who exhibit prolonged stability, especially in older adults, but must remain vigilant. Rapid detection of any radiological or clinical sign of reactivation is crucial, as reintroducing therapy may reestablish disease control.

Study Strengths and Limitations: Strengths include its randomized design, systematic imaging schedule, and thorough biomarker sampling. Limitations involve early trial termination, restricting subgroup analyses and definitive noninferiority testing. Routine spinal cord imaging was not performed, potentially underestimating subclinical disease activity.

Future Research: Longer-term observational follow-up is ongoing to clarify how these participants fare over time and to identify biomarkers that may better predict risk of rebound activity. Evaluating cost-effectiveness and long-term clinical outcomes will guide future decisions about DMT discontinuation.

Reference: Coerver EME, et al. Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial. JAMA Neurology. 2024. DOI: http://doi.org/10.1001/jamaneurol.2024.4164

 

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Three Phase 3, Placebo-Controlled Trials Show Rapid Benefits of Oral Atogepant for Migraine Prevention

26 Dec, 2024 | 12:17h | UTC

Background: Preventive therapies for migraine often require long titration and may take weeks to achieve their full effect. This analysis integrates data from three randomized, placebo-controlled Phase 3 trials (ADVANCE, ELEVATE, PROGRESS) assessing atogepant 60 mg once daily (QD) over 12 weeks, focusing on the first four weeks. A key point is that atogepant was compared only to placebo, not to other well-established migraine preventives.

Objective: To determine whether atogepant provides early efficacy in reducing migraine frequency and improving functional outcomes within the initial weeks of therapy, for both episodic and chronic migraine.

Methods: All three studies enrolled participants aged 18–80 years with a ≥1-year history of migraine. ADVANCE and ELEVATE focused on episodic migraine (EM; 4–14 monthly migraine days), while PROGRESS studied chronic migraine (CM; ≥15 monthly headache days, ≥8 of which met migraine criteria). In ELEVATE, participants had previously failed 2–4 classes of oral migraine preventives. Throughout each trial, patients recorded daily migraine-related data and completed validated functional assessments (AIM-D and EQ-5D-5L). For this pooled analysis, only the atogepant 60 mg QD and placebo arms were examined.

Results: Atogepant recipients had a significantly lower proportion of patients with a migraine day on day 1 in all three trials, suggesting a rapid onset of benefit. Reductions in weekly migraine days (WMDs) emerged as early as week 1 and remained consistently greater than placebo over the first four weeks. Functional measures improved within this same timeframe, with patients on atogepant reporting reductions in activity impairment and enhanced self-rated health. These positive findings were observed in EM (with or without prior prophylaxis failures) and in CM populations.

Conclusions: Atogepant 60 mg QD was linked to early and significant reductions in migraine days, as well as enhancements in physical functioning and daily activities, across three placebo-controlled studies. The data suggest that atogepant may offer clinically meaningful, rapid-onset prophylactic benefits.

Implications for Practice: Clinicians may consider atogepant for patients seeking a preventive migraine therapy that demonstrates a potentially faster impact on symptom frequency and daily functioning. However, direct comparisons with established active treatments are lacking, and appropriate caution in interpreting the early onset of benefit is recommended.

Study Strengths and Limitations: Major strengths include robust, double-blind methodologies and consistent findings across diverse migraine populations. A key limitation is the exclusive use of placebo as the comparator, so the relative advantage over standard preventives remains unknown. The predominantly female and White study cohorts also restrict generalizability.

Future Research: Further investigations should evaluate atogepant in direct comparisons with existing active migraine preventives, examine long-term outcomes, and recruit more diverse populations. Such efforts could better define the therapy’s place in routine migraine care.

Reference: Lipton RB, et al. Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials. Neurology. 2025;104(2). DOI: https://doi.org/10.1212/WNL.0000000000210212

 

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VisionFM: A Generalist AI Surpasses Single-Modality Models in Ophthalmic Diagnostics

25 Dec, 2024 | 13:41h | UTC

Background: Ophthalmic AI models typically address single diseases or modalities. Their limited generalizability restricts broad clinical application. This study introduces VisionFM, a novel foundation model trained on 3.4 million images from over 500,000 individuals. It covers eight distinct ophthalmic imaging modalities (e.g., fundus photography, OCT, slit-lamp, ultrasound, MRI) and encompasses multiple diseases. Compared with prior single-task or single-modality approaches, VisionFM’s architecture and large-scale pretraining enable diverse tasks such as disease screening, lesion segmentation, prognosis, and prediction of systemic markers.

Objective: To develop and validate a generalist ophthalmic AI framework that can handle multiple imaging modalities, recognize multiple diseases, and adapt to new clinical tasks through efficient fine-tuning, potentially easing the global burden of vision impairment.

Methods: VisionFM employs individual Vision Transformer–based encoders for each of the eight imaging modalities, pretrained with self-supervised learning (iBOT) focused on masked image modeling. After pretraining, various task-specific decoders were fine-tuned for classification, segmentation, and prediction tasks. The model was evaluated on 53 public and 12 private datasets, covering eight disease categories (e.g., diabetic retinopathy, glaucoma, cataract), five imaging modalities (fundus photographs, OCT, etc.), plus additional tasks (e.g., MRI-based orbital tumor segmentation). Performance metrics included AUROCs, Dice similarity coefficients, F1 scores, and comparisons with ophthalmologists of varying clinical experience.

Results: VisionFM achieved an average AUROC of 0.950 (95% CI, 0.941–0.959) across eight disease categories in internal validation. External validation showed AUROCs of 0.945 (95% CI, 0.934–0.956) for diabetic retinopathy and 0.974 (95% CI, 0.966–0.983) for AMD, surpassing baseline deep learning approaches. In a 12-disease classification test involving 38 ophthalmologists, VisionFM’s accuracy matched intermediate-level specialists. It successfully handled modality shifts (e.g., grading diabetic retinopathy on previously unseen OCTA), with an AUROC of 0.935 (95% CI, 0.902–0.964). VisionFM also predicted glaucoma progression (F1, 72.3%; 95% CI, 55.0–86.3) and flagged possible intracranial tumors (AUROC, 0.986; 95% CI, 0.960–1.00) from fundus images.

Conclusions: VisionFM offers a versatile, scalable platform for comprehensive ophthalmic tasks. Through self-supervised learning and efficient fine-tuning, it extends specialist-level performance to multiple clinical scenarios and imaging modalities. The study demonstrates that large-scale, multimodal pretraining can enable robust generalization to unseen data, potentially reducing data annotation burdens and accelerating AI adoption worldwide.

Implications for Practice: VisionFM may help address global shortages of qualified ophthalmologists and expand care in low-resource settings, though clinical decision-making still requires appropriate human oversight. Further multicenter studies are needed before widespread implementation, especially for higher-risk use cases such as tumor detection.

Study Strengths and Limitations: Strengths include its unique multimodal design, large-scale pretraining, and extensive external validation. Limitations involve demographic bias toward Chinese datasets, the need for larger cohorts in certain applications (e.g., intracranial tumor detection), and the challenges of matching real-world clinical complexity when only image-based data are used.

Future Research: Further validation in diverse populations, integration of new imaging modalities (e.g., widefield imaging, ultrasound variants), and expansion to additional diseases are planned. Hybridization with large language models could facilitate automatic generation of clinical reports.

Reference: Qiu J, Wu J, Wei H, et al. Development and Validation of a Multimodal Multitask Vision Foundation Model for Generalist Ophthalmic Artificial Intelligence. NEJM AI 2024;1(12). DOI: http://doi.org/10.1056/AIoa2300221

 

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Meta-analysis: Incidence Rate Difference of Adverse Events from Canabinoids in Middle-Aged and Older Adults

25 Dec, 2024 | 12:19h | UTC

Background: Growing evidence suggests that cannabinoid-based medicines (CBMs) are increasingly prescribed to individuals aged 50 years and above for various clinical conditions. While these agents may offer therapeutic benefits, questions remain about the incidence of adverse events (AEs), particularly in older adults with multiple comorbidities. This systematic review and meta-analysis aims to quantify the incidence rate difference (IRD) of AEs and determine whether weekly doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are associated with any dose-dependent increase in risk.

Objective: To evaluate whether adults aged ≥50 years exposed to CBMs, including THC-alone formulations and THC combined with CBD, experience a higher incidence of AEs than controls, and to assess how variations in weekly THC and CBD doses might affect AE rates.

Methods: Researchers searched MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library, and ClinicalTrials.gov from January 1, 1990, to June 12, 2023. Randomized clinical trials involving middle-aged and older adults (mean age ≥50 years) using medicinal CBMs for all indications were included. Data on common and serious AEs, withdrawals, and deaths were extracted and pooled using a random-effects model. Further meta-regression analyses examined THC and CBD weekly doses as predictors of AEs in THC-only and THC:CBD trials.

Results: Fifty-eight randomized clinical trials (n=6611) met inclusion criteria, with 3450 participants receiving CBMs. Compared to controls, individuals on THC-alone experienced significantly higher incidence of dizziness, somnolence, impaired coordination, dissociative symptoms, and dry mouth, often in a dose-dependent manner. Similarly, THC:CBD combinations increased nausea, vomiting, fatigue, dizziness, and disorientation. The incidence of serious AEs, withdrawals, or mortality did not differ significantly between CBM and control groups, although neurological or psychiatric side effects were more pronounced with higher THC doses.

Conclusions: THC-containing CBMs can provoke dose-related gastrointestinal, neurological, and psychiatric adverse events, posing additional risks in older adults susceptible to falls and cognitive disturbances. However, the meta-analysis found no significant increases in serious AEs or deaths. Clinicians should weigh potential benefits against the likelihood of common side effects, especially when prescribing higher THC doses or combining cannabinoids with other medications frequently used by older patients.

Implications for Practice:

• Physicians should exercise caution when initiating or escalating THC-based therapies in middle-aged and older adults, monitoring for neurological or psychiatric AEs.
• Using lower THC doses, titrating gradually, and adding CBD may mitigate some side effects.
• Though severe AEs are uncommon, vigilance is warranted in individuals with complex medication regimens.

Study Strengths and Limitations:

• Strength: This review merges diverse clinical conditions and provides a comprehensive assessment of THC vs. THC:CBD. Its large pooled population allows for more precise IRD estimates.
• Limitation: Short treatment durations in many trials limit understanding of long-term toxicity, and some studies lacked rigorous reporting of randomization and outcome measures, potentially introducing bias.

Future Research:

• Longer-duration trials focused on older populations are needed to clarify chronic safety profiles.
• Studies exploring drug-drug interactions between CBMs and medications commonly prescribed to older adults will further elucidate real-world tolerability.

Reference: Velayudhan L, Pisani S, Dugonjic M, McGoohan K, Bhattacharyya S. Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference. Age and Ageing. 2024;53(11):afae261. DOI: https://doi.org/10.1093/ageing/afae261

 

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Bayesian Network Meta-Analysis: Chlorpromazine IV/IM Emerges as a Top Choice for Acute Migraine Relief in the ED

25 Dec, 2024 | 11:18h | UTC

Background: Acute migraine is a prevalent cause of emergency department (ED) visits, necessitating prompt pain control. Although numerous drugs are available, there is debate about the most effective and safest options. Traditional pairwise meta-analyses fail to capture all treatment comparisons in a single framework, making network meta-analyses, particularly Bayesian, an appealing approach to inform clinical decision-making.

Objective: This systematic review and Bayesian network meta-analysis aimed to compare multiple pharmacologic therapies—single agents or combinations—for acute migraine relief in adults presenting to the ED. The goal was to identify those most likely to achieve adequate pain relief, reduce rescue medication use, and minimize significant adverse reactions.

Methods: The authors searched MEDLINE, Embase, and Web of Science from inception to February 9, 2024, for randomized controlled trials comparing any pharmacologic therapy to another or to placebo in ED patients with migraine. Four primary outcomes were analyzed: (1) adequate pain relief at two hours, (2) change in pain intensity at one hour, (3) need for rescue drug at two hours, and (4) significant adverse reaction (eg, sedation, akathisia, hypotension).

Results: Twenty-four to twenty-seven trials contributed to each outcome network. Chlorpromazine IV/IM was ranked highest for adequate pain relief (SUCRA=87.3%) and also significantly reduced the need for rescue medication (SUCRA=93.2%). Ibuprofen IV and valproate IV emerged among the least effective for pain relief, while dexamethasone IV was the most probable to cause fewer serious adverse reactions (SUCRA=79.5%). However, most comparisons were of low or very low certainty, limiting the strength of the findings.

Conclusions: Chlorpromazine IV/IM appears among the most effective single agents for acute migraine in the ED, although it may carry higher risks of sedation or hypotension. Certain analgesics (eg, ibuprofen IV, valproate IV, and possibly ketorolac IV/IM) demonstrated lower efficacy. Due to variability in trial size, dosing, and participant characteristics, the overall certainty of evidence remains limited.

Implications for Practice: Clinicians may consider parenteral chlorpromazine for rapid migraine relief, balancing its adverse event profile with potential efficacy. Dexamethasone’s lower probability of serious side effects could make it a complementary option. The findings highlight the need for individualized treatment, taking into account patient comorbidities and preferences.

Study Strengths and Limitations: This network meta-analysis offers a broad comparative perspective on diverse pharmacologic interventions for ED-based migraine management. Nonetheless, there is notable heterogeneity in study methodologies, small sample sizes, and sparse direct comparisons for many interventions, all of which reduce certainty in the estimates.

Future Research: Larger, more standardized trials are needed to confirm these results and directly compare drugs like chlorpromazine, prochlorperazine, and metoclopramide-NSAID combinations. Rigorous safety reporting is crucial to clarify adverse reaction risks for various agents, especially those with less available evidence.

Reference: deSouza IS, Anthony N, Thode H Jr, et al. Effectiveness and Safety of Pharmacologic Therapies for Migraine in the Emergency Department: A Systematic Review and Bayesian Network Meta-analysis. Annals of Emergency Medicine. DOI: http://doi.org/10.1016/j.annemergmed.2024.11.004

 

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Guideline: Metformin to Prevent Antipsychotic-Induced Weight Gain

23 Dec, 2024 | 20:55h | UTC

Introduction:
This guideline was developed to address a pressing need for strategies to prevent antipsychotic-induced weight gain (AIWG), a frequent and troubling adverse effect of treatment in individuals with severe mental illness (SMI). Although metformin has shown consistent benefits in mitigating weight gain when initiated alongside antipsychotics, clinical uptake remains limited. The guideline follows the AGREE II framework and synthesizes both randomized and observational research, including Cochrane and meta-analytic data. The primary objective is to outline explicit indications, dosing approaches, and duration for using metformin to avert AIWG.

Key Recommendations:

1. Co-initiation With High-Risk Agents: In patients requiring higher-risk antipsychotics (olanzapine, clozapine), start metformin simultaneously. Evidence suggests that concurrent treatment may lessen weight gain by 3 to 5 kg in the early months, potentially yielding greater benefits over time.
2. Co-initiation With Medium-Risk Agents: For individuals prescribed quetiapine, paliperidone, or risperidone who have at least one cardiometabolic risk factor (such as diabetes, prediabetes, hypertension, or BMI above 25) or who are 10 to 25 years old, begin metformin at antipsychotic initiation to curb rapid weight changes.
3. Initiation During the First Year: If, at any point in the first year of antipsychotic treatment, weight gain exceeds 3% over baseline, consider adding metformin regardless of the antipsychotic being used.
4. Titration Schedule and Safety: The guideline advises starting at 500 mg once daily, then moving to 500 mg twice daily after about two weeks, with subsequent increases every two weeks up to 1 g twice daily (2 g/day) as tolerated. Metformin must be discontinued if lactic acidosis is suspected, if BMI falls below 20, or if the antipsychotic is stopped. Avoid its use in harmful alcohol consumption.
5. Additional Treatment Options: In cases of obesity (BMI ≥30) or comorbid metabolic disorders, clinicians should consider adding glucagon-like peptide-1 receptor agonists (GLP-1) where available. If cost, supply, or access is limited, metformin remains a practical alternative.

Conclusion:
This is the first evidence-based guideline focused on preventing AIWG by starting metformin at the time of antipsychotic initiation or upon early weight gain signs. By reducing the magnitude of weight increase, metformin may alleviate health risks tied to obesity, as well as psychological distress and nonadherence to treatment. Implementing the guideline involves continuous weight monitoring, structured dose adjustments, and shared decision-making. Ensuring clear communication about benefits and potential side effects will be crucial for sustaining adherence and improving patient outcomes.

Reference:
Carolan A, Hynes-Ryan C, Agarwal SM, Bourke R, Cullen W, Gaughran F, Hahn MK, Krivoy A, Lally J, Leucht S, et al. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2024; sbae205.
DOI: https://doi.org/10.1093/schbul/sbae205

Additional Commentaries:

• Psychiatric News Alert: https://alert.psychnews.org/2024/12/new-guideline-advises-metformin-to.html
• Zagorski N. Metformin May Reduce Weight Gain in Youth Taking Antipsychotics. Psychiatric News. 2024; 59(01). https://psychiatryonline.org/doi/full/10.1176/appi.pn.2024.01.1.22

 

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Meta-Analysis: Endovascular Therapy for Vertebrobasilar Occlusion Improves Functional Outcomes

19 Dec, 2024 | 22:56h | UTC

Background: Acute vertebrobasilar artery occlusion (VBAO) is associated with high mortality and severe neurological deficits. Previous randomized trials of endovascular therapy (EVT) for VBAO have shown inconsistent results, leaving uncertainty about its efficacy across different patient subgroups.

Objective: To determine whether EVT confers improved 90-day functional outcomes compared with standard medical therapy alone in patients with acute VBAO and to explore treatment effect heterogeneity in prespecified subgroups.

Methods: This individual patient data meta-analysis included all four major randomized controlled trials (ATTENTION, BAOCHE, BASICS, BEST) that enrolled patients with VBAO treated within 24 hours of estimated onset. Participants received either EVT or best medical therapy. The primary outcome was a favorable functional status at 90 days (modified Rankin Scale [mRS] score 0–3). Secondary outcomes included functional independence (mRS 0–2), distribution of mRS scores (shift analysis), symptomatic intracranial hemorrhage (sICH), and all-cause mortality at 90 days.

Results: Among 988 patients (556 EVT; 432 control), median age 67 years, EVT significantly increased the proportion achieving mRS 0–3 (45% vs 30%; adjusted odds ratio [aOR] 2.41, 95% CI 1.78–3.26) and mRS 0–2 (35% vs 21%; aOR 2.52, 95% CI 1.82–3.48). EVT improved the overall distribution of functional outcomes (aOR for mRS shift 2.09, 95% CI 1.61–2.71) and reduced 90-day mortality (36% vs 45%; aOR 0.60, 95% CI 0.45–0.80). Although sICH was more common with EVT (5% vs <1%; aOR 11.98, 95% CI 2.82–50.81), the net clinical benefit remained strongly in favor of EVT. Subgroup analyses showed broadly consistent benefit, though the advantage was uncertain for patients with mild baseline severity (NIHSS <10).

Conclusions: EVT for acute VBAO significantly improves functional outcomes and reduces mortality despite a higher sICH risk. These results support EVT as a standard consideration in appropriately selected patients with moderate-to-severe VBAO. The benefit’s magnitude is comparable to that seen in anterior circulation large vessel occlusions, although caution is advised in mild cases and those with extensive baseline infarction.

Implications for Practice: Clinicians should consider EVT for most patients presenting with acute VBAO. While sICH risk is increased, the substantial improvements in function and survival justify its use in suitable candidates. Careful imaging and clinical assessment remain critical for optimal patient selection.

Study Strengths and Limitations: Strengths include a pooled individual patient dataset from all major VBAO EVT trials, allowing detailed subgroup analyses. Limitations involve early trial termination, underrepresentation of women, predominance of Asian populations, and exclusion of patients with very mild symptoms or large baseline infarcts, potentially limiting generalizability.

Future Research: Further trials are needed to define EVT’s role in patients with mild symptoms, isolated vertebral occlusion, large infarcts, or those presenting beyond 24 hours. Additional studies should assess real-world applicability and diverse patient populations.

Reference: Nogueira RG, et al. Endovascular therapy for acute vertebrobasilar occlusion (VERITAS): a systematic review and individual patient data meta-analysis. DOI: http://doi.org/10.1016/S0140-6736(24)01820-8

 

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Review: New and Emerging Treatments for Major Depressive Disorder

19 Dec, 2024 | 22:21h | UTC

Introduction: This is a summary of a review on new and emerging treatments for major depressive disorder (MDD), a globally prevalent condition with substantial morbidity and socioeconomic burden. While conventional monoaminergic antidepressants often provide benefit, many patients do not achieve remission, leading to treatment-resistant depression. Novel approaches, including psychedelics (psilocybin, ketamine/esketamine), anti-inflammatory agents, opioid modulators, neuropeptides, botulinum toxin injections, and various neuromodulatory techniques (newer forms of transcranial magnetic stimulation and light-based therapies), are under investigation. This summary highlights their potential efficacy, tolerability, and current limitations.

Key Recommendations:

1. Ketamine and Esketamine: Consider these as adjunctive treatments for patients with refractory MDD, given their rapid antidepressant and anti-suicidal effects. Carefully monitor for blood pressure elevations and potential habituation. Long-term cost-effectiveness and sustained benefits remain uncertain.
2. Psychedelics (Psilocybin, Ayahuasca): Psilocybin-assisted therapy may produce rapid symptom improvement, but scalability, required therapeutic support, and possible increases in suicidality raise concern. Ayahuasca shows early promise, yet lacks robust long-term data and standardized administration protocols.
3. Neuromodulation (rTMS, TBS, Accelerated TMS, Light Therapy): Repetitive transcranial magnetic stimulation (rTMS) and its variants (theta burst stimulation, accelerated protocols) demonstrate modest efficacy with good tolerability. Bright light therapy may enhance neuromodulation outcomes. Optimal protocols and positioning in treatment pathways are not well established.
4. Anti-inflammatory and Other Agents: Preliminary findings suggest potential adjunctive roles for minocycline, NSAIDs, statins, omega-3 fatty acids, and a buprenorphine-samidorphan combination. However, larger, high-quality trials are needed to confirm their efficacy and safety profiles.
5. Onabotulinumtoxin A: A single glabellar injection may confer antidepressant effects, but the underlying mechanism and durability are unclear. Methodological issues, including difficulties with blinding, limit strong recommendations.
6. More Invasive Interventions (DBS, MST): Deep brain stimulation (DBS) and magnetic seizure therapy (MST) are invasive approaches supported by limited evidence, restricting their use to highly refractory cases. The balance of benefit, risk, and resource intensity remains uncertain.

Conclusion: Although these emerging treatments offer potential avenues beyond traditional antidepressants, most remain investigational. Key challenges include limited comparative data, uncertain long-term outcomes, and scaling difficulties. Further rigorous research, including head-to-head trials, long-term follow-ups, and clarity regarding optimal psychotherapeutic support, is required. As evidence matures, these novel interventions may become more integrated into standard care, potentially improving outcomes for patients with difficult-to-treat MDD.

Reference: Njenga C, Ramanuj PP, Magalhães FJC, Pincus HA. New and emerging treatments for major depressive disorder. BMJ. 2024;386:e073823. DOI: https://doi.org/10.1136/bmj-2022-073823

 

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Review: Management of Atrial Fibrillation

18 Dec, 2024 | 14:22h | UTC

Introduction: This summary of a comprehensive review on atrial fibrillation (AF) focuses on an increasingly prevalent arrhythmia affecting more than 10 million adults in the United States. AF significantly elevates the risks of stroke, heart failure (HF), cognitive decline, and mortality. This guideline-based overview examines the pathophysiology, detection, prevention, and treatment strategies for AF, emphasizing risk factor modification, appropriate anticoagulation, and early rhythm control interventions to improve clinical outcomes and quality of life.

Key Recommendations:

1. Risk Factor and Lifestyle Modification: Implement weight reduction, regular exercise, optimal blood pressure control, smoking cessation, and reduced alcohol intake at all AF stages to prevent new-onset AF, reduce recurrences, and mitigate complications.
2. Screening and Diagnosis: Consider AF screening in high-risk patients using wearable devices or implantable loop recorders. Confirm suspected AF with electrocardiography and extended rhythm monitoring in those with cryptogenic stroke.
3. Stroke Prevention: Assess stroke risk using CHA2DS2-VASc. For patients with annual stroke risk ≥2%, initiate oral anticoagulation (preferably direct oral anticoagulants over warfarin) to lower stroke risk by up to 80%. Avoid aspirin monotherapy for AF-related stroke prevention due to inferior efficacy.
4. Early Rhythm Control: Begin rhythm control within one year of AF diagnosis, particularly in symptomatic patients or those with HF and reduced ejection fraction (HFrEF). Early use of antiarrhythmic drugs or catheter ablation can improve symptoms, cardiac function, and reduce hospitalizations.
5. Catheter Ablation: Utilize ablation as a first-line therapy in symptomatic paroxysmal AF to maintain sinus rhythm and prevent progression. In patients with AF and HFrEF, ablation enhances quality of life, improves left ventricular function, and lowers mortality and HF hospitalization rates.
6. Rate Control Strategies: For patients who are not candidates for rhythm control, use beta-blockers or nondihydropyridine calcium channel blockers to achieve satisfactory ventricular rate control. Consider atrioventricular nodal ablation plus pacemaker implantation if pharmacologic therapy is inadequate.
7. Staging and Long-Term Management: Recognize four AF stages (at risk, pre-AF, clinically apparent AF, and permanent AF) to tailor management. After ablation, continue anticoagulation for at least three months, then reassess stroke risk before considering discontinuation.
8. Addressing Inequities: Improve access to guideline-directed AF therapies, including ablation and specialized care, and address social determinants of health that influence disparities in diagnosis, treatment, and outcomes.

Conclusion: Guideline-directed AF management, encompassing comprehensive risk factor modification, appropriate anticoagulation, and timely rhythm control strategies, can reduce stroke incidence, improve HF outcomes, and prolong life. Catheter ablation is a key intervention for appropriate patients, especially those with symptomatic paroxysmal AF or HFrEF, while striving for equitable and evidence-based care across diverse populations remains a critical priority.

Reference: Ko D, Chung MK, Evans PT, et al. Atrial Fibrillation: A Review. JAMA. Published online December 16, 2024. doi: https://doi.org/10.1001/jama.2024.22451

 

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RCT: A Single Dose of Ceftriaxone Reduces Early Ventilator-Associated Pneumonia in Acute Brain Injury Patients

17 Dec, 2024 | 12:26h | UTC

Background: Patients with acute brain injury are at increased risk for early ventilator-associated pneumonia (VAP), which can worsen their clinical course. Although short-term antibiotic prophylaxis has been considered, its utility remains uncertain. This study evaluated whether a single early dose of ceftriaxone could reduce the incidence of early VAP in these patients.

Objective: To determine if a single 2-g intravenous dose of ceftriaxone administered within 12 hours of intubation reduces the incidence of early VAP (day 2 to day 7 of mechanical ventilation) in comatose adults (Glasgow Coma Scale ≤12) requiring prolonged mechanical ventilation after acute brain injury.

Methods: This multicenter, randomized, double-blind, placebo-controlled, assessor-masked superiority trial was conducted in nine ICUs across eight French university hospitals. Patients with acute brain injury from trauma, stroke, or subarachnoid hemorrhage who required at least 48 hours of mechanical ventilation were enrolled. Participants received either ceftriaxone 2 g or placebo once, early after endotracheal intubation. All patients received standard VAP prevention measures, but no selective oropharyngeal or digestive decontamination. The primary endpoint was the incidence of early VAP confirmed by blinded assessors using standard clinical, radiological, and microbiological criteria.

Results: Among 319 patients included in the analysis (162 ceftriaxone, 157 placebo), early VAP incidence was significantly lower with ceftriaxone (14%) compared to placebo (32%) (HR 0.60 [95% CI 0.38–0.95]; p=0.030). Patients receiving ceftriaxone had fewer overall VAP episodes, fewer ventilator and antibiotic exposure days, shorter ICU and hospital stays, and reduced 28-day mortality (15% vs 25%). No significant increase in resistant organisms or adverse events attributable to ceftriaxone was observed.

Conclusions: A single early dose of ceftriaxone significantly reduced early VAP risk in acute brain injury patients undergoing mechanical ventilation. This prophylactic approach may improve clinical outcomes without evident safety concerns.

Implications for Practice: Incorporating a single early ceftriaxone dose into VAP prevention protocols for brain-injured patients could mitigate early respiratory infections and potentially enhance clinical outcomes. Nonetheless, clinicians should remain cautious, considering overall antibiotic stewardship and the need for further evidence on long-term microbial resistance patterns.

Study Strengths and Limitations: Strengths include a robust, multicenter, double-blind, placebo-controlled design and blinded adjudication of VAP cases. Limitations include the lack of long-term assessment of the intestinal microbiota and antimicrobial resistance. Further investigation is required to confirm the safety profile regarding microbial ecology and to explore neurological outcomes in greater depth.

Future Research: Future studies should examine the long-term effects of this single-dose approach on resistance patterns, microbial flora, and functional neurological recovery.

Reference: Dahyot-Fizelier C, et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. The Lancet Respiratory Medicine. 2024; DOI: http://doi.org/10.1016/S2213-2600(23)00471-X

 

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RCT: Liberal vs Restrictive Transfusion Yields No Neurologic Outcome Benefit in Aneurysmal Subarachnoid Hemorrhage

16 Dec, 2024 | 11:26h | UTC

Background: Aneurysmal subarachnoid hemorrhage (SAH) is a critical neurologic condition associated with high morbidity and mortality. Anemia is common in this setting and may worsen cerebral oxygenation and outcomes. However, the impact of a liberal transfusion threshold compared with a restrictive approach on long-term neurologic outcomes has been uncertain.

Objective: To determine whether a liberal red blood cell transfusion strategy (transfusion at hemoglobin ≤10 g/dL) improves 12-month neurologic outcomes compared with a restrictive strategy (transfusion at hemoglobin ≤8 g/dL) in patients with aneurysmal SAH and anemia.

Methods: This was a multicenter, pragmatic, open-label, randomized controlled trial conducted at 23 specialized neurocritical care centers. Critically ill adults with a first-ever aneurysmal SAH and hemoglobin ≤10 g/dL within 10 days of admission were randomized to a liberal or restrictive transfusion strategy. The primary outcome was unfavorable neurologic outcome at 12 months, defined as a modified Rankin scale score ≥4. Secondary outcomes included the Functional Independence Measure (FIM), quality of life assessments, and imaging-based outcomes such as vasospasm and cerebral infarction. Outcome assessors were blinded to group allocation.

Results: Among 742 randomized patients, 725 were analyzed for the primary outcome. At 12 months, unfavorable neurologic outcome occurred in 33.5% of patients in the liberal group and 37.7% in the restrictive group (risk ratio 0.88; 95% CI, 0.72–1.09; p=0.22). There were no clinically meaningful differences in secondary outcomes. Mortality at 12 months was similar (approximately 27% in both arms). Radiographic vasospasm was more frequently detected in the restrictive group, though this did not translate into improved functional outcomes in the liberal arm. Adverse events and transfusion reactions were comparable between groups.

Conclusions: In patients with aneurysmal SAH and anemia, a liberal transfusion strategy did not lead to a significantly lower risk of unfavorable neurologic outcome at 12 months compared with a restrictive approach.

Implications for Practice: These findings suggest that routinely maintaining higher hemoglobin levels does not confer substantial long-term functional benefit. Clinicians may consider a more restrictive threshold (≤8 g/dL) to minimize unnecessary transfusions without compromising outcomes. Some skepticism toward adopting a more liberal transfusion policy is warranted given the lack of demonstrable benefit.

Study Strengths and Limitations: Strengths include the randomized, multicenter design, blinded outcome assessment, and a 12-month follow-up. Limitations include potential unmeasured subtle benefits, the inability to blind clinical teams, and the challenge of capturing all aspects of functional recovery with current measurement tools. Further research may clarify if more tailored transfusion strategies can yield modest but meaningful improvements.

Future Research: Future studies should evaluate intermediate hemoglobin thresholds, develop more sensitive measures of functional and cognitive recovery, and consider individualized transfusion strategies based on specific patient factors and biomarkers of cerebral ischemia.

Reference: English SW, et al. Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage. New England Journal of Medicine. Published December 9, 2024. DOI: http://doi.org/10.1056/NEJMoa2410962

 

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RCT: Adjunctive Middle Meningeal Artery Embolization Reduces Reoperation in Subdural Hematoma

24 Nov, 2024 | 13:53h | UTC

Background: Subacute and chronic subdural hematomas are common neurosurgical conditions with a high recurrence rate after surgical evacuation, affecting 8% to 20% of patients. Middle meningeal artery embolization (MMAE) is a minimally invasive procedure targeting the blood supply to these membranes. Preliminary studies suggest that adjunctive MMAE may reduce hematoma recurrence, but its impact on reoperation risk remains unclear.

Objective: To determine whether adjunctive MMAE reduces the risk of hematoma recurrence or progression leading to repeat surgery within 90 days compared to surgery alone in patients with symptomatic subacute or chronic subdural hematoma.

Methods: In this prospective, multicenter, randomized controlled trial, 400 patients aged 18 to 90 years with symptomatic subacute or chronic subdural hematoma requiring surgical evacuation were randomly assigned to receive either MMAE plus surgery (n=197) or surgery alone (n=203). The primary endpoint was hematoma recurrence or progression leading to repeat surgery within 90 days after the index treatment. The secondary endpoint was deterioration of neurologic function at 90 days, assessed using the modified Rankin Scale.

Results: Hematoma recurrence or progression requiring repeat surgery occurred in 8 patients (4.1%) in the MMAE plus surgery group versus 23 patients (11.3%) in the surgery-alone group (relative risk, 0.36; 95% CI, 0.11 to 0.80; P=0.008). Functional deterioration at 90 days was similar between groups (11.9% vs. 9.8%; risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the MMAE group and 3.0% in the control group. Serious adverse events related to the embolization occurred in 4 patients (2.0%), including disabling stroke in 2 patients.

Conclusions: Adjunctive MMAE combined with surgery significantly reduced the risk of hematoma recurrence or progression requiring reoperation within 90 days compared to surgery alone. However, there was no significant difference in neurologic functional deterioration, and the procedure was associated with procedural risks.

Implications for Practice: MMAE may be considered as an adjunct to surgical evacuation in patients with subacute or chronic subdural hematoma to reduce reoperation risk. Clinicians should carefully weigh the potential benefits against the risks of procedural complications, including stroke.

Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach, enhancing generalizability. Limitations involve the open-label design, introducing potential bias since the primary endpoint was based on surgeon judgment. A substantial loss to follow-up (13.2%) could affect results, and the study was not powered to detect differences in mortality or serious adverse events.

Future Research: Further studies with larger sample sizes are needed to fully evaluate the safety and efficacy of MMAE, including long-term outcomes. Research should focus on optimizing patient selection and assessing the procedure’s impact on mortality and serious adverse events.

Reference: Davies JM, et al. Adjunctive Middle Meningeal Artery Embolization for Subdural Hematoma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2313472

 

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Cohort Study: Oral Hormone Therapy and Tibolone Increase Cardiovascular Risk in Menopausal Women

28 Nov, 2024 | 18:42h | UTC

Background: Cardiovascular disease is the leading cause of mortality worldwide, with incidence in women increasing notably during the menopausal transition. Menopausal hormone therapy (MHT) effectively alleviates menopausal symptoms but has been associated with cardiovascular risks in previous studies. The impact of contemporary MHT formulations and administration routes on cardiovascular disease risk in women aged 50–58 remains unclear.

Objective: To assess the effect of different types of contemporary MHT on the risk of cardiovascular disease, focusing on various hormone combinations and administration methods.

Methods: This nationwide register-based emulated target trial included 919,614 Swedish women aged 50–58 years between 2007 and 2020 who had not used MHT in the previous two years. Participants were assigned to one of eight treatment groups—including oral and transdermal therapies—or to a non-initiator group. The primary outcomes were hazard ratios (HRs) for venous thromboembolism (VTE), ischemic heart disease (IHD), cerebral infarction, and myocardial infarction, analyzed separately and as a composite cardiovascular disease outcome.

Results: Among the participants, 77,512 were MHT initiators and 842,102 were non-initiators. During follow-up, 24,089 cardiovascular events occurred. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (HR 1.52, 95% CI 1.11 to 2.08) compared with non-initiators. Initiation of tibolone or oral estrogen-progestin therapy was linked to a higher risk of IHD (HRs 1.46 and 1.21, respectively). A higher risk of VTE was observed with oral continuous estrogen-progestin therapy (HR 1.61), sequential therapy (HR 2.00), and estrogen-only therapy (HR 1.57). Per protocol analyses showed that tibolone use was associated with increased risks of cerebral infarction (HR 1.97) and myocardial infarction (HR 1.94).

Conclusions: Use of oral estrogen-progestin therapy was associated with increased risks of IHD and VTE, while tibolone was linked to higher risks of IHD, cerebral infarction, and myocardial infarction but not VTE. These findings underscore the varying cardiovascular risks associated with different MHT types and administration methods.

Implications for Practice: Clinicians should exercise caution when prescribing oral estrogen-progestin therapy or tibolone for menopausal symptom relief, considering the elevated cardiovascular risks. Alternative MHT options, such as transdermal therapies, may offer a safer profile and should be considered.

Study Strengths and Limitations: Strengths include the large, nationwide cohort and the emulated target trial design, which reduces selection bias and confounding. Limitations involve the lack of data on menopausal status, smoking, and body mass index, which may affect cardiovascular risk. Potential misclassification of exposure and adherence could also impact results.

Future Research: Further studies should investigate the cardiovascular effects of specific progestins within MHT formulations and explore the impact of different doses and durations of therapy.

Reference: Johansson T, Karlsson T, Bliuc D, et al. Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. BMJ. 2024;387:e078784. DOI: http://doi.org/10.1136/bmj-2023-078784

 

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Meta-Analysis: Moderately Rapid Sodium Correction Linked to Better Outcomes in Severe Hyponatremia

20 Nov, 2024 | 16:10h | UTC

Background: Severe hyponatremia is a critical condition that can lead to hyponatremic encephalopathy, necessitating prompt treatment to prevent neurological damage or death. Traditional guidelines recommend limiting sodium correction rates to prevent osmotic demyelination syndrome (ODS). However, emerging evidence suggests that slower correction rates may be associated with increased mortality.

Objective: To evaluate the association between sodium correction rates and mortality among hospitalized adults with severe hyponatremia.

Methods: This systematic review and meta-analysis included 16 cohort studies published between January 2013 and October 2023, involving 11,811 hospitalized adults with severe hyponatremia (serum sodium <120 mEq/L or <125 mEq/L with severe symptoms). Patients were categorized based on sodium correction rates: rapid (≥8-10 mEq/L per 24 hours), slow (<8 or 6-10 mEq/L per 24 hours), and very slow (<4-6 mEq/L per 24 hours). Primary outcomes were in-hospital and 30-day mortality; secondary outcomes included hospital length of stay (LOS) and incidence of ODS.

Results: Rapid correction was associated with significantly lower in-hospital mortality compared to slow correction (odds ratio [OR], 0.67; 95% CI, 0.55-0.82) and very slow correction (OR, 0.29; 95% CI, 0.11-0.79), corresponding to 32 and 221 fewer deaths per 1,000 patients, respectively. At 30 days, rapid correction was associated with 61 and 134 fewer deaths per 1,000 patients compared to slow and very slow correction, respectively. Rapid correction also resulted in shorter hospital LOS by 1.20 days (95% CI, 0.51-1.89) compared to slow correction and 3.09 days (95% CI, 1.21-4.94) compared to very slow correction. There was no statistically significant increase in ODS risk with rapid correction.

Conclusions: In hospitalized adults with severe hyponatremia, rapid sodium correction was associated with reduced mortality and shorter hospital stays without a significant increase in ODS risk.

Implications for Practice: These findings suggest that more aggressive sodium correction may benefit patients with severe hyponatremia, challenging current guidelines that recommend slower correction rates to prevent ODS. Clinicians should weigh the potential benefits of rapid correction against the traditionally emphasized risks, although caution is still warranted given the seriousness of ODS.

Study Strengths and Limitations: Strengths include a large sample size and inclusion of recent studies reflecting current practices. Limitations involve the observational nature of included studies, potential confounding factors, heterogeneity in correction rate definitions, and possible underreporting of ODS due to its rarity and diagnostic challenges.

Future Research: Randomized controlled trials are needed to establish causality and optimal correction rates, as well as to identify patient subgroups that may benefit most from rapid correction while minimizing ODS risk.

Reference: Ayus JC, Moritz ML, Fuentes NA, et al. Correction Rates and Clinical Outcomes in Hospitalized Adults With Severe Hyponatremia: A Systematic Review and Meta-Analysis. JAMA Internal Medicine. Published online November 18, 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.5981

 

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Meta-Analysis: Spinal Cord Stimulation May Be Effective for Chronic Back and Leg Pain

15 Nov, 2024 | 13:43h | UTC

Background: Chronic back and leg pain causes significant disability worldwide. Spinal cord stimulation (SCS) offers treatment for patients unresponsive to conventional medical management (CMM). The comparative efficacy of conventional and novel SCS forms versus CMM is debated, requiring thorough evaluation.

Objective: To evaluate the efficacy of conventional and novel SCS therapies compared with CMM in adults with chronic back or leg pain who had not previously used SCS.

Methods: A systematic review and Bayesian network meta-analysis per PRISMA guidelines were performed. MEDLINE, Embase, and Cochrane Library were searched up to September 2, 2022. Thirteen RCTs with 1,561 patients were included. Interventions were conventional SCS, novel SCS modalities (e.g., high-frequency, burst stimulation), and CMM. Primary outcomes were pain intensity (visual analog scale) and responder rates (≥50% pain relief) in back or leg. Secondary outcomes were quality of life (EQ-5D index) and functional disability (Oswestry Disability Index).

Results: At 6 months, both conventional and novel SCS were superior to CMM in five of six outcomes. For back pain responder rates, conventional SCS had an OR of 3.00 (95% CrI, 1.49–6.72) and novel SCS had an OR of 8.76 (95% CrI, 3.84–22.31) versus CMM. Pain intensity in the back decreased significantly with conventional SCS (MD, –1.17; 95% CrI, –1.64 to –0.70) and novel SCS (MD, –2.34; 95% CrI, –2.96 to –1.73). Leg pain intensity also decreased significantly with conventional SCS (MD, –2.89; 95% CrI, –4.03 to –1.81) and novel SCS (MD, –4.01; 95% CrI, –5.31 to –2.75) compared to CMM. Quality of life improved with both SCS therapies (conventional SCS MD, 0.15; 95% CrI, 0.09–0.21; novel SCS MD, 0.17; 95% CrI, 0.13–0.21). Functional disability improved significantly with conventional SCS (MD, –7.10; 95% CrI, –10.91 to –3.36).

Conclusions: Both conventional and novel SCS therapies are associated with significant improvements in pain relief, quality of life, and functional ability compared with CMM in patients with chronic back and leg pain at 6 months.

Implications for Practice: The results support integrating SCS therapies into clinical practice for patients with chronic back and leg pain unresponsive to CMM.

Study Strengths and Limitations: Strengths include inclusion of recent RCTs and use of Bayesian network meta-analysis, allowing comprehensive evidence synthesis with both direct and indirect comparisons, enhancing reliability. Limitations involve potential biases due to challenges in blinding participants and assessors, as patients can perceive whether a device is active. Heterogeneity among studies in patient populations and interventions may affect generalizability. Inability to include long-term efficacy data due to crossover in many trials limits understanding of sustained outcomes.

Future Research: Long-term RCTs are needed to assess sustained efficacy and safety of SCS therapies. Future studies should compare different SCS modalities directly and identify patient subgroups most likely to benefit.

Reference: Huygen FJPM, et al. Spinal Cord Stimulation vs Medical Management for Chronic Back and Leg Pain: A Systematic Review and Network Meta-Analysis. JAMA Network Open. 2024; doi: http://doi.org/10.1001/jamanetworkopen.2024.44608

 

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Cochrane: Galantamine Improves Cognitive Function in Alzheimer’s Disease but Not in Mild Cognitive Impairment

10 Nov, 2024 | 13:40h | UTC

Background: Alzheimer’s disease is the leading cause of dementia. While incurable, symptomatic treatments like galantamine, a cholinesterase inhibitor, are approved for Alzheimer’s disease.

Objective: To assess the clinical effects and adverse events of galantamine in people with Alzheimer’s disease or mild cognitive impairment.

Methods: A systematic review of double-blind, parallel-group, randomized controlled trials comparing oral galantamine with placebo in people with Alzheimer’s disease or mild cognitive impairment. Outcomes included cognitive function, global function, activities of daily living, functional disability, behavioral function, and adverse events.

Results: Twenty-one studies with 10,990 participants were included. Treatment durations ranged from eight weeks to two years. In Alzheimer’s disease, galantamine at 16 mg to 24 mg/day for six months significantly improved cognitive function compared to placebo (MD –2.86 on ADAS-cog, 95% CI –3.29 to –2.43; six studies, 3049 participants; high-certainty evidence). Functional disability improved (MD 2.12 on DAD, 95% CI 0.75 to 3.49; three studies, 1275 participants), as did behavioral function (MD –1.63 on NPI, 95% CI –3.07 to –0.20; two studies, 1043 participants). Participants receiving galantamine had higher rates of premature discontinuation (OR 1.41, 95% CI 1.19 to 1.68; six studies, 3336 participants) and nausea (OR 2.89, 95% CI 2.40 to 3.49; seven studies, 3616 participants). Death rates were reduced in the galantamine groups (OR 0.56, 95% CI 0.33 to 0.96; six studies, 3493 participants).

In mild cognitive impairment, galantamine did not improve cognitive function (MD –0.21 on ADAS-cog/MCI, 95% CI –0.78 to 0.37; two studies, 1901 participants; low-certainty evidence) or activities of daily living (MD 0.30 on ADCS-ADL-MCI, 95% CI –0.26 to 0.86). Adverse events and discontinuation rates were higher with galantamine.

Conclusions: Galantamine at 16 mg to 24 mg/day improves cognitive function, functional ability, and behavior over six months in Alzheimer’s disease, with clinically meaningful changes. Gastrointestinal adverse events are common and may limit tolerability. Galantamine is not effective in mild cognitive impairment.

Implications for Practice: Galantamine may be considered for symptomatic treatment in mild to moderate Alzheimer’s disease to improve cognition, daily functioning, and behavior, weighing the benefits against the increased risk of gastrointestinal adverse events. It is not recommended for people with mild cognitive impairment.

Study Strengths and Limitations: Strengths include a large sample size and high-certainty evidence for key outcomes in Alzheimer’s disease. Limitations involve high attrition rates and potential bias due to higher discontinuation in galantamine groups. The evidence for mild cognitive impairment is of low certainty due to risk of bias and imprecision.

Future Research: Further trials are needed in more diverse clinical populations, including those with severe Alzheimer’s disease and over longer durations. Research should focus on quality of life outcomes, cost-effectiveness, and subgroup analyses based on individual-level factors.

Reference: Lim AWY, et al. Galantamine for dementia due to Alzheimer’s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2024. DOI: http://doi.org/10.1002/14651858.CD001747.pub4

 

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