Blueprints for Better Care: 2024 Neurology Guideline Highlights

The field of neurology saw significant advancements in 2024, with new consensus guidelines introduced across various specialties, including stroke, epilepsy, neuromuscular conditions, and movement disorders. These updates reflect the growing body of research and evolving clinical practices, providing essential frameworks for improving patient care.

In this feature, NeurologyLive^® highlights some of the most notable guideline updates from 2024. These key recommendations offer valuable insights to help clinicians stay informed and ensure optimal care for their patients across a range of neurological conditions.

Revised Guideline in the Treatment of Restless Legs Syndrome (RLS)

An updated clinical practice guideline from the American Academy of Sleep Medicine (AASM) provided evidence-based recommendations for treating restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in both adults and pediatric patients. The guideline incorporated the latest clinical trial data and systematic reviews to inform treatment decisions, with an emphasis on patient-centered care. RLS is characterized by an urge to move the legs, often accompanied by uncomfortable sensations, while PLMD involves repetitive leg movements during sleep, leading to disturbances in both sleep and daytime function. The guideline stressed the importance of addressing exacerbating factors and emphasizes iron supplementation for many patients with RLS.

These updated recommendations reflect changes in the understanding of treatment efficacy, particularly concerning dopamine agonists and their association with augmentation, a condition where RLS symptoms worsen with prolonged use. As a result, the AASM has revised its treatment hierarchy to include only "strong" or "conditional" recommendations. The guideline now includes specific treatments such as gabapentin, pregabalin, and ferric carboxymaltose, while advising against the routine use of certain dopaminergic agents like pramipexole and ropinirole. It also highlight the importance of regular monitoring using the International RLS Severity Scale to assess symptom severity and guide treatment adjustments.

Key take-home messages from the revised guideline on the treatment of RLS and PLMD:

• Iron supplementation: In patients with clinically significant RLS, regular testing of serum iron studies is recommended to guide the use of oral or intravenous iron supplementation, with specific thresholds for ferritin and transferrin saturation.
• Address exacerbating factors: The first step in managing RLS should be to address lifestyle and medical factors such as alcohol, caffeine, certain medications, and untreated obstructive sleep apnea.
• Pregnancy considerations: When treating RLS in pregnant patients, clinicians should consider the pregnancy-specific safety profile of treatments.

Adult RLS:

• Gabapentin enacarbil: Strongly recommended over no treatment for RLS (moderate evidence).
• Gabapentin and pregabalin: Both are strongly recommended over no treatment (moderate evidence).
• IV iron therapy: Strongly recommended for patients with appropriate iron status (moderate evidence).
• Alternative treatments: Conditional recommendations for IV low molecular weight iron dextran, ferumoxytol, and ferrous sulfate in patients with appropriate iron status (low to very low evidence).
• Dipyridamole and opioids: Conditional recommendations with moderate evidence for use in RLS treatment.
• Peroneal nerve stimulation: Suggested as a treatment option (moderate evidence).

Medications and Treatments to Avoid:

• Levodopa, pramipexole, rotigotine, ropinirole: Conditional recommendations against routine use due to concerns about long-term side effects like augmentation.
• Other medications: Bupropion, carbamazepine, clonazepam, valerian, and valproic acid are also discouraged due to limited or poor evidence supporting their use.

Special Populations:

• RLS in ESRD: Gabapentin, IV iron sucrose, and vitamin C are suggested for use in RLS patients with end-stage renal disease (ESRD) (conditional recommendations with varying levels of evidence).

Pediatric RLS:

• Ferrous sulfate: Suggested for children with RLS and low iron status, although the evidence is very low.

This updated clinical practice guideline underscoresthe evolving treatment strategies for RLS and PLMD, emphasizing the importance of long-term management and patient-centered care. Although dopamine agonists were once the first-line treatment for RLS, concerns regarding augmentation and other adverse effects have led to a shift toward alternative therapies. The guideline strongly recommended the use of α-2-delta ligands, such as gabapentin enacarbil, and iron supplementation, particularly intravenous ferric carboxymaltose, while cautioning against the routine use of dopamine agonists because of the risks associated with long-term use. It also encouraged regular monitoring of RLS symptoms and emphasizes the need for further research to develop effective, targeted treatments for RLS.

McDonald Criteria for Multiple Sclerosis (MS)

New updates to the McDonald diagnostic criteria for multiple sclerosis (MS) aim to improve the speed and accuracy of diagnosis, ensuring that patients receive timely treatment for better outcomes. Established in 2001 and revised in 2017, these criteria have evolved to keep pace with advancements in MS research. A panel of experts have worked since 2021 to integrate new insights into the disease’s biological mechanisms, enhancing the diagnostic process through advanced imaging and biomarker tools alongside clinical evaluations.

The latest revisions, unveiled at the 2024 ECTRIMS Congress, include the adoption of more precise diagnostic methods, such as age-specific criteria and the use of biomarkers beyond observable symptoms. These updates prioritize earlier diagnoses in both younger and older populations, with a focus on improving diagnostic accuracy. The finalized guidelines are expected in early 2025, with efforts from organizations like the National MS Society and ECTRIMS to educate clinicians on effective implementation, ultimately enhancing MS diagnosis and patient care globally.

Here are the key take-home messages from the updated MS diagnostic criteria:

• Integration of Advanced Tools: New criteria incorporate advanced imaging, biomarkers, and clinical evaluations to improve diagnostic accuracy and enable earlier treatment.
• Age-Specific Criteria: The revised guidelines include age-specific criteria for more accurate diagnosis in both younger and older populations.
• Radiologically Isolated Syndrome (RIS): RIS is now recognized as MS in specific cases, expanding diagnostic possibilities.
• Optic Nerve as a Diagnostic Location: The optic nerve is added as a fifth anatomical location in the MS diagnostic criteria.
• Elimination of Dissemination in Time (DIT) Requirement: DIT is no longer required for diagnosis, streamlining the diagnostic process.
• Inclusion of Kappa Free Light Chains: Kappa free light chains are now included as a diagnostic tool for MS.
• Applicability Across MS Types: The revised criteria can be applied to both primary progressive MS and relapsing-remitting MS, with stricter standards for older patients and those with comorbidities.
• Optional Diagnostic Tools: Optional tools like central vein sign (CVS) and paramagnetic rim lesions (PRLs) can be used in specific cases to aid diagnosis.
• Myelin Oligodendrocyte Glycoprotein Antibodies: Myelin oligodendrocyte glycoprotein antibody tests are recommended for diagnosing MS in children and adolescents.
• Focus on Paraclinical Evidence: Paraclinical evidence is emphasized for confirming MS diagnoses across various patient populations.

As the McDonald diagnostic criteria for MS continue to evolve, there are still several areas that warrant further investigation. Techniques such as visual evoked potentials (VEP) and optical coherence tomography (OCT) may offer more precise insights for demonstrating dissemination in time (DIT), while the use of PRL and CVS as diagnostic tools could be refined in specific cases. Additionally, further research may be needed on the application of these criteria to atypical MS presentations and how they perform across diverse populations, especially in regions with different MS risk factors, such as Asia and Latin America.

Moving forward, the revised criteria represent a significant milestone in the diagnosis and treatment of MS. The forthcoming publication of these guidelines, along with planned papers on imaging advancements and biomarkers, will provide clinicians with more detailed resources. However, successful global implementation will require careful consideration of healthcare resources, provider education, and patient accessibility. A global education campaign could be essential to ensure that these updated criteria are adopted worldwide, ultimately improving diagnostic accuracy and patient outcomes for those living with MS.

Spinal Muscular Atrophy (SMA) Updates in Best Practices

Historically, spinal muscular atrophy (SMA) was diagnosed either through symptomatic presentation followed by referral for evaluation or observation of symptom progression, or via genetic testing in cases of family history or known carrier status. In late 2024, Cure SMA, an advocacy organization for those living with the disease, convened experts in the field to publish updated recommendations and best practices for diagnosing the rare disorder.

Through modified Delphi surveys and discussions, the health care provider group concluded that newborn screening (NBS) is essential for SMA diagnosis and the first step to optimizing outcomes for patients. In addition, the working groups agreed that additional work includes defining which signs and symptoms to monitor and how to define SMA stages in a clinically meaningful and easily understandable way. Furthermore, the team of experts concluded that understanding of adult-onset SMA natural history will facilitate efficient diagnosis and may be best accomplished by combining real-world datasets.

Below, the NeurologyLive team summarized some of the main recommendations from the guidelines, giving clinicians an understanding of the most vital takeaways:

Recommendation 1: Characterization of SMA Infants Before Treatment

• SMN2 Copy Number:Determining SMN2 copy number is critical for confirmatory diagnosis. A higher SMN2 copy number typically correlates with less severe disease, although exceptions exist. It should be included in confirmatory testing to guide treatment decisions.
• Motor Function: Assessing motor function and development is essential for newly diagnosed, NBS-identified infants before treatment. Standardized tests like the Bayley Scales or CHOP-INTEND should be used to evaluate motor function and weakness.
• Age at Symptom Onset: Age at symptom onset is important, as earlier onset may correlate with more severe disease. Understanding this relationship with treatments is crucial for improving care.
• Symptom Severity: Severity of symptoms provides prognostic guidance and helps inform treatment discussions. Some infants may be symptomatic at birth or soon after. Characterizing symptom severity aids caregiver conversations and treatment access.
• Symptomatic vs. Presymptomatic: Distinguishing between symptomatic and presymptomatic states can be challenging, with some infants showing vague early symptoms. Further clarity is needed on this continuum, with potential terms like “paucisymptomatic” or “prodromal.”
• Additional Considerations: Age at treatment initiation may have prognostic value but is outside the scope of this work. A future objective biomarker to monitor disease progression could further refine clinical evaluation.

Recommendation 2: Minimum Requirements for SMA Newborn Screening (NBS) Programs

To ensure timely and effective care for SMA NBS-identified infants, the following minimum requirements should be in place:

• Notification and Coordination: Caregivers should be notified urgently (same day) about positive SMA NBS results, with an initial visit scheduled within 2-3 days.
• Timely Treatment: Processes should be in place to prevent delays in starting treatment.
• Referral to Specialists: Infants should be promptly referred to appropriate SMA specialists.
• Motor Function Evaluation: The care team must include experts who evaluate motor function.
• Treatment Coverage and Reimbursement: Efficient processes should be established for determining treatment coverage, cost, and reimbursement.

Public Health NBS Laboratories are responsible for urgent notification to the primary care provider and ensuring access to an SMA specialty care center (SCC). The primary care provider facilitates caregiver communication, referrals, and appointment scheduling. The SMA SCC team ensures timely evaluations, treatments, and referrals to additional specialists.

Recommendation 3: SMA Specialty Care Centers (SCCs)

SMA SCCs should provide the following services for infants identified through SMA NBS:

• Timely Visits: Evaluate infants within 2-3 days and schedule follow-up visits with motor function assessments, test results, symptom monitoring, and treatment discussions.
• Comprehensive Treatment Options: Present all treatment options with clear explanations of benefits, risks, and limitations. Emphasize that treatments slow disease progression but don’t cure SMA.
• Confirmatory Testing: Complete diagnostic testing (e.g., SMN1/SMN2 analysis) and relevant lab studies (e.g., AAV9 antibody titers) at the first visit.
• Education and Resources: Provide unbiased, high-quality education and direct caregivers to relevant advocacy organizations and multidisciplinary teams (genetic counselors, case managers).
• Care Plan and Follow-ups: Clearly communicate care plans with goals, timelines, and expectations. Ensure follow-ups and treatment monitoring are scheduled with caregivers.
• Coordination with Providers: Share comprehensive documentation with primary care providers (PCPs) and facilitate referrals to specialists (pulmonologists, PTs, nutritionists) for a multidisciplinary approach.
• Efficient Processes: Streamline treatment and lab processes to expedite approvals, with staff dedicated to ensuring fast documentation and authorization.

Recommendation 4: Caregiver Partnership and Support
Individuals with SMA and their caregivers should be active partners in diagnosis, care, and treatment decisions.

• Information about SMA: Caregivers should receive unbiased, culturally aligned education on SMA diagnosis, functional status, and supportive care. Information should be clear and accessible, with time for questions. Health care providers should guide shared decision-making.
• SMA Care Beyond Approved Treatments: Multidisciplinary specialists should manage symptoms and monitor nutrition, motor function, respiratory status, and more. Ongoing SMA care must go hand-in-hand with treatments to reduce morbidity and mortality. Access to SMA SCC staff for care coordination is crucial.
• Access to Community Resources: Caregivers should be connected to peer support groups, patient advocacy organizations, psychological support, and early developmental programs to aid understanding and address the emotional impact of SMA.
• Adult-Onset 5q SMA: This form of SMA involves proximal muscle weakness in adults, often misdiagnosed as myopathic disorders. Early signs include weakness, falls, and cramps. Genetic testing and EMG are essential for diagnosis, as CK levels may be elevated but not specific to SMA. Further research on adult-onset SMA’s natural history is needed.

American Heart Association (AHA)/American Stroke Association (ASA) Guideline for Primary Prevention of Stroke

The AHA/ASA clinical practice guidelines for stroke, published in October 2024, provided a vital framework for improving cerebrovascular care through evidence-based recommendations. Developed without commercial influence and shaped by a diverse group of experts, these guidelines enhance the quality of care for patients with or at risk of stroke. While primarily designed for U.S. medical practice, their relevance extends globally. Emphasizing individualized care, the guidelines aim to align medical practices with patients’ best interests, complementing clinical judgment rather than replacing it.

Recent updates focus on accessibility and usability, presenting recommendations in a concise, modular format supported by tables, synopses, and flow diagrams. They also highlight knowledge gaps and suggest future research areas. By promoting inclusivity, scientific rigor, and equity, these guidelines serve as an essential resource for neurologists committed to advancing cerebrovascular health and optimizing patient outcomes.

Here are some major takeaways clinicians should be aware of:

• Brain Health Across the Lifespan:
  Regular engagement with primary care providers throughout life is essential for promoting brain health and identifying opportunities for stroke prevention.
• Addressing Social Determinants of Health (SDOH):
  Recognizing the impact of adverse SDOH on stroke risk and care, clinicians are encouraged to screen for SDOH in at-risk patients. Although interventions to address SDOH are evolving, this step integrates social factors into stroke prevention strategies.
• Mediterranean Diet for Stroke Prevention:
  Adherence to a Mediterranean diet, particularly when supplemented with nuts and olive oil, is strongly recommended for reducing stroke risk in patients with no prior cardiovascular disease or those at moderate to high cardiovascular risk. Low-fat diets have demonstrated minimal impact.
• Physical Activity and Sedentary Behavior: Reducing sedentary behavior is a new priority in stroke prevention. Clinicians should screen for sedentary habits and counsel patients on minimizing prolonged inactivity, in addition to encouraging regular moderate-to-vigorous physical activity.
• Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: These agents are recommended for patients with type 2 diabetes and high cardiovascular risk or established cardiovascular disease due to their benefits in weight loss, improved glycemic control, and stroke risk reduction.
• Blood Pressure Management: Optimal blood pressure control for stroke prevention typically requires a combination of ≥2 antihypertensive medications. Monotherapy is effective in achieving target blood pressure in only about 30% of patients.
• Antiplatelet and Anticoagulant Therapy: Antiplatelet therapy is recommended for patients with systemic lupus erythematosus or antiphospholipid syndrome without a history of stroke or venous thromboembolism.
• For patients with antiphospholipid syndrome and prior unprovoked venous thrombosis, vitamin K antagonists (target INR: 2–3) are preferred over direct oral anticoagulants.
• Pregnancy-Related Stroke Prevention: Hypertension management is key, with treatment thresholds of systolic BP ≥160 mmHg or diastolic BP ≥110 mmHg during pregnancy and the postpartum period. Screening for adverse pregnancy outcomes is advised, given their association with chronic hypertension and elevated long-term stroke risk.
• Stroke Risk in Women’s Health: Conditions such as endometriosis, premature ovarian failure (<40 years), and early-onset menopause (<45 years) are associated with increased stroke risk. Screening and risk factor modification in these populations are reasonable strategies for stroke prevention.
• Transgender Health and Stroke Risk: Transgender women using estrogen for gender affirmation are at increased stroke risk. Risk factor evaluation and modification should be prioritized to reduce this risk and ensure inclusive stroke prevention practices.

Acute Care of Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, severe autoimmune disease of the central nervous system, initially identified with the discovery of aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). The 2015 international diagnostic criteria are used to diagnose NMOSD, making it easier to identify AQP4-IgG-positive cases, and AQP4-IgG-negative patients can also be diagnosed using these criteria. If untreated, NMOSD can lead to significant disability because of recurrent attacks and inadequate recovery. Although there is no cure, treatment focuses on managing acute attacks and preventing future episodes through early immunotherapy initiation after a definitive diagnosis.

Recent clinical advancements have led to FDA approvals of the first immunotherapies for AQP4-IgG-positive NMOSD, including eculizumab, inebilizumab, and satralizumab. Rituximab was approved for NMOSD in Japan, and ravulizumab received EMA approval in 2023. The Neuromyelitis Optica Study Group (NEMOS) has updated its recommendations for diagnosing and managing NMOSD, incorporating insights from clinical experts. These guidelines emphasize the importance of acute attack management, immunotherapy for attack prevention, and considerations for off-label treatments, while recognizing myelin-oligodendrocyte-glycoprotein (MOG)-IgG-associated disease (MOGAD) as a separate entity with its own treatment recommendations.

Here are some of the major points from the recommendations:

Attack Therapy:

• Early initiation of attack therapy is critical for NMOSD attacks.
• Post-attack, taper glucocorticoids orally for 3–6 months, especially when starting or switching long-term immunotherapy.
• Apheresis therapy should be introduced early for patients not responding to high-dose glucocorticoids.
• Apheresis may be the first-line treatment for patients with previous insufficient glucocorticoid response, a prior positive response to apheresis, or severe myelitis.
• Both plasma exchange and immunoadsorption are acceptable methods of apheresis therapy.
• For severe attacks, a combination of high-dose glucocorticoids and apheresis can be considered.

Long-Term Therapy: Principal Recommendations:

• Offer long-term immunotherapy to AQP4-IgG-positive NMOSD patients after their first attack.

Off-Label Therapies:

• Patients stable on off-label therapies without significant side effects should not be switched.
• Conventional therapies like azathioprine and mycophenolate mofetil are less effective than biologicals.
• Low-dose glucocorticoids should not be used alone for attack prevention unless no other options are available.

Initiation and Selection Criteria for Long-Term Therapy:

• Eculizumab, inebilizumab, rituximab, satralizumab, and tocilizumab are highly effective therapies for AQP4-IgG-positive NMOSD.
• The choice of therapy should be based on factors like attack severity, recovery, comorbidities, and patient preferences.
• Monoclonal antibodies should be initiated as monotherapy, unless a combination with classical immunosuppressives is needed due to comorbidities.

Switching Drugs:

• Switch to a monoclonal antibody after treatment failure with classical immunosuppressives.
• Switch monoclonal antibodies if one fails, preferably to one with a different mode of action.
• Bridging therapy with low-dose glucocorticoids may be necessary when switching immunotherapy.

Duration of Long-Term Therapy:

• Immunotherapy should continue in stable AQP4-IgG-positive patients, with close monitoring if treatment is discontinued.
• Re-evaluate immunotherapy for stable double-negative NMOSD patients after 5 years.

Family Planning and Pregnancy:

• Female patients of reproductive age must be counseled early on family planning and immunotherapy options during pregnancy.
• Pregnancy should occur during disease stability, and teratogenic drugs must be avoided.
• Monoclonal antibodies or azathioprine should continue during pregnancy, with careful monitoring of risks and benefits.
• Rituximab is preferred for patients planning pregnancy due to limited data on monoclonal antibodies.
• Continue azathioprine during pregnancy if the patient is stable on it.
• Post-pregnancy, resume long-term immunotherapy promptly.

Vaccinations:

• Do not delay therapy initiation due to incomplete vaccination status; update vaccinations as soon as possible.
• Further research is needed on the impact of vaccinations and vaccination response during long-term immunotherapy in NMOSD.

Recent advancements in understanding NMOSD have led to the development of targeted, highly effective therapies for AQP4-IgG-positive patients. These treatments offer a personalized approach, considering factors like disease activity, comorbidities, patient preferences, and costs. They also allow for flexibility, enabling treatment switches if side effects or insufficient response occur. However, long-term data on therapy sequences and comprehensive risk management for lifelong treatments are still needed, and real-world evidence should possibly begathered through registries and platform trials with standardized data collection.

There remain several unmet needs in NMOSD treatment, including better understanding the long-term disease progression, optimal immunotherapy duration, and strategies for treatment cessation or de-escalation. Identifying biomarkers to predict attack risk could also be crucial. Additionally, double-negative NMOSD, a rare form of the disease, should potentially be prioritized in collaborative research efforts. Ensuring global access to therapies and treatment knowledge could be essential for improving outcomes for all NMOSD patients, regardless of location.

In Utero Exposure to Antiseizure Medications – Practice Guidelines From the AAN, AES, and SMFM

The 2024 guidelines, published in Neurology, served as a significant update to the previous 2017 clinical guidelines regarding the use of antiseizure medications (ASMs) during pregnancy. This guideline was developed by a collaboration of the American Academy of Neurology (AAN), the American Epilepsy Society (AES), and the Society for Maternal-Fetal Medicine (SMFM). It builds on prior research and addresses critical gaps in knowledge surrounding the effects of ASMs on teratogenesis (birth defects), perinatal outcomes, and neurodevelopmental consequences for children exposed to these medications in utero.

The latest update are important for improving patient care by offering evidence-based recommendations for managing epilepsy during pregnancy, reducing risks for both mothers and fetuses. It encourages multidisciplinary collaboration to create comprehensive treatment plans and highlights the need for future research on newer medications and factors like genetics and lifestyle. Overall, it provided a comprehensive approach to care that benefits both public health and individual patients.

1. Preconception Care and Shared Decision-Making

• Recommendation 1A: Clinicians should engage in shared decision-making with people with epilepsy who are contemplating pregnancy (PWECP), taking individual preferences into account when selecting ASMs and adjusting dosing.
• Recommendation 1B: It is crucial to recommend ASMs and doses that balance seizure control and fetal outcomes as early as possible, ideally before conception.

2. Seizure Control During Pregnancy

• Recommendation 2A: Clinicians must minimize the occurrence of convulsive seizures (including generalized tonic-clonic seizures) during pregnancy to reduce risks to both the birth parent and fetus.
• Recommendation 2B: Caution is advised when attempting to change or remove an effective ASM like valproic acid during pregnancy, even if it poses some fetal risk.
• Recommendation 2C: Regular monitoring of ASM levels throughout pregnancy is essential.
• Recommendation 2D: Adjust doses of ASMs during pregnancy as necessary based on serum levels or seizure control.
• Recommendation 2E: Clinicians should inform patients about the limited data available regarding the pregnancy outcomes for certain ASMs (e.g., acetazolamide, lacosamide, pregabalin).

3. Antiseizure Medications and Major Congenital Malformations (MCMs)

• Recommendation 3A: Provide patients with epilepsy with a comparison framework, explaining that the general population’s risk of major congenital malformations (MCMs) is 2.4%–2.9%.
• Recommendation 3B: Lamotrigine, levetiracetam, and oxcarbazepine are preferable in PWECP when possible, to reduce the risk of MCMs.
• Recommendation 3C: Avoid using valproic acid in PWECP to reduce the risk of MCMs, if clinically feasible.
• Recommendation 3D: Counsel patients on the high risk of MCMs associated with valproic acid exposure.
• Recommendation 3E: To minimize the risk of cardiac malformations, phenobarbital should be avoided in PWECP if possible.
• Recommendation 3F: Avoid using phenobarbital and topiramate if possible to reduce the risk of oral clefts.
• Recommendation 3G: Valproic acid should be avoided if possible to reduce the risk of urogenital and renal malformations.
• Recommendation 3H: Fetal screening, including anatomical ultrasound, should be recommended for PWECP using ASMs during pregnancy to enable early detection of MCMs.

4. Antiseizure Medications and Perinatal Outcomes

• Recommendation 4A: The risk of intrauterine death does not differ across ASM exposures in monotherapy.
• Recommendation 4B: Avoid using valproic acid or topiramate to minimize the risk of small for gestational age (SGA) births.
• Recommendation 4C: Screen for fetal growth restriction during pregnancy in PWECP taking valproic acid or topiramate.

5. Antiseizure Medications and Neurodevelopmental Outcomes

• Recommendation 5A: To reduce the risk of poor neurodevelopmental outcomes (e.g., autism spectrum disorder or lower IQ), clinicians should avoid using valproic acid in PWECP, if possible.
• Recommendation 5B: Counsel patients about the potential neurodevelopmental risks (reduced IQ and increased risk of ASD) associated with in utero exposure to valproic acid.
• Recommendation 5C: Counsel PWECP that valproic acid exposure may increase the risk of ASD compared to other ASMs.
• Recommendation 5D: Conduct age-appropriate developmental screening in children exposed to ASMs in utero.

6. Folic Acid Supplementation

• Recommendation 6A: Prescribe at least 0.4 mg of folic acid supplementation daily to PWECP preconceptionally and during pregnancy to reduce the risk of neural tube defects (NTDs).
• Recommendation 6B: Folic acid supplementation is associated with improved neurodevelopmental outcomes in the offspring, including reduced risk of ASD and improved global IQ.
• Recommendation 6C: Counsel PWECP on the importance of adhering to recommended folic acid supplementation to minimize risks of MCMs and neurodevelopmental delays.

Alzheimer’s Association Guideline for Diagnosing Alzheimer Disease

A major global health challenge is the early detection, accurate diagnosis, and appropriate management of mild cognitive impairment (MCI) or dementia because of Alzheimer disease (AD) and related dementias (ADRD), such as frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), vascular contributions to cognitive impairment and dementia (VCID), and others. With the number of patients living with dementia in the United States expected to more than double by 2050, from 5.8 million to 13.8 million, the already high individual and societal costs of dementia are set to increase significantly.

Unfortunately, cognitive and behavioral symptoms of AD/ADRD are often not diagnosed, disclosed, or are misattributed, with many primary care providers lacking confidence in diagnosing dementia. A significant percentage of patients with AD/ADRD are not informed about their diagnosis, despite evidence supporting the benefits of early diagnosis. Delayed diagnosis and disclosure can result in distressing and costly delays in receiving appropriate care.

To address these gaps, the Alzheimer’s Association has developed a clinical practice guideline focused on diagnostic evaluation, testing, counseling, and disclosure for patients presenting with symptoms of AD/ADRD. This guideline aims to provide clinicians with a structured, patient-centered approach to timely diagnosis, clear communication with patients and care partners, and the development of individualized care plans to improve patients' quality of life.

Here are some of the key points from the recommendations:

• Recommendation 1: Initiate a multitiered evaluation when cognitive, behavioral, or functional changes are reported by the patient, care partner, or clinician.
• Recommendation 2: Use patient-centered communication to establish shared goals and assess the patient's capacity for goal-setting during the evaluation process.
• Recommendation 3: Customize the evaluation process with tiers of assessments based on the patient's presentation, risk factors, and profile to determine impairment level, syndrome, and likely causes.
• Recommendation 4: Obtain reliable informant information on cognition, ADLs, mood, neuropsychiatric symptoms, and sensory/motor function during history taking, using structured instruments where possible.
• Recommendation 5: Gather individualized risk factor information for cognitive decline during history taking.
• Recommendation 6: Conduct a mental status exam and dementia-focused neurologic exam to diagnose the cognitive–behavioral syndrome.
• Recommendation 7: Use validated tools to assess cognition in patients with cognitive or behavioral symptoms.
• Recommendation 8: Perform multitiered and individualized laboratory testing based on the patient’s medical risks and profile, with routine Tier 1 tests for all patients.
• Recommendation 9: Obtain structural brain imaging to identify the cause(s) of cognitive–behavioral syndrome; CT can be used if MRI is unavailable or contraindicated.
• Recommendation 10: Engage the patient and care partner in understanding and appreciating the cognitive–behavioral syndrome’s severity for better education and diagnostic communication.
• Recommendation 11: Use a structured approach to communicate diagnostic findings, including disease name, severity, stage, treatment options, safety concerns, and available resources.
• Recommendation 12: Expedite further evaluation, including referral to a specialist, for atypical findings or suspected early-onset/rampant cognitive decline.
• Recommendation 13: Specialists should perform a comprehensive history and office-based examination to diagnose the cognitive–behavioral syndrome and its causes.
• Recommendation 14: Neuropsychological evaluation is recommended when initial cognitive assessments are insufficient, especially with complex clinical profiles or discrepant findings.
• Recommendation 15: Additional (Tier 2–4) laboratory tests may be obtained when diagnostic uncertainty remains, based on the patient's profile.
• Recommendation 16: For unresolved diagnostic uncertainty, dementia specialists can use FDG PET molecular imaging to improve diagnostic accuracy.
• Recommendation 17: If uncertainty persists after structural imaging, FDG PET, and/or CSF analysis, consider CSF analysis for amyloid and tau biomarkers to evaluate Alzheimer's pathology.
• Recommendation 18: If uncertainty remains after structural imaging, FDG PET, and CSF biomarkers, consider amyloid PET scans to evaluate cerebral amyloid pathology.
• Recommendation 19: In cases with a likely autosomal dominant family history, consider genetic testing with the involvement of a genetic counselor.

Improved diagnostic approaches for AD and ADRD can be effective in primary care settings if they are efficient, cost-effective, widely accessible, and accurate enough to be interpreted without requiring high expertise. In parallel, research should possibly continue advancing new pharmacotherapies, biological interventions, behavioral strategies, and care solutions to improve patient outcomes. Along with federal agencies allocating more resources through initiatives like the National Alzheimer's Project Act Advisory Council, advocacy groups are driving public-private partnerships to achieve more timely and accurate diagnoses, improved disclosures, and better management for patients.

Excitement is growing in the field for new diagnostic tools that could provide primary care clinicians with actionable insights, such as digital biomarkers like wearables for monitoring behavior or cognitive tests, as well as plasma biomarkers that can detect key disease-related proteins in blood. Although these innovations hold significant promise, further research could be necessary to assess their effectiveness across diverse, real-world populations. It’s important to note that biomarkers, especially blood-based ones, are recommended to not be used in isolation for diagnosis, but rather as part of a comprehensive assessment, including confirmation via CSF or PET imaging. Additionally, the clinicopathologic relationships and biomarker characteristics of AD and ADRD may differ in minoritized populations, highlighting the need for maybe more inclusive research.

Clinical Criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy

The guidelines, published in February 2024, aim to address a significant gap in the diagnosis and treatment of LATE-NC (limbic predominant age-related TDP-43 encephalopathy neuropathologic change), a common form of dementia that often overlaps with Alzheimer's disease (AD). Despite its prevalence, especially in individuals over 85, LATE-NC lacks distinct biomarkers for in vivo detection, making it difficult to differentiate from AD during life. This diagnostic challenge is compounded by the fact that AD and LATE-NC frequently co-occur in the same brain regions, accelerating cognitive decline, while LATE-NC alone tends to progress more slowly. With the FDA's approval of anti-amyloid drugs targeting AD, there is a pressing need to develop specific guidelines for diagnosing LATE-NC to ensure appropriate treatment decisions and improve prognostic clarity for patients.

The significance of these guidelines lies in their potential to advance clinical and research efforts by enabling more accurate diagnoses of LATE-NC. Such diagnoses are essential for developing and testing treatments targeting LATE, especially as patients with mixed AD and LATE pathology may respond differently to anti-amyloid therapies. Establishing clinical criteria for LATE-NC also helps clinicians inform families and caregivers, fostering better decision-making regarding treatment options and prognosis. Given the high prevalence of LATE-NC, particularly in older adults, and the ongoing development of combination therapies for multiple pathologies, these guidelines will be crucial for addressing the growing need for accurate diagnoses and personalized care in dementia.

Here's an overview of some of the major changes:

Possible LATE

• Core Clinical Syndrome: The diagnosis of Possible LATE is made based on the presence of core clinical symptoms (primarily amnestic syndrome) combined with significant hippocampal atrophy. However, because hippocampal atrophy can also be present in AD, it is difficult to distinguish LATE from AD without additional supportive features. Therefore, this diagnosis is provisional until further evidence can be gathered.
• Diagnostic Similarity to AD: This approach is similar to past criteria for Possible AD, where an alternative etiology (such as LATE) is considered but not fully confirmed. The lack of distinctive biomarkers for TDP-43 makes this distinction particularly difficult.

Probable LATE

To confirm a diagnosis of Probable LATE, additional supportive features are required, primarily aimed at ruling out AD and confirming the presence of LATE-related pathology.

• Core Features: The presence of hippocampal atrophy combined with the core clinical syndrome is necessary. The key distinction for Probable LATE is the use of biomarkers to rule out Alzheimer's disease neurodegenerative changes (ADNC) since these conditions share overlapping symptoms, particularly in the limbic system.
• Biomarkers for ADNC: Biomarkers such as amyloid PET scans, CSF Aβ42/40 ratios, and tau-related markers (e.g., p-tau181/Aβ42 ratios) are crucial for ruling out AD. A negative result in these biomarkers strongly supports a diagnosis of LATE, as the absence of amyloid plaques in the absence of tau pathology indicates that AD is less likely to be contributing to cognitive symptoms.
• Tau Considerations: If amyloid biomarkers are positive but tau biomarkers (e.g., tau PET or CSF p-tau181) are negative, the absence of tau pathology may point to LATE-NC as the primary pathology, given that tau-related neurodegeneration is more strongly linked to cognitive decline than amyloid plaques alone.
• Mixed Pathology: In cases with both ADNC and LATE-NC, tau pathology plays a critical role in determining the primary pathology. If tau biomarkers are negative (or not significant), LATE-NC becomes a more plausible explanation for the cognitive decline. Additionally, considering tau pathology is important when amyloid-positive, tau-negative cases are encountered.
• Additional Imaging: FDG-PET scans can provide helpful clues, particularly for ruling out AD. In AD, a posterior parietal and temporal hypometabolic pattern is typically seen. LATE-NC, on the other hand, exhibits a distinct hypometabolic pattern in the medial temporal lobe and orbitofrontal cortex, which can support a diagnosis of LATE when AD features are not present.
• MRI: Structural MRI is less precise than FDG-PET but may help differentiate LATE-NC from AD by showing greater anterior-to-posterior hippocampal atrophy in LATE-NC. Quantitative imaging can further support this distinction, although these patterns are still being validated for widespread clinical use.

Challenges in Diagnosing LATE in the Context of AD

The difficulty in diagnosing LATE arises from several key challenges:

1. Overlap in Pathology: Both AD and LATE share pathologic involvement in the limbic system, including regions like the hippocampus, entorhinal cortex, and amygdala. This results in overlapping cognitive symptoms, particularly memory impairment, making it difficult to separate the two disorders based solely on clinical presentation.
2. Co-occurrence of Pathologies: LATE often co-occurs with AD, especially in older individuals. Research has shown that nearly 50% of severe AD cases in older individuals have comorbid LATE-NC. This dual pathology complicates the diagnosis and may contribute to faster cognitive decline than seen in AD alone.
3. Genetic Risk Factors: The APOE ε4 allele is a known risk factor for both AD and LATE, further blurring the line between these two conditions.
4. Mixed Pathology Diagnosis: In cases with both ADNC and LATE-NC, definitive diagnosis requires ruling out AD as the primary cause of cognitive symptoms while considering LATE-NC as a contributing factor. This mixed pathology scenario complicates the development of tailored therapeutic interventions and diagnostic strategies.

Additional Supportive Features for Both Possible and Probable LATE

While the main diagnostic criteria focus on clinical and biomarker evidence, several imaging features can provide increased diagnostic certainty:

• FDG-PET: A pattern of hypometabolism in the posterior parietal and temporal regions supports AD, while hypometabolism in the medial temporal lobe and orbitofrontal cortex can support LATE-NC. These patterns can be used to rule out AD, enhancing the likelihood of LATE as the primary driver of cognitive symptoms.
• MRI: MRI showing greater anterior-to-posterior hippocampal atrophy can indicate LATE-NC, especially if the pattern differs from the more uniform atrophy seen in AD.
• Tau Imaging and Biofluid Markers: Tau imaging (e.g., tau PET) and biomarkers like CSF p-tau181 provide additional insight into whether tau pathology is present, which is critical in differentiating between AD and LATE-NC.

LATE in the Context of ADNC

In individuals with both AD and LATE pathology, diagnosing LATE-NC becomes particularly challenging due to the overlap of clinical features, shared brain regions, and potential co-occurrence of pathologies. In these cases, significant hippocampal atrophy beyond what is expected for the clinical stage of AD can be a strong indicator of co-existing LATE. Additionally, early cognitive decline, particularly memory loss, may progress more rapidly in these individuals.

• Hippocampal Atrophy and Tau: Severe hippocampal atrophy in individuals with mild cognitive impairment (MCI) or early-stage AD that exceeds what would typically be expected for their clinical stage supports the possibility of co-occurring LATE. Similarly, a mismatch between the degree of hippocampal atrophy and tau accumulation (as seen with tau PET) may further suggest LATE-NC.

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