User:Julinka Auta Fernandes/sandbox MS ECG

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D. Julinka Auta Fernandes

Overview

An electrocardiogram (ECG) is not used to diagnose multiple sclerosis (MS), and there are no ECG findings that are specific or diagnostic for MS. The diagnosis of MS is established using clinical findings together with appropriate paraclinical evidence, including MRI and, when appropriate, cerebrospinal fluid (CSF) biomarkers, according to the 2024 revisions of the McDonald criteria.

The principal roles of ECG in a person with MS are evaluation of suspected cardiovascular disease or arrhythmia, assessment of selected cardiovascular autonomic abnormalities, and cardiac safety monitoring when initiating certain disease-modifying therapies, particularly sphingosine-1-phosphate receptor modulators.

Electrocardiogram

ECG and the diagnosis of multiple sclerosis

An ECG does not establish or exclude a diagnosis of MS. The 2024 McDonald criteria do not include ECG findings as a diagnostic criterion.

MRI has a central role in the diagnosis of MS. The 2024 MAGNIMS-CMSC-NAIMS consensus recommendations address MRI assessment of the brain and spinal cord and incorporate the optic nerve as a fifth anatomical location, in addition to the periventricular, juxtacortical or cortical, infratentorial, and spinal cord regions. The consensus also addresses susceptibility-sensitive MRI markers, including the central vein sign and paramagnetic rim lesions, when appropriate.

Therefore, ECG abnormalities such as atrial fibrillation, ventricular arrhythmias, PR-interval abnormalities, U waves, Q waves, bundle branch block, or other nonspecific ECG abnormalities should not be described as findings suggestive or diagnostic of MS. Such findings require evaluation according to standard cardiovascular practice and the clinical context.

Cardiovascular autonomic dysfunction

MS may be associated with abnormalities of cardiovascular autonomic regulation. A systematic review and meta-analysis of 43 studies involving 1,518 people with MS and 1,062 healthy controls found differences in several measures of heart rate variability (HRV), including reduced RMSSD, pNN50, high-frequency power, and low-frequency power in people with MS compared with healthy controls.

Other systematic reviews have similarly reported abnormalities of cardiac autonomic regulation in MS, particularly involving measures of heart-rate variability, although studies have used heterogeneous methods.

ECG-derived HRV assessment may provide information about autonomic cardiovascular regulation in selected patients or research settings. However, HRV abnormalities are not specific for MS and are not diagnostic criteria for MS.

When cardiovascular autonomic dysfunction is clinically suspected, assessment may include orthostatic heart rate and blood-pressure measurements and, when appropriate, additional autonomic testing. ECG-based HRV assessment should be selected according to the clinical question and is not routinely required in every patient with MS.

ECG and sphingosine-1-phosphate receptor modulators

ECG has an important role in the cardiac safety assessment of selected sphingosine-1-phosphate receptor modulators used for MS. These medications can cause reductions in heart rate and slowing of atrioventricular conduction, particularly during treatment initiation. Cardiac assessment and monitoring requirements differ among individual agents because of differences in dose-titration regimens and cardiac safety profiles.

Before initiating an S1P receptor modulator, cardiovascular history, baseline heart rate, relevant medications, and potential conduction or rhythm abnormalities should be assessed according to the prescribing information for the individual drug. Cardiology consultation should be considered when clinically significant pre-existing cardiovascular disease or conduction abnormalities are present.

Fingolimod

Before initiating fingolimod, an ECG should be obtained as part of first-dose cardiac assessment. Initiation of fingolimod can cause bradycardia and atrioventricular conduction abnormalities.

Patients initiating fingolimod should be observed for at least 6 hours after the first dose for signs and symptoms of bradycardia, with hourly pulse and blood-pressure measurements. ECG should be obtained before dosing and at the end of the observation period.

Additional monitoring should be provided if clinically important bradycardia or conduction abnormalities occur. Overnight continuous ECG monitoring is required in specified higher-risk circumstances, including certain pre-existing cardiovascular or cerebrovascular conditions, prolonged QTc or increased risk of QT prolongation, and concomitant treatment with drugs that slow heart rate or atrioventricular conduction.

First-dose monitoring is also required when fingolimod is restarted after specified treatment interruptions because effects on heart rate and atrioventricular conduction may recur after reinitiation.

Siponimod

Before initiating siponimod, cardiovascular assessment should include consideration of baseline ECG findings and pre-existing conduction abnormalities. Siponimod can cause bradycardia and atrioventricular conduction delays, particularly during treatment initiation.

Patients with certain pre-existing cardiac conditions, including sinus bradycardia with a heart rate below 55 beats per minute, a history of first- or second-degree Mobitz type I atrioventricular block, myocardial infarction, or heart failure, should be observed for 6 hours after the first dose for signs and symptoms of bradycardia. In these patients, ECG should be obtained before dosing and at the end of the observation period.

If clinically significant bradyarrhythmia or conduction abnormalities occur, further evaluation and monitoring should be performed according to the product information and clinical circumstances.

Ozanimod

Ozanimod is initiated using a dose-titration regimen that attenuates the magnitude of the initial heart-rate reduction.

Before starting ozanimod, patients should be assessed for relevant cardiovascular disease and conduction abnormalities. Ozanimod can cause a transient decrease in heart rate and atrioventricular conduction delays, particularly during treatment initiation.

Routine prolonged first-dose cardiac monitoring is not universally required with the recommended ozanimod titration regimen. Cardiology consultation should be considered in patients with relevant conduction abnormalities or concomitant use of drugs that decrease heart rate or atrioventricular conduction.

Ponesimod

Before initiating ponesimod, an ECG should be obtained to identify pre-existing conduction abnormalities. Ponesimod is initiated using a dose-titration regimen to reduce cardiac effects during treatment initiation.

First-dose 4-hour monitoring is recommended for patients with sinus bradycardia with a heart rate below 55 beats per minute, first- or second-degree Mobitz type I atrioventricular block, or a history of myocardial infarction or heart failure occurring more than 6 months before treatment initiation and in stable condition.

For patients requiring first-dose monitoring, the patient should be monitored for 4 hours with at least hourly pulse and blood-pressure measurements. ECG should be obtained at the end of the observation period.

Additional monitoring is required if clinically significant bradycardia or conduction abnormalities occur, according to the product information.

ECG abnormalities in patients with multiple sclerosis

ECG abnormalities in a patient with MS should not be considered characteristic ECG manifestations of MS.

Potential abnormalities may include:

• Sinus bradycardia or other heart-rate abnormalities, particularly during initiation of S1P receptor modulator therapy.
• Atrioventricular block or PR-interval prolongation, particularly during initiation of S1P receptor modulator therapy.
• QTc prolongation, particularly in the presence of pre-existing QT prolongation, electrolyte abnormalities, concomitant QT-prolonging medications, or specific drug-related risks.
• Atrial fibrillation or other atrial arrhythmias.
• Ventricular arrhythmias.
• Bundle branch block or other conduction abnormalities.

These findings are nonspecific and should be evaluated according to standard cardiovascular practice. Their presence does not establish a diagnosis of MS.

The previously reported association of individual ECG findings such as atrial fibrillation, ventricular arrhythmia, Q waves, U waves, or isolated PR-interval changes with MS should not be interpreted as evidence that these findings are diagnostic of MS.

Ambulatory ECG monitoring

Ambulatory ECG monitoring, including Holter monitoring or longer-duration rhythm monitoring, is not routinely indicated solely because a patient has MS.

Ambulatory ECG monitoring may be appropriate when symptoms or clinical findings suggest intermittent arrhythmia, including unexplained palpitations, syncope, presyncope, episodic bradycardia, unexplained tachycardia, or other suspected intermittent rhythm disturbances.

The choice and duration of ambulatory monitoring should be based on symptom frequency and standard cardiovascular practice.

ECG in patients with cardiovascular symptoms

Patients with MS should undergo cardiovascular evaluation according to their symptoms and individual cardiovascular risk factors. A 12-lead ECG is appropriate when clinically indicated, including evaluation of chest pain, suspected ischemia, palpitations, syncope or presyncope, unexplained dyspnea, suspected arrhythmia, or suspected medication-related cardiac effects.

These cardiovascular indications should be distinguished from MS diagnosis: ECG is not a routine diagnostic investigation for MS.

Interpretation of an abnormal ECG

An abnormal ECG in a patient with MS should not automatically be attributed to MS. The differential diagnosis should include primary cardiac disease, myocardial ischemia, electrolyte abnormalities, medication effects, autonomic dysfunction, structural heart disease, conduction-system disease, and primary cardiac arrhythmias.

ECG findings should be interpreted together with the patient's symptoms, cardiovascular history, medication list, physical examination, and relevant laboratory and imaging findings. Additional evaluation, such as echocardiography or ambulatory rhythm monitoring, should be performed when clinically indicated.

Key clinical points

• ECG is not a diagnostic test for multiple sclerosis.
• There are no ECG findings that are specific or diagnostic for MS.
• The 2024 McDonald criteria do not include ECG as a diagnostic criterion.
• MRI and appropriate CSF/biomarker assessment, together with clinical findings, are central to modern MS diagnosis.
• MS may be associated with cardiovascular autonomic dysfunction and altered HRV, but these findings are not specific for MS and are not diagnostic criteria.
• ECG may be useful when cardiovascular symptoms, suspected arrhythmia, or selected autonomic dysfunction are present.
• ECG has an important medication-safety role with S1P receptor modulators, but monitoring requirements differ among fingolimod, siponimod, ozanimod, and ponesimod.
• Fingolimod requires pre-dose and post-observation ECG assessment with at least 6 hours of first-dose observation.
• Siponimod requires cardiovascular assessment and 6-hour first-dose monitoring with ECG in patients with specified pre-existing cardiac conditions.
• Ozanimod uses dose titration, and routine prolonged first-dose cardiac monitoring is not universally required with the recommended titration regimen.
• Ponesimod requires baseline cardiovascular assessment, with 4-hour first-dose monitoring for patients with specified pre-existing cardiac conditions.
• Ambulatory ECG monitoring is reserved for clinically indicated evaluation of suspected intermittent arrhythmia and is not routinely required solely because of MS.