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European Headache Federation Consensus on Resistant and Refractory Migraine Definition

• Some patients with migraine do not experience adequate pain relief with acute and preventive treatments.

• The aim of the document is to provide a definition of those migraines which are difficult-to-treat.

• The consensus process using the Delphi method was used to establish definitions.

• Two categories of difficult-to-treat migraine were recognized, resistant migraine and refractory migraine.

• Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement.

• Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months.

• Drug failure may include lack of efficacy or lack of tolerability.

• Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy.

• Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved.

• It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

• Triggers and comorbidities which may contribute to resistant or refractory migraine need to be identified and managed before assigning patients to those categories.

• Careful differential diagnosis with mimicking conditions must be done.Proposed Criteria for Resistant or Refractory Migraine

• A patient with >50% reduction in headache days with treatment may be labeled as resistant or refractory.

• The criteria proposed by the EHF Expert Consensus Group rely on the presence of a given number of days of debilitating headache attacks.

• Adequate timing of drug administration, dosage, and formulations used should be considered when assessing the efficacy of acute headache medications.

• The EHF Expert Consensus Group did not choose to use cut scores at common validated instruments to measure function or disability.

• Failure of at least two triptans is required before a patient can be labeled as resistant or refractory.

• Establishing drug failure or contraindication is pivotal to identifying resistant or refractory migraine.

• Patients suffering from migraine frequently have comorbid disorders that should be addressed and managed before labeling them as resistant or refractory.

• Differential diagnosis should be considered to rule out other primary or secondary headaches that may entirely account for the clinical picture or coexist with migraine.

• The present definition did not consider failure to devices or nonpharmacological therapies.

• Patients with resistant migraine should be managed in special interest headache care settings, and patients with refractory migraine must be managed in tertiary level headache clinics.

• Establishing previous treatment failures should be done by chart review, and information on duration, dose, and adverse events should be reliable.

• A minimum follow-up of 6 months is suggested for patients with refractory migraine who were never followed by a headache specialist.Implications and Future Perspectives of the Diagnosis of Resistant or Refractory Migraine

• The diagnosis of resistant or refractory migraine is a serious matter that requires careful establishment.

• The concept of resistant or refractory migraine may have profound psychological implications for patients, as it can contribute to stigmatization.

• Education and effort are needed to help patients and physicians understand the possible fluctuations of the disease.

• There could be legal and healthcare implications for patients diagnosed with resistant or refractory migraine, such as access to newer treatments or social welfare.

• The introduction of the concept of resistant and refractory migraine will have clinical and political implications, and operational criteria are needed to define these subpopulations.

• The proposed updated European Headache Federation (EHF) definition identifies two subsets of difficult-to-treat migraine: resistant and refractory migraine, and considers both frequency and disability from single and frequent attacks.

• The proposed criteria will allow inclusion of new migraine preventive treatments when there is good evidence for their use.

• Reliable criteria are needed to identify factors that may lead to refractoriness, such as genetic predisposition, changes in brain structure and function, and mechanisms like central sensitization.

• Field-testing of the proposed updated EHF definition is needed to identify possible deficiencies and make further improvements, and adaptations at the country level may be necessary to make the definition more usable.

• A widely accepted definition of difficult-to-treat migraine is necessary to achieve progress in research, identify underlying mechanisms, and develop evidence-based treatments.

• The proposed updated EHF definition aims to increase understanding of the impact of migraine as a disease with social, legal, and healthcare implications.

• The EHF Expert Consensus Group hopes that the proposed criteria will stimulate further clinical, scientific, and social attention to patients who suffer from difficult-to-treat migraine.Key Points from Recent Research on Migraine

• Multiple studies have been conducted on the use of onabotulinumtoxinA and monoclonal antibodies for the prevention of chronic migraine.

• Clinical trials have shown that triptan nonresponders exist and may benefit from alternative treatments, such as polytherapy.

• Comorbidities, including sleep disturbances and cardiovascular diseases, are common in migraine patients and should be considered in treatment plans.

• The American Headache Society and the European Federation of Neurological Societies have issued guidelines on the drug treatment of migraine and integrating new treatments into clinical practice.

• The use of hormonal contraceptives in women with migraine has been the subject of consensus statements from the European Headache Federation and the European Society of Contraception and Reproductive Health.

• Behavioral therapy has been shown to be effective in the treatment of chronic migraine.

• The development of national migraine strategies, such as in Canada, can help improve the management of migraine and reduce healthcare costs.

• The stigma associated with migraine can negatively impact patients' quality of life and should be addressed in clinical practice.

• Patients with chronic migraine who have failed preventive treatments experience a high disease burden and reduced quality of life.

• Acute migraine treatment options have been assessed and evaluated by the American Headache Society.

• The global campaign against headache has developed indices to measure the burden of migraine for clinical management and population-based research.

• Withdrawal therapy and drug misuse can be a concern in the treatment of drug-induced headache.

European Headache Federation Consensus on Resistant and Refractory Migraine Definition

• Some patients with migraine do not experience adequate pain relief with acute and preventive treatments.

• The aim of the document is to provide a definition of those migraines which are difficult-to-treat.

• The consensus process using the Delphi method was used to establish definitions.

• Two categories of difficult-to-treat migraine were recognized, resistant migraine and refractory migraine.

• Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement.

• Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months.

• Drug failure may include lack of efficacy or lack of tolerability.

• Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy.

• Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved.

• It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

• Triggers and comorbidities which may contribute to resistant or refractory migraine need to be identified and managed before assigning patients to those categories.

• Careful differential diagnosis with mimicking conditions must be done.Proposed Criteria for Resistant or Refractory Migraine

• A patient with >50% reduction in headache days with treatment may be labeled as resistant or refractory.

• The criteria proposed by the EHF Expert Consensus Group rely on the presence of a given number of days of debilitating headache attacks.

• Adequate timing of drug administration, dosage, and formulations used should be considered when assessing the efficacy of acute headache medications.

• The EHF Expert Consensus Group did not choose to use cut scores at common validated instruments to measure function or disability.

• Failure of at least two triptans is required before a patient can be labeled as resistant or refractory.

• Establishing drug failure or contraindication is pivotal to identifying resistant or refractory migraine.

• Patients suffering from migraine frequently have comorbid disorders that should be addressed and managed before labeling them as resistant or refractory.

• Differential diagnosis should be considered to rule out other primary or secondary headaches that may entirely account for the clinical picture or coexist with migraine.

• The present definition did not consider failure to devices or nonpharmacological therapies.

• Patients with resistant migraine should be managed in special interest headache care settings, and patients with refractory migraine must be managed in tertiary level headache clinics.

• Establishing previous treatment failures should be done by chart review, and information on duration, dose, and adverse events should be reliable.

• A minimum follow-up of 6 months is suggested for patients with refractory migraine who were never followed by a headache specialist.Implications and Future Perspectives of the Diagnosis of Resistant or Refractory Migraine

• The diagnosis of resistant or refractory migraine is a serious matter that requires careful establishment.

• The concept of resistant or refractory migraine may have profound psychological implications for patients, as it can contribute to stigmatization.

• Education and effort are needed to help patients and physicians understand the possible fluctuations of the disease.

• There could be legal and healthcare implications for patients diagnosed with resistant or refractory migraine, such as access to newer treatments or social welfare.

• The introduction of the concept of resistant and refractory migraine will have clinical and political implications, and operational criteria are needed to define these subpopulations.

• The proposed updated European Headache Federation (EHF) definition identifies two subsets of difficult-to-treat migraine: resistant and refractory migraine, and considers both frequency and disability from single and frequent attacks.

• The proposed criteria will allow inclusion of new migraine preventive treatments when there is good evidence for their use.

• Reliable criteria are needed to identify factors that may lead to refractoriness, such as genetic predisposition, changes in brain structure and function, and mechanisms like central sensitization.

• Field-testing of the proposed updated EHF definition is needed to identify possible deficiencies and make further improvements, and adaptations at the country level may be necessary to make the definition more usable.

• A widely accepted definition of difficult-to-treat migraine is necessary to achieve progress in research, identify underlying mechanisms, and develop evidence-based treatments.

• The proposed updated EHF definition aims to increase understanding of the impact of migraine as a disease with social, legal, and healthcare implications.

• The EHF Expert Consensus Group hopes that the proposed criteria will stimulate further clinical, scientific, and social attention to patients who suffer from difficult-to-treat migraine.Key Points from Recent Research on Migraine

• Multiple studies have been conducted on the use of onabotulinumtoxinA and monoclonal antibodies for the prevention of chronic migraine.

• Clinical trials have shown that triptan nonresponders exist and may benefit from alternative treatments, such as polytherapy.

• Comorbidities, including sleep disturbances and cardiovascular diseases, are common in migraine patients and should be considered in treatment plans.

• The American Headache Society and the European Federation of Neurological Societies have issued guidelines on the drug treatment of migraine and integrating new treatments into clinical practice.

• The use of hormonal contraceptives in women with migraine has been the subject of consensus statements from the European Headache Federation and the European Society of Contraception and Reproductive Health.

• Behavioral therapy has been shown to be effective in the treatment of chronic migraine.

• The development of national migraine strategies, such as in Canada, can help improve the management of migraine and reduce healthcare costs.

• The stigma associated with migraine can negatively impact patients' quality of life and should be addressed in clinical practice.

• Patients with chronic migraine who have failed preventive treatments experience a high disease burden and reduced quality of life.

• Acute migraine treatment options have been assessed and evaluated by the American Headache Society.

• The global campaign against headache has developed indices to measure the burden of migraine for clinical management and population-based research.

• Withdrawal therapy and drug misuse can be a concern in the treatment of drug-induced headache.

European Headache Federation Consensus on Resistant and Refractory Migraine Definition

• Some patients with migraine do not experience adequate pain relief with acute and preventive treatments.

• The aim of the document is to provide a definition of those migraines which are difficult-to-treat.

• The consensus process using the Delphi method was used to establish definitions.

• Two categories of difficult-to-treat migraine were recognized, resistant migraine and refractory migraine.

• Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement.

• Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months.

• Drug failure may include lack of efficacy or lack of tolerability.

• Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy.

• Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved.

• It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

• Triggers and comorbidities which may contribute to resistant or refractory migraine need to be identified and managed before assigning patients to those categories.

• Careful differential diagnosis with mimicking conditions must be done.Proposed Criteria for Resistant or Refractory Migraine

• A patient with >50% reduction in headache days with treatment may be labeled as resistant or refractory.

• The criteria proposed by the EHF Expert Consensus Group rely on the presence of a given number of days of debilitating headache attacks.

• Adequate timing of drug administration, dosage, and formulations used should be considered when assessing the efficacy of acute headache medications.

• The EHF Expert Consensus Group did not choose to use cut scores at common validated instruments to measure function or disability.

• Failure of at least two triptans is required before a patient can be labeled as resistant or refractory.

• Establishing drug failure or contraindication is pivotal to identifying resistant or refractory migraine.

• Patients suffering from migraine frequently have comorbid disorders that should be addressed and managed before labeling them as resistant or refractory.

• Differential diagnosis should be considered to rule out other primary or secondary headaches that may entirely account for the clinical picture or coexist with migraine.

• The present definition did not consider failure to devices or nonpharmacological therapies.

• Patients with resistant migraine should be managed in special interest headache care settings, and patients with refractory migraine must be managed in tertiary level headache clinics.

• Establishing previous treatment failures should be done by chart review, and information on duration, dose, and adverse events should be reliable.

• A minimum follow-up of 6 months is suggested for patients with refractory migraine who were never followed by a headache specialist.Implications and Future Perspectives of the Diagnosis of Resistant or Refractory Migraine

• The diagnosis of resistant or refractory migraine is a serious matter that requires careful establishment.

• The concept of resistant or refractory migraine may have profound psychological implications for patients, as it can contribute to stigmatization.

• Education and effort are needed to help patients and physicians understand the possible fluctuations of the disease.

• There could be legal and healthcare implications for patients diagnosed with resistant or refractory migraine, such as access to newer treatments or social welfare.

• The introduction of the concept of resistant and refractory migraine will have clinical and political implications, and operational criteria are needed to define these subpopulations.

• The proposed updated European Headache Federation (EHF) definition identifies two subsets of difficult-to-treat migraine: resistant and refractory migraine, and considers both frequency and disability from single and frequent attacks.

• The proposed criteria will allow inclusion of new migraine preventive treatments when there is good evidence for their use.

• Reliable criteria are needed to identify factors that may lead to refractoriness, such as genetic predisposition, changes in brain structure and function, and mechanisms like central sensitization.

• Field-testing of the proposed updated EHF definition is needed to identify possible deficiencies and make further improvements, and adaptations at the country level may be necessary to make the definition more usable.

• A widely accepted definition of difficult-to-treat migraine is necessary to achieve progress in research, identify underlying mechanisms, and develop evidence-based treatments.

• The proposed updated EHF definition aims to increase understanding of the impact of migraine as a disease with social, legal, and healthcare implications.

• The EHF Expert Consensus Group hopes that the proposed criteria will stimulate further clinical, scientific, and social attention to patients who suffer from difficult-to-treat migraine.Key Points from Recent Research on Migraine

• Multiple studies have been conducted on the use of onabotulinumtoxinA and monoclonal antibodies for the prevention of chronic migraine.

• Clinical trials have shown that triptan nonresponders exist and may benefit from alternative treatments, such as polytherapy.

• Comorbidities, including sleep disturbances and cardiovascular diseases, are common in migraine patients and should be considered in treatment plans.

• The American Headache Society and the European Federation of Neurological Societies have issued guidelines on the drug treatment of migraine and integrating new treatments into clinical practice.

• The use of hormonal contraceptives in women with migraine has been the subject of consensus statements from the European Headache Federation and the European Society of Contraception and Reproductive Health.

• Behavioral therapy has been shown to be effective in the treatment of chronic migraine.

• The development of national migraine strategies, such as in Canada, can help improve the management of migraine and reduce healthcare costs.

• The stigma associated with migraine can negatively impact patients' quality of life and should be addressed in clinical practice.

• Patients with chronic migraine who have failed preventive treatments experience a high disease burden and reduced quality of life.

• Acute migraine treatment options have been assessed and evaluated by the American Headache Society.

• The global campaign against headache has developed indices to measure the burden of migraine for clinical management and population-based research.

• Withdrawal therapy and drug misuse can be a concern in the treatment of drug-induced headache.

Therapeutic Approaches for Traumatic Brain Injury: Intracranial Pressure and Cerebral Perfusion Pressure

• A significant number of patients with severe TBI develop raised intracranial pressure (ICP) depending on intracranial lesion, age, and definition.

• The most widely accepted ICP threshold for therapy is 20 mmHg, although the latest guidelines suggest 22 mmHg.

• Critical ICP thresholds may vary between young and old and male and female patients, with older patients (age ≥55 years) and females having lower ICP thresholds (18 mmHg vs. 22 mmHg) for prediction of poor outcome.

• Intracranial pressure monitoring has been the cornerstone of TBI care since the 1980s, although a multicenter trial did not show superiority of management using continuous measurement of ICP compared to repeated clinical examination and CT scans.

• Cerebral perfusion pressure (CPP) is more important than just targeting an increased ICP, particularly in patients with maintained autoregulation.

• Critical threshold for CPP lies between 50 and 60 mmHg, and brain monitoring techniques such as jugular venous oximetry, monitoring of brain tissue oxygen tension (PbtO2), and cerebral microdialysis could provide complementary and specific information that allows for selecting the optimal CPP for the individual patient.

• The latest guidelines suggest discrimination between individuals with and without preserved autoregulation.

• CPP-targeted treatment concept includes basic measures, active interventions, and aggressive treatment of refractory elevated intracranial pressure.

• The Lund concept, an ICP and volume targeted concept, focuses on the reduction of ICP by decreasing intracranial volumes.

• The goals of the Lund concept are to preserve a normal colloid osmotic pressure, reduce capillary hydrostatic pressure, and reduce cerebral blood volume by vasoconstriction.

• Osmolar agents like hypertonic saline and Na-lactate are effective in reducing ICP, but evidence for improved neurological outcome for all these interventions is still very limited and they bear a risk of fluid overload including cardiovascular events and risks of osmotic diuresis, including dehydration.

• Decompressive craniectomy (DC) for selected cases only as DC is a last-resort treatment for severe refractory ICP, reducing ICP and mortality while increasing incidence of unfavorable outcome at six months.Advanced Management Strategies for Traumatic Brain Injury: Bedside Physiological Monitoring and Tailored Therapy

• The Lund concept is a management strategy for traumatic brain injury (TBI) that includes analgosedation, reduction of hydrostatic capillary pressure, and control of fluid balance.

• The Lund concept has not been widely accepted outside of Sweden due to limited evidence of superiority compared to other treatments and controversial issues.

• A target cerebral perfusion pressure (CPP) of 60-70 mmHg is used in the Lund concept, which contradicts the common treatment goal of cerebral blood flow optimization by augmentation of CPP.

• Advanced bedside physiological monitoring techniques can provide more precise understanding of the influencing factors of TBI and allow for better-tailored therapies.

• Increased intracranial pressure (ICP) is not a diagnosis by itself but rather a symptom resulting from different processes, including intracranial mass lesions, increased cerebral blood volume, brain edema, and impaired cerebrospinal fluid reabsorption.

• Jugular bulb oximetry (SjVO2) is a fiberoptic catheter that allows for continuous monitoring of the balance between global cerebral oxygen delivery and utilization and reflects cerebral oxygen deficit.

• SjVO2 has a prognostic value, and a decrease in SjVO2 below 55% is associated with a poor outcome.

• Brain tissue partial tension of oxygen (PbtO2) provides a continuous measurement of extracellular oxygen tension as an indicator of the adequacy of oxygen delivery.

• Reduced PbtO2 has been associated with a poor outcome after neurotrauma.

• Oxygen diffusion can modulate PbtO2, which can be further modulated in pericontusional tissue.

• Advanced bedside physiological monitoring techniques include autoregulation assessment, continuous electroencephalography (EEG) or its surrogate bispectral index (BIS), and different imaging modalities (e.g., transcranial doppler ultrasound).

• A proposed algorithm to manage abnormal SjVO2 includes hypertonic saline therapy. However, SjVO2 measurement is not used frequently in clinical routine due to technical reasons.

Management of Traumatic Brain Injury: Intracranial Pressure Monitoring and Cerebral Perfusion Pressure Guided Therapy

• A significant number of severe TBI patients develop raised intracranial pressure (ICP), with the most widely accepted threshold for therapy being 20 mmHg.

• Critical ICP thresholds may vary between young and old and male and female patients, with older patients (age ≥55 years) and females having lower ICP thresholds (18 mmHg vs. 22 mmHg) for prediction of poor outcome.

• ICP monitoring is indicated in patients with severe TBI (GCS ≤8) and protocols for ICP therapy vary in detail and are mainly based on experience and consensus guidelines.

• Targeting cerebral perfusion pressure (CPP) as a surrogate for relative cerebral perfusion is more important than just targeting an increased ICP, especially in patients with maintained autoregulation.

• The optimal level of CPP is uncertain, but a CPP above 70 mmHg should be avoided due to the risk of acute respiratory distress syndrome (ARDS).

• A low CPP causes a reduction in cerebral blood flow (CBF) and may induce an elevation in cerebral blood volume (CBV) and thus ICP within the range of autoregulation, predisposing the injured brain to cerebral ischemia and infarction.

• The critical threshold for CPP lies between 50 and 60 mmHg, but brain monitoring techniques such as jugular venous oximetry (SvJO2), monitoring of brain tissue oxygen tension (PbtO2), and cerebral microdialysis could provide complementary and specific information that allows for selecting the optimal CPP for the individual patient.

• The CPP-targeted treatment concept includes basic measures such as analgosedation, normocapnic mechanical ventilation, normovolemia, and maintenance of a cerebral perfusion pressure of 60-70 mmHg if autoregulation is preserved.

• Aggressive treatment of refractory elevated intracranial pressure includes metabolic suppression (e.g., burst suppression targeted EEG-guided barbiturate coma), hypothermia, decompressive craniectomy (DC), and hypnocapnic ventilation (rescue therapy only).

• The Lund concept is a therapeutic approach that focuses on the reduction of ICP by decreasing intracranial volumes, emphasizing a reduction in microvascular pressures to minimize cerebral edema formation.

• The goals of the Lund concept include preserving a normal colloid osmotic pressure by infusion of albumin and correction of anemia, reducing capillary hydrostatic pressure by medical control of blood pressure, and reducing cerebral blood volume by vasoconstriction.

• Osmolar agents such as NaCl 7.5%, hypertonic saline (HTS), and Mannitol are effective in reducing ICP but bear a risk of fluid overload including cardiovascular events and risks of osmotic diuresis, including dehydration. Evidence forAdvanced Bedside Physiological Monitoring for Tailored Management of Cerebral Perfusion Pressure in Traumatic Brain Injury

• The Lund concept for Traumatic Brain Injury (TBI) management includes reduction of stress and brain metabolism, reduction of hydrostatic capillary pressure, and maintenance of colloid-oncotic pressure.

• The Lund concept has not been compared to other treatments in larger studies, but small randomized trials have shown superior outcomes.

• The Lund approach contradicts common treatment goals of cerebral blood flow optimization by augmentation of cerebral perfusion pressure.

• Use of microdialysis, jugular venous oximetry, and brain tissue oxygen saturation (PbO2) can provide more detailed identification of pathophysiological derangements in TBI patients.

• Jugular Bulb Oximetry (SjVO2) allows for estimation of the balance between global cerebral oxygen delivery and utilization and reflects cerebral oxygen deficit.

• Continuous monitoring of SjVO2 helps to determine the optimal cerebral perfusion pressure (CPP) required for the maintenance of cerebral oxygenation.

• Brain Tissue Partial Tension of Oxygen (PbtO2) provides a continuous measurement of extracellular oxygen tension as an indicator of the adequacy of oxygen delivery.

• Normal PbtO2 is in the range of 35-50 mmHg, and reduced PbtO2 has been associated with a poor outcome after neurotrauma.

• Ischemic thresholds between 5-20 mmHg have been suggested for PbtO2.

• SjVO2 has a prognostic value, and a decrease below 55% is associated with a poor outcome.

• The use of albumin and steroids contradicts findings in the SAFE and CRASH trials, respectively.

• SjVO2 measurement is cumbersome, and PbtO2 provides a localized measurement of extracellular oxygen tension with limited sensitivity to regional changes.